Improved Preservation of Rat Small Intestine Transplantation Graft by Introduction of Mesenchymal Stem Cell-Secreted Fractions.

Segmental grafts from living donors have advantages over grafts from deceased donors when used for small intestine transplantation. However, storage time for small intestine grafts can be extremely short and optimal graft preservation conditions for short-term storage remain undetermined. Secreted factors from mesenchymal stem cells (MSCs) that allow direct activation of preserved small intestine grafts. Freshly excised Luc-Tg LEW rat tissues were incubated in preservation solutions containing MSC-conditioned medium (MSC-CM). Preserved Luc-Tg rat-derived grafts were then transplanted to wild-type recipients, after which survival, injury score, and tight junction protein expression were examined. Luminance for each graft was determined using in vivo imaging. The findings indicated that 30-100 and 3-10 kDa fractions of MSC-CM have superior activating effects for small intestine preservation. Expression of the tight-junction proteins claudin-3, and zonula occludens-1 preserved for 24 h in University of Wisconsin (UW) solution containing MSC-CM with 50-100 kDa, as shown by immunostaining, also indicated effectiveness. Reflecting the improved graft preservation, MSC-CM preloading of grafts increased survival rate from 0% to 87%. This is the first report of successful transplantation of small intestine grafts preserved for more than 24 h using a rodent model to evaluate graft preservation conditions that mimic clinical conditions.

Moyamoya disease presenting with symptomatic ischemic stroke during new-generation tyrosine kinase inhibitor treatment: two illustrative cases.

Tyrosine kinase inhibitors (TKIs) have been widely used to treat chronic myeloid leukemia. Nilotinib and ponatinib, which are second- and third-generation TKIs, have been reported to cause cerebrovascular arterial complications. Here, we present two cases of moyamoya disease presenting with symptomatic ischemic stroke during new-generation TKI treatment. We judged that new-generation TKI treatment was a factor in symptomatic ischemic stroke of unknown moyamoya disease in both cases. Noninvasive examinations using magnetic resonance imaging or carotid ultrasonography should be performed before and during new-generation TKI treatment in order to prevent symptomatic ischemic stroke.

Liver stiffness measured by virtual touch quantification predicts the occurrence of posthepatectomy refractory ascites in patients with hepatocellular carcinoma.

PURPOSE: This study assessed the significance of measuring liver stiffness using virtual touch quantification before hepatectomy to predict posthepatectomy refractory ascites. METHODS: A total of 267 patients with hepatocellular carcinoma who underwent hepatectomy were prospectively analyzed. Liver stiffness was defined as the median value of the virtual touch quantification (Vs; m/s) by acoustic radio-force-impulse-based virtual touch. RESULTS: A multivariate analysis showed that Vs and the aspartate aminotransferase-to-platelet ratio index were independent risk factors for postoperative refractory ascites (odds ratio = 3.27 and 3.08, respectively). The cutoff value for Vs was 1.52 m/s (sensitivity: 59.5%, specificity: 88.6%) as determined by the analysis of the receiver-operating characteristic curve, and the area under the receiver-operating characteristic curve was 0.79. The cutoff value for the aspartate aminotransferase-to-platelet ratio was 0.952 (sensitivity: 65.5%, specificity: 82.9%), and the area under the receiver-operating characteristic curve was 0.75. CONCLUSIONS: Vs is an independent risk factor for refractory ascites after hepatectomy. The measurement of liver stiffness by virtual touch quantification before hepatectomy can help estimate the risk of postoperative refractory ascites. Nonsurgical treatments should be considered for the management of patients who are at high risk for refractory ascites.

Activation of whole body by high levels of polyamine intake in rats.

Polyamines are important to the survival and activation of organs and tissues via a homeostatic cell-metabolic process, and the polyamine content in cytoplasm decreases with aging. Decreases in cellular polyamine have been known to augment mutagenesis and cell death. Thus, supplementary polyamine in food is important to the prevention of aging. Here we show the anti-aging effects of oral intake of polyamine using luciferase-transgenic rats. Healthy rats, 10-12 weeks old, were given foods containing 0.01% and 0.1% (w/w) of polyamine, as compared a control food without polyamine, for 4 weeks. Using a bioimaging system, the photon intensities seen in the whole bodies and livers of rats consuming 0.1% of polyamine in food were stronger than those in rats consuming 0.01% and 0% of polyamine. However, there were no differences between groups in other characteristics, such as liver damage and body weight. In conclusion, we found that polyamine intake can activate cells throughout the whole body, providing an anti-aging effect.

Bolus Administration of Polyamines Boosts Effects on Hepatic Ischemia-Reperfusion Injury and Regeneration in Rats.

BACKGROUND: It was demonstrated that polyamines ameliorate ischemia-reperfusion injury (IRI) and promote regeneration in the liver. An optimal protocol of polyamine treatment remains unknown in the clinical setting. We examined 2 types of administration methods using rat models. METHODS: Experiment 1: evaluation of pharmacokinetics of polyamines. Experiment 2: for 3 days preoperatively and 5 days postoperatively, polyamines were given to male Lewis rats in the following three groups: the control group, no polyamine administration; the chow group, 0.05% polyamines mixed in chow; the bolus group, polyamines (200 µmol/kg) given by gastric tube once a day. All rats received 70% hepatectomy after 40 min of warm IRI. Postoperatively, IRI and regeneration were evaluated with assessment of serum levels of hepatic enzymes, histology and immunohistochemistry of liver tissue, and measurement of remnant liver weight. RESULTS: The blood concentrations of polyamines in the portal vein increased at 1 h of bolus administration, while they did not increase without the bolus. The bolus group was significantly associated with lower serum levels of aspartate/alanine aminotransferases (p < 0.05), decreased hepatocyte congestion, vacuolization and necrosis in histopathological scoring (p < 0.05), a lower number of TUNEL-positive hepatocytes (p < 0.05), higher remnant liver weight at 24, 48, and 168 h (p < 0.05), and a higher Ki-67 labeling index (24 h, p < 0.01) compared with the chow group. CONCLUSION: The bolus administration of polyamines was more effective in ameliorating IRI and promoting regeneration than chow administration. Perioperative bolus administration of polyamines might be an optimal treatment, when clinically applied.

Younger Age is an Independent Factor for Graft Weight Overestimation: Analysis of the Clinical Impact on Recipient Outcomes in 340 Japanese Living Liver Donors.

BACKGROUND: Accurate preoperative estimation of graft weight is essential for improving outcomes in living donor liver transplantation. METHODS: This retrospective study sought to identify factors associated with graft weight overestimation. From April 2006 to August 2015, 340 living donors were assigned to no-overestimate (n = 284) or overestimate (n = 56) groups. We defined graft weight overestimation as a discrepancy ≥15% between estimated graft volume and actual graft weight. Donor data were compared, and associated factors for graft weight overestimation were analyzed. Recipient outcomes were compared between the groups according to identified factors. RESULTS: Donors were significantly younger in the overestimate group than in the no-overestimate group (35.0 vs. 46.0 years; p < 0.001). Multivariate analysis identified donor age <45 years as an independent risk factor for graft weight overestimation (odds ratio 2.068; 95% confidence interval 1.114-3.839; p = 0.021). Among recipients with donors <45 years (n = 168), incidence of small-for-size dysfunction (SFSD) was significantly higher in the overestimate group than in the no-overestimate group (7/37 patients vs. 7/131 patients; p = 0.016); no significant difference was observed among recipients with donors ≥45 years (n = 172). First-year mortality was lower in SFSD recipients with donors <45 years (14.3 vs. 60.9%, p = 0.007). Among recipients with younger donors, graft survival was not significantly different between overestimate and no-overestimate groups. CONCLUSIONS: Younger donor age was an independent risk factor for graft weight overestimation leading to SFSD in recipients, but did not impair graft survival.

Liver graft preservation using perfluorocarbon improves the outcomes of simulated donation after cardiac death liver transplantation in rats.

The outcomes of liver transplantation (LT) from donation after cardiac death (DCD) donors remain poor due to severe warm ischemia injury. Perfluorocarbon (PFC) is a novel compound with high oxygen carrying capacity. In the present study, a rat model simulating DCD LT was used, and the impact of improved graft oxygenation provided by PFC addition on liver ischemia/reperfusion injury (IRI) and survival after DCD LT was investigated. Orthotopic liver transplants were performed in male Lewis rats, using DCD liver grafts preserved with cold University of Wisconsin (UW) solution in the control group and preserved with cold oxygenated UW solution with addition of 20% PFC in the PFC group. For experiment I, in a 30-minute donor warm ischemia model, postoperative graft injury was analyzed at 3 and 6 hours after transplantation. For experiment II, in a 50-minute donor warm ischemia model, the postoperative survival was assessed. For experiment I, the levels of serum aspartate aminotransferase, alanine aminotransferase, hyaluronic acid, malondialdehyde, and several inflammatory cytokines were significantly lower in the PFC group. The hepatic expression levels of tumor necrosis factor α and interleukin 6 were significantly lower, and the expression level of heme oxygenase 1 was significantly higher in the PFC group. Histological analysis showed significantly less necrosis and apoptosis in the PFC group. Sinusoidal endothelial cells and microvilli of the bile canaliculi were well preserved in the PFC group. For experiment II, the postoperative survival rate was significantly improved in the PFC group. In conclusion, graft preservation with PFC attenuated liver IRI and improved postoperative survival. This graft preservation protocol might be a new therapeutic option to improve the outcomes of DCD LT. Liver Transplantation 23 1171-1185 2017 AASLD.

Impact of Skeletal Muscle Mass, Muscle Quality, and Visceral Adiposity on Outcomes Following Resection of Intrahepatic Cholangiocarcinoma.

BACKGROUND: Decrease in skeletal muscle mass and function, known as sarcopenia, is associated with poor prognosis. Visceral fat accumulation also is related to mortality. This study investigated the impact of preoperative skeletal muscle mass, muscle quality, and visceral adiposity on outcomes in patients undergoing resection of intrahepatic cholangiocarcinoma (ICC). METHODS: A retrospective analysis was performed of 109 patients undergoing resections of ICC between January 2004 and April 2015. Skeletal muscle mass [skeletal muscle index (SMI)], skeletal muscle quality [muscle attenuation (MA)], and visceral adiposity [visceral to subcutaneous adipose tissue area ratio (VSR)] were measured on preoperative computed tomography images. The impacts of these parameters on outcomes after ICC resections were analyzed. RESULTS: The overall survival rates were significantly lower in patients with low SMI (P = 0.002), low MA (P = 0.032), and high VSR (P = 0.026) compared with patients with high SMI, high MA, and low VSR, respectively. With multivariate analyses, in patients with stage I-III, low SMI (hazard ratio (HR) 3.29, P = 0.003) and low MA (HR 2.86, P = 0.010) were revealed as independent significant risk factors for mortality. In patients with stage IV, none of these parameters was identified as risk factors, with only the absence of adjuvant chemotherapy identified as an independent risk factor for mortality (HR 5.92, P = 0.001). CONCLUSIONS: Although stage was the most important factor, low skeletal muscle mass and quality were closely related to mortality after resection of ICC in patients with stage I-III.

Influence of hepatorenal syndrome on outcome of living donor liver transplantation: A single-center experience in 357 patients.

AIM: Liver transplantation is the only curative treatment for hepatorenal syndrome (HRS); however, the influence of HRS on the patient and renal outcome after living donor liver transplantation (LDLT) is still unclear. The aim of the present study was to evaluate the influence of HRS on the outcome of LDLT. METHODS: We retrospectively analyzed 357 consecutive adult patients who underwent primary LDLT between January 2005 and March 2013 at Kyoto University Hospital. The outcome of the patients with HRS was compared with those without HRS. RESULTS: A total of 29 patients (8%) were diagnosed as HRS (Group-HRS) preoperatively, and the other 328 patients (92%) were not diagnosed as HRS (Group-Non-HRS). Group-HRS showed a significantly lower preoperative estimated glomerular filtration rate (22.1 vs 78.3 mL/min/1.73m2 , P < 0.001) and higher Child-Pugh-Turcotte score (13 vs 10, P < 0.001) than Group-non-HRS. After a median follow up of 60 months, the 1-, 3- and 5-year recipients' survival were 60.7%, 57.1% and 57.1% in Group-HRS, and 83.7%, 79.4% and 76.2% in Group-Non-HRS, respectively (P = 0.030). Concomitant HRS significantly elongated postoperative hospital stays (75 vs 50 days, P = 0.003), as well as predisposed patients to higher in-hospital mortality (41% vs 18%, P = 0.005). Multivariate analysis showed that preoperative renal dysfunction (estimated glomerular filtration rate on admission <40 mL/min/1.73m2 , OR 2.106, P = 0.03) was an independent risk factor for 1-year recipients' survival after LDLT, in addition to donor age ≥38 years (OR 3.114, P < 0.001), Child-Pugh-Turcotte score ≥13 (OR 2.929, P < 0.001) and left lobe graft (OR 2.225, P = 0.004). CONCLUSION: Coincidence of HRS is associated with significantly worse outcome after LDLT, especially in the early post-transplant period.

Short-term outcomes of laparoscopy-assisted hybrid living donor hepatectomy: a comparison with the conventional open procedure.

BACKGROUND: Although minimally invasive living donor surgery has been increasingly accepted, its safety remains to be fully clarified in a large-scale study. This study evaluated the safety and effectiveness of our laparoscopy-assisted hybrid living donor surgery (LAHDS) procedure with an upper median incision in comparison with conventional open donor hepatectomy (ODH). METHODS: From 2011 to 2016, 153 adult living donors [right lobe (RL) graft: 80 donors; left lobe (LL) graft: 73 donors] were enrolled and divided into LAHDS (n = 76) and ODH (n = 77) groups. Donor characteristics, surgical outcomes, and postoperative complications were compared between the 2 groups in each graft subgroup. Postoperative liver function tests (LFTs), inflammatory markers, pain parameters, incision-related symptoms, and recipient outcomes were compared between the 2 groups in all donors. RESULTS: In RL donors, operative blood loss was significantly lower in the LAHDS group than in the ODH group (201 vs. 313 g; p = 0.034). In LL donors, duration of surgery was significantly longer in the LAHDS group than in the ODH group (459 vs. 403 min; p = 0.034). The incidence of complications, length of hospital stay, and postoperative changes in both LFTs and inflammatory markers were comparable. The incidence of postoperative scar discomfort or tightness was significantly lower in the LAHDS group than in the ODH group (2.6 vs. 31.2%; p < 0.001), whereas postoperative pain parameters were comparable. The incidence of wound problems and abdominal wall numbness tended to be lower, but not significantly so, in the LAHDS group. CONCLUSIONS: This large consecutive case series demonstrates that our LAHDS procedure can be performed as safely as ODH, and it can improve quality of life without impaired donor and recipient outcomes.

Left lobe graft poses a potential risk of hepatic venous outflow obstruction in adult living donor liver transplantation.

Hepatic venous outflow obstruction (HVOO) is a critical complication after living donor liver transplantation (LDLT). This study aimed to evaluate the incidence of HVOO and the risk factors for HVOO in adults. From 2005 to 2015, 430 adult LDLT patients (right lobe [RL] graft, 270 patients; left lobe [LL] graft, 160 patients) were enrolled and divided into no HVOO (n = 413) and HVOO (n = 17) groups. Patient demographics and surgical data were compared, and risk factors for HVOO were analyzed. Furthermore, the longterm outcomes of percutaneous interventions as treatment for HVOO were assessed. HVOO occurred in 17 (4.0%) patients. The incidence of HVOO in patients receiving a LL graft was significantly higher than in those receiving a RL graft (8.1% versus 1.5%; P = 0.001). The body weight and caliber of hepatic vein anastomosis in the HVOO group were significantly lower compared with the no HVOO group (P = 0.02 and P = 0.008, respectively). Multivariate analysis revealed that only LL graft was an independent risk factor for HVOO (OR, 4.782; 95% CI, 1.387-16.488; P = 0.01). Among 17 patients with HVOO, 7 patients were treated with single balloon angioplasty, and 9 patients who developed recurrence were treated with repeated interventions. Overall, 6 patients underwent stent placement: 1 at the initial procedure, 3 at the second procedure for early recurrence, and 2 following repeated balloon angioplasty (≥3 interventions). These 6 patients experienced no recurrence. Overall graft survival was not significantly different between the HVOO and no HVOO groups (P = 0.99). In conclusion, the use of a LL graft was associated with HVOO, and percutaneous interventions were effective for treating adult HVOO after LDLT. Liver Transplantation 22 785-795 2016 AASLD.

Oral administration of polyamines ameliorates liver ischemia/reperfusion injury and promotes liver regeneration in rats.

Polyamines are essential for cell growth and differentiation. They play important roles in protection from liver damage and promotion of liver regeneration. However, little is known about the effect of oral exogenous polyamine administration on liver damage and regeneration. This study investigated the impact of polyamines (spermidine and spermine) on ischemia/reperfusion injury (IRI) and liver regeneration. We used a rat model in which a 70% hepatectomy after 40 minutes of ischemia was performed to mimic the clinical condition of living donor partial liver transplantation (LT). Male Lewis rats were separated into 2 groups: a polyamine group given polyamines before and after operation as treatment and a vehicle group given distilled water as placebo. The levels of serum aspartate aminotransferase and alanine aminotransferase at 6, 24, and 48 hours after reperfusion were significantly lower in the polyamine group compared with those in the vehicle group. Polyamine treatment reduced the expression of several proinflammatory cytokines and chemokines at 6 hours after reperfusion. Histological analysis showed significantly less necrosis and apoptosis in the polyamine group at 6 hours after reperfusion. Sinusoidal endothelial cells were also well preserved in the polyamine group. In addition, the regeneration of the remnant liver at 24, 48, and 168 hours after reperfusion was significantly accelerated, and the Ki-67 labeling index and the expressions of proliferating cell nuclear antigen and phosphorylated retinoblastoma protein at 24 hours after reperfusion were significantly higher in the polyamine group compared with those in the vehicle group. In conclusion, perioperative oral polyamine administration attenuates liver IRI and promotes liver regeneration. It might be a new therapeutic option to improve the outcomes of partial LT. Liver Transplantation 22 1231-1244 2016 AASLD.

Validation of the FIB-4 index for evaluation of fibrosis in patients with recurrent hepatitis C after living donor liver transplantation: A single center experience.

AIM: The FIB-4 index has been proposed as a simple, non-invasive surrogate marker of liver fibrosis in patients with hepatitis C virus (HCV). However, the utility of FIB-4 in HCV positive patients after living donor liver transplantation (LDLT) has not been assessed. The aim of this study was to evaluate the efficacy of FIB-4 in the detection of significant liver graft fibrosis caused by recurrent HCV infection after LDLT compared with other simple fibrosis markers. METHODS: A total of 259 liver biopsies (LB) with evidence of recurrent HCV were taken from 110 HCV positive LDLT patients who had undergone concomitant splenectomy before administration of antiviral therapy. In LB performed at 3 months or later after LT (n = 202, subject group), FIB-4 was compared between fibrosis stages and the accuracy of FIB-4 in predicting significant fibrosis (METAVIR, F ≥ 2) was assessed compared with aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio, age-platelet index, and AST to platelet ratio index (APRI). RESULTS: FIB-4 was significantly different between all fibrosis stages (F0 and F1-F4, P = 0.022; F0/1 and F2-F4, P < 0.0005; and F0-F2 and F3F4, P = 0.034) and provided the best area under the receiver-operator curve (AUROC) compared with other markers (FIB-4, 0.711; APRI, 0.693; age-platelet index, 0.663; and AST to ALT ratio, 0.562). The optimal cut-off value to identify significant fibrosis was 2.20 with 65% sensitivity and 69% specificity. CONCLUSION: FIB-4 is a more reliable marker for diagnosing significant liver fibrosis than APRI, age-platelet index, and AST to ALT ratio in LDLT patients with HCV.

Muscle Steatosis is an Independent Predictor of Postoperative Complications in Patients with Hepatocellular Carcinoma.

BACKGROUND: Skeletal muscle depletion, referred to as sarcopenia, has been shown to be an independent predictor of lower disease-free and overall survivals in various kinds of diseases. The quality of skeletal muscle has recently attracted much attention as a new parameter of sarcopenia, but its impact on surgical complications is still unknown. METHODS: A retrospective analysis of 492 patients undergoing hepatectomy for hepatocellular carcinoma (HCC) in our institution between April 2005 and December 2014 was performed. The quality of skeletal muscle was evaluated by intramuscular adipose tissue content (IMAC) using preoperative CT imaging at the umbilical level. The impact of sarcopenia on postoperative complications and the predictors of surgical complications after hepatectomy for HCC were analyzed. RESULTS: Patients with high IMAC were older and had higher body mass index, higher indocyanine green retention test at 15 min, and more operative blood loss. Among 492 patients, 108 (22 %) patients had major postoperative complications (Clavien grade ≥ III), and infectious complications were found in 74 (15 %) patients. Twelve (2 %) patients died from postoperative complications. On multivariate analysis, preoperative high IMAC was an independent risk factor for increased major postoperative complications [odds ratio (OR) 1.580; P = 0.049] and infectious complications (OR 1.903; P = 0.021). CONCLUSIONS: Preoperative muscle steatosis evaluated with IMAC was closely correlated with increased postoperative complications, especially infectious complications. The preoperative nutritional intervention and rehabilitation might lead to the improvement of postoperative outcomes after hepatectomy for HCC.

Epidemiology of invasive fungal infections after liver transplantation and the risk factors of late-onset invasive aspergillosis.

Invasive fungal infection (IFI) in liver transplant recipients is associated with poor outcomes. Targeted antifungal prophylaxis is recommended for high-risk populations; however, the epidemiology of IFI has changed, and the risk criteria remain unclear. In addition, the risk factors for late-onset invasive aspergillosis (IA) have not been fully characterized. We examined 279 recipients over 16 years of age to uncover their IFI epidemiology, clinical characteristics and outcomes. In addition, a case-control study was performed to identify the risk factors of late-onset IA. Of the 279 recipients, 96.1% underwent living donor liver transplantation. Antifungal prophylaxis was administered to 80.6% of the recipients. IFI occurred in 15 patients, among which 8 cases were early-onset (≤90 days after liver transplantation) and 7 cases were late-onset (>90 days after liver transplantation). Five of the late-onset cases were invasive pulmonary aspergillosis, and 2 were fungemia cases. The mortality rate of late-onset IA was 80.0%. According to a multivariate analysis, steroid use before liver transplantation, bloodstream infection within 90 days after liver transplantation and reoperation within 90 days after liver transplantation were significant risk factors for late-onset IA after liver transplantation. The prevalence of IFI was low in our population given that over 80% of liver recipients received antifungal prophylaxis. The prognosis of late-onset IA remains poor, and predictors associated with late-onset IA, such as steroid use before liver transplantation, bloodstream infection and reoperation after liver transplantation, may help clinicians to optimize prevention measures for these devastating infections.

Liver transplantation for advanced hepatocellular carcinoma in patients with Child-Pugh A and B.

PURPOSE: To investigate the outcomes of living donor liver transplantation for advanced hepatocellular carcinoma in Child-Pugh A/B patients and the usefulness of our expanded selection criteria, the Kyoto criteria. METHODS: A total of 82 recipients with a Child-Pugh class A (n = 27) or B (n = 55) status having either multiple hepatic nodules or solitary tumors ≥5 cm in size treated between February 1999 and August 2012 were enrolled in this study. RESULTS: The overall recurrence rate was significantly less for the Child-Pugh B patients than for the Child-Pugh A patients (P = 0.042), while the survival rates did not differ. In the Child-Pugh A and B patients, the survival rate was significantly greater, while the recurrence rate was lower among the patients meeting the Kyoto criteria than those exceeding these criteria (P = 0.006, P = 0.001, P = 0.032 and P < 0.001, respectively). In the Child-Pugh B patients, the overall survival and recurrence rates did not differ between the patients treated with and without pretreatment for hepatocellular carcinoma. In the Child-Pugh B patients treated with pretreatment, the overall survival rate was significantly greater, while the recurrence rate was lower among the patients meeting the Kyoto criteria than those exceeding these criteria (P < 0.001, P < 0.001, respectively). CONCLUSIONS: Living donor liver transplantation performed within the Kyoto criteria achieves excellent overall survival and recurrence rates, especially for Child-Pugh B patients, even those with advanced hepatocellular carcinoma.

A non-smooth tumor margin on preoperative imaging predicts microvascular invasion of hepatocellular carcinoma.

PURPOSES: Microvascular invasion (mVI) is known to be a risk factor of hepatocellular carcinoma (HCC) recurrence. Several factors such as the tumor grade, tumor size, tumor margin status on imaging studies, fluorine-18 fluorodeoxyglucose-positron emission tomography ((18)F-FDG-PET) results, and tumor markers have been proposed to predict mVI of HCC. However, the values of these factors have not yet been validated. METHODS: Among the patients evaluated using enhanced CT/MRI, (18)F-FDG-PET, and tumor markers prior to hepatectomy from 2007 to 2012, 79 HCC patients without apparent macrovascular invasion in preoperative imaging were enrolled in this study. The image tumor margin status (smooth/non-smooth), (18)F-FDG-PET, and tumor markers, which were previously described as predictors for mVI, were evaluated. RESULTS: Fifteen patients had mVI (mVI+ group) and 64 patients had no evidence of mVI (mVI- group) on pathological examinations. A univariate analysis showed that the mVI+ group had a higher SUV and TNR (5.2 vs 3.8, p = 0.02 and 1.8 vs 1.3, p = 0.02, respectively) and a higher portion of non-smooth tumor margin (87 vs 27 %, p = 0.0001). There was no significant difference in the tumor markers. A multivariate analysis showed that non-smooth tumor margin alone could independently predict mVI (odds ratio 18.3, 95 % CI 3.27-102.6, p = 0.0009). CONCLUSION: A non-smooth tumor margin on preoperative imaging predicts microvascular invasion of HCC.

Impact of elderly donors for liver transplantation: A single-center experience.

Elderly donor grafts for liver transplantation (LT) are recognized to be marginal grafts. The present study investigated the impact of using elderly donors for LT. Between June 1990 and August 2012, 1631 patients received LT at Kyoto University Hospital. Out of 1631 patients, 1597 patients received living donor liver transplantation (LDLT), whereas the other 34 patients underwent deceased donor liver transplantation (DDLT). Seventy-five grafts that were used came from individuals who were ≥60 years old. We retrospectively analyzed the recipients' survival rates according to donor age. The overall survival rates of the recipients of all LDLT (P < 0.001), adult-to-adult LDLT (P = 0.007), all DDLT (P = 0.026), and adult-to-adult DDLT (P = 0.011) were significantly lower for the elderly donor group versus the younger group and especially for those who were hepatitis C-positive. A multivariate analysis revealed that donor age, ABO incompatibility, and preoperative intensive care unit stay were independent risk factors for poor patient survival in adult-to-adult LDLT. However, no significant differences existed between the 2 groups among those who received adult-to-adult LDLT in and after April 2006. No significant association was found between donor age and incidence of acute cellular rejection. In conclusion, donor age was closely related to the survival rate for LDLT and DDLT, although the impact of donor age was not shown in the recent cases.

Impact of cytochrome P450 3A5 polymorphism in graft livers on the frequency of acute cellular rejection in living-donor liver transplantation.

OBJECTIVE: We investigated whether the cytochrome P450 3A5*3 (CYP3A5*3) genotype affects tacrolimus pharmacokinetics and the risk of acute cellular rejection in living-donor liver transplant patients in Japan. MATERIALS AND METHODS: Between July 2004 and June 2011, we enrolled 410 living-donor liver transplant patients receiving tacrolimus. Biopsy specimens of intestinal mucosa and graft liver at surgery were obtained to examine the mRNA expression of CYP3A subfamilies as well as the genotyping of CYP3A5*3 polymorphism. RESULTS: The CYP3A5 genotype in the native intestine had no significant effect on the occurrence of acute cellular rejection between postoperative days 14 and 23 in cases with identical or compatible ABO blood types (11.5% for the CYP3A5*1 allele vs. 7.4% for CYP3A5*3/*3; P=0.2643), although the concentration/dose ratio of tacrolimus was significantly higher in patients with the intestinal CYP3A5*3/*3 genotype than in those with the CYP3A5*1 allele for 5 post-transplant weeks. However, patients who received a graft liver with the CYP3A5*1 allele showed a higher rate of acute cellular rejection than those who received a graft liver with the CYP3A5*3/*3 genotype (14.5 vs. 5.7%; P=0.0134). The relative risk for acute cellular rejection associated with the CYP3A5*1 liver allele was 2.629 (P=0.018, Cox regression model). Consequently, graft liver CYP3A5*1 genotype might increase the risk for acute cellular rejection after living-donor liver transplantation, possibly by associating with the local hepatic tacrolimus concentration. CONCLUSIONS: The target level of tacrolimus may be affected by the CYP3A5*3 genotype of the liver, rather than by that of the small intestine, after postoperative day 14.

Perioperative changes in nutritional parameters and impact of graft size in patients undergoing adult living donor liver transplantation.

Derangements of various serum biochemical nutritional/metabolic parameters are common in patients with end-stage liver disease who undergo liver transplantation (LT). The aim of this study was to explain the benefit of LT with respect to parameter changes and to examine the impact of the graft-to-recipient weight ratio (GRWR) on such changes. We investigated each parameter's course in 208 adult recipients for 1 year after living donor LT and analyzed changes in the parameters with a GRWR of 0.8% as the cutoff point. Bonferroni corrections were applied to account for multiple testing. Liver disease-induced high pretransplant ammonia and tyrosine levels and low branched-chain amino acids to tyrosine ratio (BTR) and zinc levels normalized within 2 weeks after transplantation, and the total lymphocyte count (TLC) normalized within 2 months, whereas low pretransplant prealbumin levels took 1 year to normalize. Branched-chain amino acids (BCAA), zinc, and TLC levels transiently dropped shortly after transplantation and then were corrected later. An accelerated recovery of ammonia and tyrosine levels and the BTR were found with larger grafts, especially early after transplantation, whereas zinc, prealbumin, BCAA, and TLC levels recovered regardless of the graft size. In conclusion, graft size had little effect on the recovery of nutritional/metabolic parameters except for ammonia and tyrosine levels.