Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

<title>Abstract</title>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.

DOI： 10.1007/s00726-021-03079-4

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Other Link： https://link.springer.com/article/10.1007/s00726-021-03079-4/fulltext.html

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BACKGROUND: The purpose of this study was to examine the impact of pretreatments on outcomes after living donor liver transplantation (LDLT) for hepatocellular carcinoma (HCC). METHODS: From February 1999 to March 2015, 223 patients underwent LDLT for HCC. Until December 2006, there was no restriction in patient selection criteria regarding the number and size of tumors, following which we implemented the Kyoto criteria (tumor number ≤10, maximal diameter ≤5 cm, and des-gamma-carboxy prothrombin ≤400 mAU/ml) since January 2007. RESULTS: Of 223 patients, 156 had a history of pretreatments. Among 101 patients meeting the Milan criteria at the initial diagnosis, 38 progressed to beyond the criteria at liver transplantation (LT). Twenty-two out of 38 met the Kyoto criteria, and their survival and recurrence rates were significantly better than those of patients exceeding the Kyoto criteria (P = 0.004 and 0.035, respectively). Regarding the number of pretreatments (0 vs. 1-4 vs. ≥5), recurrence rate was significantly higher in the ≥5 pretreatments group than the 0 group. However, for patients meeting the Kyoto criteria, there were no significant differences in recurrence rates between these three groups. CONCLUSION: Better outcomes will be achieved by performing LT for HCCs meeting the Kyoto criteria even after repeated pretreatments.

DOI： 10.1002/jhbp.602

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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.

DOI： 10.1159/000497434

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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.

DOI： 10.1111/hepr.12764

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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.

DOI： 10.1245/s10434-016-5668-3

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BACKGROUND: Smaller size grafts for living donor liver transplantation (LDLT) can enhance donor safety and expand donor availability. We previously reported that modulation of portal venous pressure (PVP) was key for successful LDLT with small grafts, and that it actively lowered graft-to-recipient weight ratio (GRWR) for adult-to-adult LDLT. This retrospective study investigated the outcome of LDLT using small grafts with PVP modulation. METHOD: This study analyzed 221 adult LDLT patients between March 2008 and December 2013 and divided them into 3 groups based on GRWR: large (L), GRWR ≥ 0.8% (n = 154), medium (M), ≥ 0.7% GRWR < 0.8% (n = 38); and small (S) GRWR < 0.7% (n = 29). Donor and recipient factors, PVP, pressure gradient between PVP and central venous pressure (CVP), occurrence of small for size syndrome (SFSS), ascites, and posttransplant laboratory data were compared across the 3 groups. Patient and graft survival were compared using Kaplan-Meier methods. RESULTS: There was no difference in patient or graft survival between the 3 groups. Amount of posttransplant ascites and posttransplant International Normalized Ratio were similar, but the S and M groups had more prolonged cholestasis. SFSS was identified in 17%, 13%, and 13% in the S, M, and L groups, respectively (P = NS). Patients with a final PVP of ≤15 mmHg had better survival than patients with a final PVP of >15 mmHg (P < .001). Multivariate analysis showed that donor age >40 years old, final PVP of >15 mmHg, and pressure gradient of PVP-CVP >5 mmHg were risk factors for inferior patient survival. CONCLUSION: We achieved satisfactory outcomes in LDLT with GRWR as low as 0.6% using PVP modulation. Thus, we currently set a lower limit of GRWR at 0.6% while protecting donor safety and expanding donor availability.

DOI： 10.1016/j.surg.2016.01.009

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BACKGROUND: Little is known as to whether the interleukin4 (IL4) gene polymorphisms in recipients or donors affect the incidence of acute cellular rejection (ACR) following living donor liver transplantation (LDLT). Therefore, we determined the effect of IL4 T-33C polymorphisms in recipients and donors on ACR in a large cohort of patients that underwent LDLT. METHODS: We examined 155 LDLT cases treated at Nagoya University or Kyoto University, Japan, between 2004 and 2009. IL4 T-33C polymorphisms were analyzed in recipients and donors. RESULTS: Forty-seven recipients (30.3%) developed early ACR. The genotype frequency of IL4 T-33C in the recipients was associated with ACR incidence (P=0.008, P<0.0125 considered significant). Patients with the IL4-33C carrier genotype (C/C or C/T) were significantly associated with a higher incidence of ACR relative to those with the T/T genotype (OR=3.27, 95% CI: 1.56-6.88, P=0.002). The genotype frequencies of IL4 T-33C in the donors were not associated with rejection incidence. In addition, there was no significant effect of IL4 T-33C genotype combinations on ACR incidence in donors and recipients. CONCLUSIONS: Genotyping of IL4 T-33C in recipients might be useful to stratify the liver transplant recipients according to their risk of ACR.

DOI： 10.1016/j.clinre.2015.06.019

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DOI： 10.1111/cei.12740

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BACKGROUND: Skeletal muscle depletion, referred to as sarcopenia, predicts mortality after major surgery. This study investigated the impact of preoperative skeletal muscle quantity and quality on outcomes in patients undergoing resection of extrahepatic biliary cancer. METHODS: We performed a retrospective analysis of 207 patients undergoing resection for biliary cancer between 2004 and 2013. The quantity and quality of skeletal muscle, indicated by the psoas muscle mass index (PMI) and intramuscular adipose tissue content (IMAC), were measured on preoperative images of computed tomography. Overall survival (OS) and recurrence-free survival (RFS) rates were compared by PMI and IMAC, and prognostic factors after operation were assessed. RESULTS: The OS and RFS rates were less in patients with low PMI (low muscle quantity) than in those with normal PMI (P < .001 and P < .001; 5-year OS, 15.7 vs 53.5%). The OS and RFS rates were also less in patients with high IMAC (low muscle quality) than in those with normal IMAC (P < .001 and P < .001; 5-year OS, 23.8 vs 55.9%). Low PMI and high IMAC were independent factors predictive of poor OS (hazard ratio [HR], 2.921 [95% CI, 1.920-4.470; P < .001] and HR, 1.725 [95% CI, 1.159-2.590; P = .007]) and RFS (HR, 2.141 [95% CI, 1.464-3.129, P < .001] and HR, 1.492 [95% CI, 1.032-2.166, P = .034]). CONCLUSION: Preoperative sarcopenia, indicating a low quantity and quality of skeletal muscle, is related closely to mortality after resection of biliary cancer.

DOI： 10.1016/j.surg.2015.08.047

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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.

DOI： 10.1016/j.jiac.2015.11.005

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Language：English   Publisher：WILEY-BLACKWELL  

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DOI： 10.1111/tid.12425

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We report the first case of initially unresectable advanced hepatocellular carcinoma (HCC) with portal vein and hepatic venous tumor thrombosis and multiple lung metastases that allowed for curative hepatectomy after multidisciplinary treatment including sorafenib. A 54-year-old male presented with a large HCC in the right liver with tumor thrombosis of the left portal vein and middle hepatic vein (MHV) as well as multiple lung metastases. His serum alpha-fetoprotein level was elevated at 52,347 ng/mL and palliative treatment with sorafenib was initiated. One month later, a significant reduction in the serum AFP level, decrease in the tumor size with recanalization of the portal vein and the absence of lung metastases were noted. Three months after the start of sorafenib treatment, external-beam radiotherapy was performed to treat enlargement of the area of MHV thrombosis, and the thrombosis regressed. Five months after the initiation of sorafenib treatment, central bisegmentectomy associated with removal of the tumor thrombus in the inferior vena cava was performed. A microscopic examination revealed complete necrosis of the tumor. Sorafenib treatment may be a bridge to curative resection in selected patients with initially unresectable advanced HCC, even in cases involving multiple extrahepatic metastases.

DOI： 10.1007/s12328-015-0594-7

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Surgical site infections (SSIs) are a major threat for liver transplant recipients. We prospectively studied SSIs after living donor liver transplantation (LDLT) at Kyoto University Hospital from April 2001 to March 2002 (1st period) and from January 2011 to June 2012 (2nd period). We investigated the epidemiology of SSIs after LDLT and determined the differences between the two periods. A total of 129 adult recipients (66 during the 1st period and 63 during the 2nd period) and 72 pediatric recipients (39 and 33) were included in this study. The SSI rates for each period were 30.3% (1st period) and 41.3% (2nd period) among the adult recipients and 25.6% and 30.3% among the pediatric recipients. The overall rates of 30-day mortality among adult transplant recipients with SSIs were 10.0% (1st period) and 3.9% (2nd period). No pediatric recipient died from SSIs after LDLT in either period. The incidence of Enterococcus faecium increased from 5.0% to 26.9% in the adults and from 10.0% to 40.0% in the pediatric patients. Extended-spectrum β-lactamase-producing Enterobacteriaceae were emerging important isolates during the 2nd period. For this period, a univariate analysis showed that ABO incompatibility (P = 0.02), total operation duration (P = 0.01), graft-to-recipient body weight ratio (GRWR [P = 0.04]), and Roux-en-Y biliary reconstruction (P<0.01) in the adults and age (P = 0.01) and NHSN risk index (P = 0.02) in the children were associated with SSI development. In a multivariate analysis, lower GRWR (P = 0.02) and Roux-en-Y biliary reconstruction (P<0.01) in the adults and older age (P = 0.01) in the children were independent risk factors for SSIs during the 2nd period. In conclusion, SSIs caused by antibiotic resistant bacteria may become a major concern. Lower GRWR and Roux-en-Y biliary reconstruction among adult LDLT recipients and older age among pediatric LDLT recipients increased the risk of developing SSIs after LDLT.

DOI： 10.1371/journal.pone.0136559

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DOI： 10.1111/cei.12588

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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BACKGROUND: Skeletal muscle depletion, referred to as sarcopenia, is predictive of mortality in patients undergoing digestive operations. The impact of muscle quality on outcomes, however, is unclear. This retrospective study investigated the impact of preoperative skeletal muscle quantity and quality on survival in patients undergoing resection of pancreatic cancer. METHODS: We investigated 230 patients who underwent resection of pancreatic cancer between 2004 and 2013. The quantity and quality of skeletal muscle, indicated by psoas muscle mass index (PMI) and intramuscular adipose tissue content (IMAC), were measured in preoperative computed tomography images. Overall survival (OS) and recurrence-free survival (RFS) rates were compared according to PMI and IMAC, and prognostic factors after pancreatic resection were assessed. RESULTS: The OS and RFS rates in patients with low PMI were lesser than in those with normal/high PMI (P < .001, P < .001), with a mean survival time of 17.7 and 33.2 months, respectively. The OS and RFS rates in patients with high IMAC also were less than in those with normal/low IMAC (P < .001, P = .003) (mean survival time = 21.5 and 56.5 months, respectively). Low PMI (low muscle mass) and high IMAC (low muscle quality) were independent prognostic factors of poor OS (hazard ratio [HR] = 1.999, P < .001; HR = 2.527, P < .001) and RFS (HR = 1.607, P = .007; HR = 1.640, P = .004), respectively. CONCLUSION: Preoperative sarcopenia, indicating low quality and quantity of skeletal muscle, is closely related to mortality after resection of pancreatic cancer.

DOI： 10.1016/j.surg.2015.02.002

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Language：English   Publisher：WILEY-BLACKWELL  

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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.

DOI： 10.1002/lt.24086

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During a prospective surveillance using PCR for the detection of plasmid-mediated AmpC β-lactamase (pAmpC)-producing Enterobacteriaceae, outbreaks due to pAmpC-producing Klebsiella pneumoniae (pAmpC-Kp) occurred in an adult liver transplantation unit (aLTU) and a paediatric liver transplantation unit (pLTU), with carbapenem-resistant (CR) variants. Between April 2010 and March 2012, a total of 32 patients infected with pAmpC-Kp were found by prospective surveillance using PCR detection at a Japanese university hospital. Multilocus sequence typing, analysis of outer membrane proteins, and detection of carbapenemases were performed. Clinical courses of patients with bloodstream infection (BSI) were reviewed. Of 32 pAmpC-Kp isolates from each patient, 20 (18 from aLTU patients) were DHA-1-producing sequence type 11 (DHA-1-ST11), 9 were CMY-2-ST45/778 (all from pLTU patients) and the other 3 isolates had different sequence types. CR variants were isolated from 8 aLTU patients with DHA-1-ST11 and from 1 pLTU patient with CMY-2-ST45. All of the pAmpC-Kp isolates, including CR variants, were negative for carbapenemases. All of the DHA-1-ST11 and CMY-2-ST45 isolates lacked OmpK35, and seven CR variants also lacked OmpK36. BSIs due to DHA-1-ST11 isolates, including CR variants, occurred in six aLTU patients, four of whom died. The outbreaks were controlled after application of intensified infection control measures. During pAmpC-Kp outbreaks involving 27 liver transplants, CR variants with porin loss developed in nine patients, and DHA-1-ST11 K. pneumoniae caused BSIs with high mortality.

DOI： 10.1016/j.ijantimicag.2014.08.015

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PURPOSE: Uncontrollable hepatic hydrothorax and massive ascites (H&MA) requiring preoperative drainage are sometimes encountered in liver transplantation (LT). We retrospectively analyzed the characteristics of such patients and the impact of H&MA on the postoperative course. METHODS: We evaluated 237 adult patients who underwent LT in our institute between April 2006 and October 2010. RESULTS: Recipients with uncontrollable H&MA (group HA: n = 36) had more intraoperative bleeding, higher Child-Pugh scores, lower serum albumin concentrations and higher blood urea nitrogen concentrations than those without uncontrollable H&MA (group C: n = 201). They were also more likely to have preoperative hepatorenal syndrome and infections. The incidence of postoperative bacteremia was higher (55.6 vs. 46.7%, P = 0.008) and the 1- and 3-year survival rates were lower (1 year: 58.9 vs. 82.9%; 3 years: 58.9 vs. 77.7%; P = 0.003) in group HA than in group C. The multivariate proportional regression analyses revealed that uncontrollable H&MA and the Child-Pugh score were independent risk factors for the postoperative prognosis. CONCLUSIONS: Postoperative infection control may be an important means of improving the outcome for patients with uncontrollable H&MA undergoing LT, and clinicians should strive to perform surgery before H&MA becomes uncontrollable.

DOI： 10.1007/s00595-014-0839-y

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Intramuscular fat accumulation has come to be associated with loss of muscle strength and function, one of the components of sarcopenia. However, the impact of preoperative quality of skeletal muscle on outcomes after living donor liver transplantation (LDLT) is unclear. The present study evaluated the intramuscular adipose tissue content (IMAC) and psoas muscle mass index (PMI) in 200 adult patients undergoing LDLT at our institution between January 2008 and October 2013. Correlations of IMAC with other factors, overall survival rates in patients classified according to IMAC or PMI, and risk factors for poor survival after LDLT were analyzed. IMAC was significantly correlated with age (r = 0.229, P = 0.03) and PMI (r = -0.236, P = 0.02) in males and with age (r = 0.349, P < 0.001) and branched-chain amino acid (BCAA)-to-tyrosine ratio (r = -0.250, P = 0.01) in females. The overall survival rates in patients with high IMAC or low PMI were significantly lower than those for patients with normal IMAC or PMI (P < 0.001, P < 0.001, respectively). Multivariate analysis showed that high IMAC [odds ratio (OR) = 3.898, 95% confidence interval (CI) = 2.025-7.757, P < 0.001] and low PMI (OR = 3.635, 95% CI = 1.896-7.174, P < 0.001) were independent risk factors for death after LDLT. In conclusion, high IMAC and low PMI were closely involved with posttransplant mortality. Preoperative quality and quantity of skeletal muscle could be incorporated into new selection criteria for LDLT. Perioperative nutritional therapy and rehabilitation could be important for good outcomes after LDLT.

DOI： 10.1002/lt.23970

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This study investigated adequate liver graft selection for donor safety by comparing postoperative donor liver function and morbidity between the right and left hemilivers (RL and LL, respectively) of living donors. Between April 2006 and March 2012, RL (n = 168) and LL (n = 140) donor operations were performed for liver transplantation at Kyoto University Hospital. Postoperative hyperbilirubinemia and coagulopathy persisted in RL donors, whereas the liver function of LL donors normalized more rapidly. The overall complication rate of the RL donors was significantly higher than that of the LL donors (59.5% vs. 30.7%; P < 0.001). There were no significant differences in severe complications worse than Clavien grade IIIa or in biliary complication rates between the two donor groups. In April 2006, we introduced an innovative surgical procedure: hilar dissection preserving the blood supply to the bile duct during donor hepatectomy. Compared with our previous outcomes (1990-2006), the biliary complication rate of the RL donors decreased from 12.2% to 7.2%, and the severity of these complications was significantly lower. In conclusion, LL donors demonstrated good recovery in postoperative liver function and lower morbidity, and our surgical innovations reduced the severity of biliary complications in living donors.

DOI： 10.1111/tri.12414

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Language：Japanese   Publisher：日本アフェレシス学会  

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CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1097/FPC.0000000000000060

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BACKGROUND: Liver transplant outcomes using grafts donated after cardiac death (DCD) remain poor. METHODS: We investigated the effects of ex vivo reconditioning of DCD grafts with venous systemic oxygen persufflation using nitric oxide gas (VSOP-NO) in rat liver transplants. Orthotopic liver transplants were performed in Lewis rats, using DCD grafts prepared using static cold storage alone (group-control) or reconditioning using VSOP-NO during cold storage (group-VSOP-NO). Experiment I: In a 30-min warm ischemia model, graft damage and hepatic expression of inflammatory cytokines, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and endothelin-1 (ET-1) were examined, and histologic analysis was performed 2, 6, 24, and 72 hr after transplantation. Experiment II: In a 60-min warm ischemia model, grafts were evaluated 2 hr after transplantation (6 rats/group), and survival was assessed (7 rats/group). RESULTS: Experiment I: Group-VSOP-NO had lower alanine aminotransferase (ALT) (P<0.001), hyaluronic acid (P<0.05), and malondialdehyde (MDA) (P<0.001), hepatic interleukin-6 expression (IL-6) (P<0.05), and hepatic tumor necrosis factor-alpha (TNF-α) expression (P<0.001). Hepatic eNOS expression (P<0.001) was upregulated, whereas hepatic iNOS (P<0.01) and ET-1 (P<0.001) expressions were downregulated. The damage of hepatocyte and sinusoidal endothelial cells (SECs) were lower in group-VSOP-NO.Experiment II: VSOP-NO decreased ET-1 and 8-hydroxy-2'deoxyguanosine (8-OHdG) expression and improved survival after transplantation by 71.4% (P<0.01). CONCLUSION: These results suggest that VSOP-NO effectively reconditions warm ischemia-damaged grafts, presumably by decreasing ET-1 upregulation and oxidative damage.

DOI： 10.1097/TP.0000000000000025

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BACKGROUND: Chronic rejection (CR) has been reported to be associated with antiviral therapy for recurrent hepatitis C in liver transplant (LT) recipients. The aims of this study were to clarify the details of antiviral therapy-associated CR after living-donor liver transplantation (LDLT) and to identify the factors associated with CR. METHODS: A retrospective chart review was performed on 125 recipients who had received antiviral therapy for recurrent hepatitis C after LDLT between January 2001 and September 2012. The characteristics of patients who developed CR during or within 6 months after antiviral therapy were compared with those of 76 patients who did not develop CR despite receiving antiviral therapy for more than 1 year. RESULTS: Seven of 125 (6%) patients developed CR during or within 6 months after the end of antiviral therapy. CR was diagnosed after a median (range) of 9 (1-16) months of antiviral therapy. In five patients, rejection progressed rapidly and resulted in death within 3 months after diagnosis. Analysis revealed two significant factors associated with CR: reduction of the immunosuppressant dose during antiviral therapy and a low fibrosis score as the indication for antiviral therapy. CONCLUSIONS: CR developed in association with antiviral therapy for recurrent hepatitis C after LDLT. This complication may be prevented by ensuring that the immunosuppressant dose is not reduced during antiviral therapy.

DOI： 10.1097/01.TP.0000435702.61642.0a

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.transproceed.2013.07.077

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society for the Study of Xenobiotics  

  We retrospectively examined whether cytochrome P450 (CYP) 3A5 genotypes are associated with high-dose steroid pulse treatment-induced functional gain of tacrolimus biotransformation in living-donor liver transplant patients. Concentrations of tacrolimus and its 3 primary metabolites, 13-<i>O</i>-demethyl tacrolimus (M-I), 31-<i>O</i>-demethyl tacrolimus (M-II), and 15-<i>O</i>-demethyl tacrolimus (M-III), were measured in trough blood samples from 18 liver transplant patients, by liquid chromatography–tandem mass spectrometry/mass spectrometry (LC-MS/MS). In patients engrafted with a <i>CYP3A5*1</i>-carrying liver but not with a <i>CYP3A5*3/*3</i>-carrying liver, the concentration/dose ratio of tacrolimus significantly fell after therapy, while ratios of M-I/tacrolimus, M-II/tacrolimus, and M-III/tacrolimus were significantly higher after therapy than before (p = 0.032, p = 0.023, and p = 0.0078, respectively). After steroid pulse therapy, the concentration of tacrolimus measured by immunoassay was significantly higher than that measured by LC-MS/MS in patients engrafted with a <i>CYP3A5*1</i>-carrying liver, but not those engrafted with a <i>CYP3A5*3/*3</i>-carrying liver. This suggests that the increased ratio of tacrolimus metabolites/tacrolimus can be explained by induction of CYP3A5 <i>via</i> high-dose steroid pulse therapy. Further, the concentrations of tacrolimus measured by the immunoassays were overestimated, partly because of cross-reactivity of the monoclonal antibody they incorporated to detect tacrolimus, with the increased metabolites in patients with a <i>CYP3A5*1</i>-carrying graft liver.<br>

DOI： 10.2133/dmpk.dmpk-13-rg-060

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Language：English   Publisher：WILEY-BLACKWELL  

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PURPOSE: Despite improvements in immunosuppressive therapy, acute cellular rejection (ACR) remains an important cause of graft loss in patients undergoing liver transplantation. Recently, associations between cytokine gene polymorphisms in recipients and the occurrence of ACR have been reported. However, most studies did not investigate gene polymorphisms in donors or were limited by the number of cases investigated. METHODS: We examined 155 living donor liver transplantation (LDLT) patients treated at Nagoya University or Kyoto University from 2004 to 2009. The following gene polymorphisms in recipients and donors were analyzed: tumor necrosis factor A (TNF-A) T-1031C, interleukin 2 (IL-2) T-330G, IL-10C-819T, IL-13C-1111T, and transforming growth factor B (TGF-B) T29C. RESULTS: Forty-seven recipients (30.3 %) developed early ACR. Of the investigated gene polymorphisms, the IL-13 -1111C/C genotype in recipients was significantly associated with a higher incidence of ACR relative to the other two genotypes (OR = 2.64, 95 % CI 1.19-5.86, p = 0.017), while we showed the lack of association between investigated gene polymorphisms in donors and ACR incidence. CONCLUSION: The IL-13 -1111C/C genotype in recipients might be a risk factor for ACR in LDLT, and this might contribute to individualized immunosuppression strategies for recipients. On the other hand, the current study showed no associations of cytokine gene polymorphisms in donors with ACR incidence.

DOI： 10.1007/s12072-013-9443-2

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Skeletal muscle depletion, referred to as sarcopenia, predicts morbidity and mortality in patients undergoing digestive surgery. However, the impact on liver transplantation is unclear. The present study investigated the impact of sarcopenia on patients undergoing living donor liver transplantation (LDLT). Sarcopenia was assessed by a body composition analyzer in 124 adult patients undergoing LDLT between February 2008 and April 2012. The correlation of sarcopenia with other patient factors and the impact of sarcopenia on survival after LDLT were analyzed. The median ratio of preoperative skeletal muscle mass was 92% (range, 67-130%) of the standard mass. Preoperative skeletal muscle mass was significantly correlated with the branched-chain amino acids to tyrosine ratio (r=-0.254, p=0.005) and body cell mass (r=0.636, p&lt;0.001). The overall survival rate in patients with low skeletal muscle mass was significantly lower than in patients with normal/high skeletal muscle mass (p&lt;0.001). Perioperative nutritional therapy significantly increased overall survival in patients with low skeletal muscle mass (p=0.009). Multivariate analysis showed that low skeletal muscle mass was an independent risk factor for death after transplantation. In conclusion, sarcopenia was closely involved with posttransplant mortality in patients undergoing LDLT. Perioperative nutritional therapy significantly improved overall survival in patients with sarcopenia.

DOI： 10.1111/ajt.12221

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Acute rejection of a small-bowel transplant is often difficult to diagnose due to complicated immune responses. The present study aimed to elucidate the specific immune responses involved in intestinal transplant rejection. We correlated immunohistologic findings with an increase in crypt apoptosis, which has been commonly accepted as a criterion for the diagnosis of acute cellular rejection (ACR). Of 8 patients who received an intestinal allograft at Kyoto University Hospital, biopsy specimens from 7 patients were assessed immunohistologically with antibodies against 20 types of lymphocytic antigens including CD3, CD4, CD8, CD79a, CD20, IgG, and T-cell receptor, along with assessment of the patients' clinical courses. It was revealed that, in addition to apoptotic crypts, T-lymphocyte apoptosis and phagocytosis of apoptotic bodies in the lamina propria of villi were findings of ACR; both were observed in all cases. Immunostaining of the Fas ligand, one of the apoptosis-inducing molecules, was useful for the identification of the apoptotic bodies in the lamina propria of villi. Apoptotic body phagocytosis may be a surrogate diagnostic finding of grafts undergoing ACR.

DOI： 10.1097/PAS.0b013e31826393fe

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It has previously been demonstrated that glutathione S-transferase T1 (GSTT1) genetic mismatch between recipient and donor is a risk factor for developing immune-mediated hepatitis following liver transplantation and for antibody-mediated rejection in renal transplantation. Little is known whether the GSTT1 gene polymorphism affects the incidence of acute cellular rejection (ACR) following living donor liver transplantation (LDLT). Patients underwent LDLT at Nagoya University or Kyoto University, Japan, between 2004 and 2009. Genotyping of GSTT1 genes (null or present genotype) was conducted in recipients and donors. A total of 155 LDLT cases were examined. Forty-seven recipients (30.3%) developed early ACR. There was no association of recipient GSTT1 genotype with ACR incidence. However, ACR incidence was significantly higher in recipients transplanted from GSTT1 present genotype donors than in those transplanted from GSTT1 null genotype donors [odds ratio (OR)=2.64, 95% confidence interval (CI)=1.12-5.83, p=0.016]. Moreover, GSTT1 recipient/donor genotype mismatch (present/null or null/present) was significantly associated with ACR development (OR=2.28, 95% CI=1.12-4.61, p=0.022). The genotyping of GSTT1 in recipients and donors might be useful to stratify the liver transplant recipients according to risk of ACR.

DOI： 10.1016/j.trim.2012.11.002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Pharmaceutical Society of Japan  

Association between cytochrome P450 (CYP) <i>3A4*1G</i> genotype of donors (<i>n</i>=412) and/or recipients (<i>n</i>=410), and the pharmacokinetics of tacrolimus and the risk of acute cellular rejection was examined in Japanese living-donor liver transplant patients between 2004 and 2011. The concentration/dose (C/D) ratio of tacrolimus in patients carrying graft liver with <i>CYP3A4*1/*1</i> was significantly higher during 7 d after surgery than in that with <i>CYP3A4*1/*1G</i> (214 <i>vs.</i> 157 [ng/mL]/[mg/kg/day], <i>p</i><0.01). After postoperative day 8, no significant difference was observed among <i>CYP3A4*1G</i> genotypes in the graft liver. However, the C/D ratio in <i>CYP3A4*1/*1</i> of the intestine was significantly higher than that in <i>CYP3A4*1G/*1G</i> for 5 weeks after surgery (postoperative days 1–14; <i>p</i><0.001, postoperative days 15–35; <i>p</i><0.01). During postoperative days 14 and 26, acute cellular rejection incidences tended to be lower in the patients with graft liver carrying the <i>CYP3A4*1</i>/*<i>1</i> allele than in the patients carrying <i>CYP3A4*1G</i> allele (8.7% <i>vs.</i> 14.6%, <i>p</i>=0.0973). However, <i>CYP3A4*1G</i> in the intestine had almost no effect on the incidence of rejection (9.9% in <i>CYP3A4*1/*1</i> <i>vs.</i> 12.5% in <i>CYP3A4*1G</i> allele, <i>p</i>=0.4824). <i>CYP3A4*1G</i> was significantly related to mRNA expression of CYP3A5 rather than of CYP3A4 in the graft liver and intestine and was strongly linked with the <i>CYP3A5*1</i>. Thus, we elucidated that <i>CYP3A4*1G</i> genotype in the intestine was an important indicator of the pharmacokinetics of tacrolimus, whereas this genotype in the graft liver tended to influence the frequency of acute cellular rejection after transplantation.

DOI： 10.1248/bpb.b13-00509

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Language：Japanese   Publisher：特定非営利活動法人 日本小児外科学会  

DOI： 10.11164/jjsps.48.4_810_3

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BACKGROUND: Ischemia-reperfusion (I/R) injury associated with living donor liver transplantation impairs liver graft regeneration. Mesenchymal stem cells (MSCs) are potential cell therapeutic targets for liver disease. In this study, we demonstrate the impact of MSCs against hepatic I/R injury and hepatectomy. METHODOLOGY/PRINCIPAL FINDINGS: We used a new rat model in which major hepatectomy with I/R injury was performed. Male Lewis rats were separated into two groups: an MSC group given MSCs after reperfusion as treatment, and a Control group given phosphate-buffered saline after reperfusion as placebo. The results of liver function tests, pathologic changes in the liver, and the remnant liver regeneration rate were assessed. The fate of transplanted MSCs in the luciferase-expressing rats was examined by in vivo luminescent imaging. The MSC group showed peak luciferase activity of transplanted MSCs in the remnant liver 24 h after reperfusion, after which luciferase activity gradually declined. The elevation of serum alanine transaminase levels was significantly reduced by MSC injection. Histopathological findings showed that vacuolar change was lower in the MSC group compared to the Control group. In addition, a significantly lower percentage of TUNEL-positive cells was observed in the MSC group compared with the controls. Remnant liver regeneration rate was accelerated in the MSC group. CONCLUSIONS/SIGNIFICANCE: These data suggest that MSC transplantation provides trophic support to the I/R-injured liver by inhibiting hepatocellular apoptosis and by stimulating regeneration.

DOI： 10.1371/journal.pone.0019195

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Language：English   Publisher：Clinical Transplantation  

Living donor liver transplantation (LDLT) has evolved based on the premise that donor safety is most important. In 2005, we encountered a donor who developed a pulmonary embolism during the early post-operative period. As it is important for donors to be healthy, most risk factors related to perioperative thrombosis, such as obesity, age, and malignancy are used as exclusion criteria during the evaluation process. We speculated that thrombophilia not detected by conventional laboratory examinations may cause post-operative thrombotic complications and should be investigated by application of additional parameters, including protein S, protein C, antithrombin III, anti-β2-glycoprotein I antibodies (anti-β2GPI), and lupus anticoagulant. From July 2005 to June 2007, we evaluated 44 donor candidates for LDLT using our novel algorithm for screening of thrombophilia, which revealed two suspected candidates (one with low protein S, one with low protein C, and positive anti-β2GPI findings), who were subsequently excluded from the donor pool. Thereafter, all donor hepatectomies, which included two borderline donors given anticoagulants perioperatively, were performed without complications. Four donors (two suspected, two borderline) would not have been recognized without additional screening. In conclusion, we were able to detect thrombophilia and avoid donor thrombosis using additional screening criteria and our novel algorithm. © 2010 John Wiley & Sons A/S.

DOI： 10.1111/j.1399-0012.2010.01216.x

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Language：English   Publisher：WILEY-BLACKWELL PUBLISHING, INC  

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The transjugular portosystemic shunt, widely used to treat portal hypertension today, may increase the risk of encephalopathy and reduce effective hepatic flow. To address these issues, a strategy to produce a portocaval shunt (PCS) with hepatic function using intestinal grafts was conceived, and rat models were developed. We transplanted ileal grafts from wild-type and luciferase transgenic Lewis rats to wild-type Lewis rats, anastomosing the graft mesenteric artery (SMA) and portal vein (PV) to the recipient PV trunk and inferior vena cava, respectively. Recipient survival was significantly longer in the partial PCS model, in which the graft SMA was anastomosed to the recipient PV trunk in an end-to-side fashion, than in the total PCS model, with the end-to-end anastomosis. In the partial PCS model, histological and luminescence analyses showed graft survival for 1 month. These results suggest that intestinal grafts can be maintained in the particular conditions required for our strategy.

DOI： 10.1002/micr.20751

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Language：Japanese   Publisher：一般社団法人日本外科学会  

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Language：Japanese   Publisher：一般社団法人日本外科学会  

CiNii Research

Language：Japanese   Publisher：一般社団法人日本外科学会  

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

Addition of the middle hepatic vein (MHV) or reconstruction of its tributaries to increase noncongestive graft volume is expected to improve graft function in right liver living donor liver transplantation (LDLT). However, the relationship between noncongestive graft volume and graft function after transplantation has not been clarified and definitive criteria for the reconstruction of MHV tributaries have yet to be established. We analyzed 29 right liver LDLT cases. The noncongestive graft weight was calculated as the total weight of the graft regions drained by hepatic veins reconstructed without postoperative occlusion. We calculated the noncongestive graft-to-recipient weight ratio (ncGRWR) by comparing it to the GRWR. Indocyanine green (ICG) clearance results on days 1 and 3 were significantly correlated with ncGRWR, but not with GRWR. Patients were then divided into 2 groups based on ncGRWR: lower than the median (L-ncGRWR group) and above the median (H-ncGRWR group). ICG clearance in the H-ncGRWR group was significantly better on days 1 and 3. For a different analysis, the patients were again divided into 2 groups, those with and without prolonged cholestasis after transplantation. ncGRWR was significantly lower in patients with prolonged cholestasis, and 7 of 9 patients with an ncGRWR value lower than 0.65 suffered from prolonged cholestasis. Our results demonstrated that the noncongestive volume of a right liver graft has a significant association with early graft function. Further, ncGRWR can play a key role in preoperative determination for additional vein reconstruction of MHV tributaries. When the estimated ncGRWR value with reconstruction of only the right hepatic vein (RHV) (+ inferior right hepatic vein [IRHV]) is)ess than 0.65, additional vein reconstruction of MHV tributaries should be planned. © 2007 AASLD.

DOI： 10.1002/lt.21231

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Language：English   Publisher：American Journal of Transplantation  

A major concern in adult-to-adult living donor liver transplantation is the selection of graft type; that is, is it is better to use the right lobe with or without the middle hepatic vein (MHV)? This choice has a considerable impact on donor safety, vascular reconstruction and graft function in the recipient. To facilitate making an appropriate choice, on the basis of a preliminary study (n = 17), we herein propose a graft selection algorithm using three parameters: graft-to-recipient body weight ratio (GRWR), percentage remnant liver volume (%RLV) and estimated congestion ratio (ECR). The algorithm was evaluated with 50 consecutive cases with respect to postoperative liver function of donors and recipients and survival of recipients. Postoperative recovery was comparable between the two groups (p = NS). The overall cumulative 18-month survival rate was 86.7% for the 'with MHV graft group', and 76.1% for the gwithout MHV graft grouph (p = NS). For 41 cases (82%), graft types were chosen according to the algorithm, whereas the remaining 9 cases (18%) needed detailed discussion of donor, recipient and operative factors. In conclusion, we constructed a graft selection algorithm based on congestion volume, which will contribute to objective graft-type selection in adult-to-adult LDLT. © 2007 The Authors.

DOI： 10.1111/j.1600-6143.2007.01849.x

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Language：Japanese   Publisher：一般社団法人日本外科学会  

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Language：Japanese   Publisher：一般社団法人日本外科学会  

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Language：Japanese   Publisher：一般社団法人日本外科学会  

CiNii Research

Language：Japanese   Publisher：一般社団法人日本消化器外科学会  

CiNii Research

Language：Japanese   Publisher：一般社団法人日本消化器外科学会  

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

The primed status of T cells is markedly different among liver transplant recipients, due to a lifetime of antigen exposure and reduced thymopoiesis by aging, and diseases. This study aims to characterize the preoperative immunological status of CD8+ T cell subpopulations and relate it to the outcome for liver transplant recipients. We classified 112 liver transplant recipients into 5 groups, based on hierarchical clustering of the CD8+CD45 isoform proportion of T cells. In Groups I and II (pediatric), the naive T cell proportion was more than 50%. In adult recipients, Group III was characterized by a naive T cell proportion of 50%, Group IV had the greatest effector/memory T cells (EM), and Group V had the greatest proportion of effector T cells. In Groups IV and V, the effector T cell proportion was considerably higher, and was accompanied by marked downregulation of the CD27+CD28+ subsets and upregulation of interferon gamma (IFN)-gamma, tumor necrosis factor-alpha, and perforin expression. Group V recipients tended to be complicated postoperatively, with a significantly reduced survival rate (1 yr, 66.8%) and markedly reduced Eastern Cooperative Oncology Group performance status.

DOI： 10.1002/lt.20705

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This study examined the decision-making processes of donors in adult-to-adult living donor liver transplantation. Twenty-two donors were interviewed using a semi-structured format. Interview contents were transcribed verbatim and analyzed qualitatively using grounded theory. A decision-making model was developed consisting of 5 stages: (1) recognition, (2) digestion, (3) decision-making, (4) reinforcement, and (5) resolution. The second and the third stages described donors' experiences of "reaching a decision"; the fourth and fifth stages described those of "facing transplantation." The central theme of this model was "having no choice," which consisted of 4 codes: (1) priority of life, (2) only LDLT, (3) for family, and (4) only me. In conclusion, this model can help health care professionals to understand the donor experience and, based on that understanding, to provide sufficient support to the donor.

DOI： 10.1002/lt.20689

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Language：English   Publisher：Japan Surgical Society (JSS)  

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Complement C4d deposition in graft capillaries has been reported to be associated with antibody-mediated rejection in kidney and other solid organ transplantation. The correlation of C4d deposits and humoral rejection in liver transplants, however, is not well understood. We investigated the C4d immunostaining pattern in 34 patients whose liver biopsy was taken within the first 3 postoperative weeks for suspected acute rejection after ABO blood type-incompatible liver transplantation. The staining pattern was classified as positive (portal stromal staining), indeterminate (endothelial staining only), and negative (no staining). Positive C4d immunostaining was seen in 17 (50%) patients and was significantly associated with high (x64 or more) postoperative antidonor A/B antibody (immunoglobulin M (IgM)) titers (88 vs. 35%, P = 0.002) and poorer overall survival rate (41 vs. 88%, P = 0.007). Ten of 11 (91%) cases with histological acute humoral rejection (periportal edema and necrosis (PEN) or portal hemorrhagic edema) were positive for C4d, all of which showed high postoperative antibody titers. The other histologies associated with C4d positivity was purulent cholangitis (n = 4), coagulative hepatocyte necrosis (n = 1), acute cellular rejection (n = 1), and hepatocanalicular cholestasis (n = 1). Full clinical recovery was observed in only 6 of 17 (35%) C4d-positive patients, and tended to be associated with a lower rejection activity index (RAI). In conclusion, our study indicates that C4d deposits in the portal stroma can be a hallmark of acute humoral rejection in ABO-incompatible liver transplantation, and allograft damage can be reversible in a minority of cases.

DOI： 10.1002/lt.20652

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Graft-versus-host disease (GVHD) is an uncommon but potentially devastating complication following liver transplantation. Recently, it was shown that use of a human leukocyte antigen (HLA)-homozygous donor leading to one-way HLA matching significantly increases the risk of GVHD after living donor liver transplantation (LDLT). However, the precise impact of HLA matching between donor and recipient on the risk of GVHD is not yet clear. We surveyed instances of fatal GVHD following LDLT in Japan and reviewed all 8 cases in detail, especially with respect to HLA matching. Serological typing showed that 7 of those cases had donor-dominant one-way HLA matching in the 3 loci of HLA-A, -B, and -DR, while one had donor-dominant one-way HLA matching in the 2 loci of HLA-A and -DR and identical alleles in the B locus. However, DNA typing revealed that the latter case had 1-way HLA matching in the 3 loci. Further, we analyzed HLA typing of 906 donor-recipient pairs who underwent LDLT. There were 5 cases with donor-dominant one-way matching in 2 loci and 2 with donor-dominant one-way matching in 1 locus. All of those cases except 1, who died from an unrelated cause, are alive without an obvious presentation of GVHD. In conclusion, our results suggest that the total number of loci with donor-dominant one-way HLA matching is important for determining the risk of fatal GVHD following LDLT, and that DNA typing of HLA alleles is indispensable in some cases to identify the true risk of donor-dominant 1-way HLA matching. © 2005 AASLD.

DOI： 10.1002/lt.20573

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Technical improvements in adult-to-adult living-donor liver transplantation (LDLT) have led to the use of right-lobe grafts to overcome the problems encountered with 'small-for-size grafts'. The major controversy remains that the venous drainage from anterior segment substantially depends on tributaries of the middle hepatic vein (MHV), and deprivation of such tributaries may critically influence the postoperative graft function. Right-lobe grafts with MHV could resolve the potential problem of congestion in anterior segment. From December 2000 to January 2004, we performed 217 right-lobe LDLTs for adult patients. Of these, 40 patients received a right lobe with MHV graft (18.4%). The overall cumulative 3-year graft survival rate of a right lobe with (n = 40) and without MHV (n = 177) was 86.2% and 74.8% (p = NS). The proximal side of the MHV and the drainage vein of segment IV to the MHV (the left medial superior vein) were preserved in 24 patients. All of them needed venous interposition graft for anastomosis. All patients had a patent right hepatic vein (RHV) and MHV anastomosis during the follow-up period. We adopted the right lobe with MHV graft in 40 LDLT cases. Vein graft is essential for safe MHV anastomosis in cases which preserve proximal side of the MHV.

DOI： 10.1111/j.1600-6143.2005.00817.x

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Auxiliary partial orthotopic liver transplantation (APOLT) was initially indicated as a potentially reversible fulminant hepatic failure and non-cirrhotic metabolic liver disease to compensate for enzyme deficiency without complete removal of the native liver. We expand our indication of APOLT for small-for-size grafts to support the function of implanted grafts during the early post-operative period, and for ABO-incompatibility to sustain a patient's life if the patient has a graft failure. We retrospectively reviewed 31 patients undergoing APOLT from living donor. The indication of APOLT was fulminant hepatic failure in 6, non-cirrhotic metabolic liver disease in 6, small-for-size grafts in 13 and ABO-incompatible cases in 6. The cumulative survival rate for APOLT at 1 and 5 years was 57.9% and 50.6%, and 78.8% and 73.8% for standard LDLT. None of the patients who underwent transplantation with APOLT for fulminant hepatic failure had long-term patient survival. The incidence of acute cellular rejection was higher in APOLT (58.1%) than standard LDLT (35.0%). Biliary complication was higher and the need for retransplantation was greater in APOLT than standard LDLT (p < 0.01). The results suggest that the indications of APOLT should be reconsidered in view of the risk for complications and retransplantation.

DOI： 10.1111/j.1600-6143.2005.00717.x

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Language：English   Publisher：BLACKWELL PUBLISHING ASIA  

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Auxilliary partial orthotopic liver transplantation (APOLT) was introduced initially as a tentative or permanent support for patients with potentially reversible fulminant hepatic failure and has extended its indication to congenital metabolic disorder of the liver that has otherwise normal functional integrity. Postoperative management of APOLT is complicated because of functional portal flow competition between the native and graft liver. The native portal vein diversion to the graft is sometimes indicated to prevent functional competition; however, it is still an open question whether this technique can be theoretically indicated for APOLT patients. The authors report a on patient with ornithine transcarbamylase deficiency who received APOLT from a living donor without native portal vein diversion. Because of functional portal vein competition between the native and graft liver, the patient had to have portal vein diversion, portal vein embolization, and finally native hepatectomy to induce the graft regeneration after APOLT. After the experience of the current case, primary portal vein diversion for APOLT with noncirrhotic metabolic liver disease patients to prevent functional portal flow competition is recommended.

DOI： 10.1016/j.jpedsurg.2004.03.079

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In the development of adult-to-adult living donor liver transplantation (LDLT), the small-for-size graft has been associated with poor clinical outcome. Persistent portal hypertension or portal venous overperfusion are considered to be causative factors, and partial diversion of portal flow to systemic circulation may be effective for avoiding injuries that occur in the small-for-size (SFS) graft. Recently, we constructed an end-to-side portocaval shunting using 1 of the portal branches and anastomosed the other branch with the portal vein of the graft in 2 cases of LDLT recipients transplanted with a SFS graft. With the suppression of portal hypertension, as well as sufficient portal flow to the graft, the recipients recovered successfully with favorable graft function. This new and simple technique may be able to be used as a feasible and effective method to attenuate the SFS syndrome.

DOI： 10.1002/lt.20164

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BACKGROUND: Although living-donor liver transplantation (LDLT) has been accepted for adult populations, the occurrence and pathogenesis of small-for-size syndrome remain highly controversial. METHODS: Portal venous pressure (PVP) was measured in 79 cases of LDLT from anhepatic phase to day 14. PVP was monitored through a catheter inserted via the inferior mesenteric vein. In a separate series of seven cases of adult LDLT, the splenic artery was ligated following arterial reperfusion. RESULTS: For days 2 to 4 and 9 to 11, recipients of small-for-size graft (<0.8% of body weight) displayed significantly higher PVP than recipients of larger grafts. The 13 patients with elevated mean PVP (>or=20 mm Hg) early in the first week (days 0-4) demonstrated significantly worse survival (84.5% vs. 38.5% at 6 months; P < 0.01), but this was not applicable to elevated mean PVP late in the first week (days 5-7). Elevated PVP early in the first week was also associated with higher incidence of bacteremia, cholestasis, prolonged prothrombin time, and ascites. Splenic artery ligation (SAL) immediately reduced PVP from 10 to 20 mm Hg (median, 16 mm Hg) to 9 to 13 mm Hg (median, 11 mm Hg; P = 0.02). Posttransplant PVP was significantly lower in SAL patients than in non-SAL patients from days 2 to 7 despite small graft size. Early PVP in SAL patients was consistently below 20 mm Hg, and survival was significantly better than in non-SAL patients with high early PVP (P < 0.01). CONCLUSION: Elevated PVP in the early phase is strongly associated with poor patient survival attributable, at least in part, to small-for-size graft. Further elucidation of the pathogenesis behind this phenomenon and efforts to modify PVP will be key to improving results.

DOI： 10.1097/01.TP.0000063707.90525.10

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Liver transplantation is a fundamental treatment for patients with end-stage hepatic failure. In order to perform living-donor liver transplantations under safer conditions, apheresis plays a major role in Japan due to the prevalence of living-donor liver transplantation wherein later retransplantation is difficult. In our department, the roles of apheresis in liver transplantation are as follows: as bridge therapy to liver transplantation (n = 45); as a supplement to the graft liver until the recovery of hepatic function (n = 77); as treatment for multiple organ failure including posttransplantation renal failure (n = 15); and as a means with which to reduce antibody titers for antibodies such as anti-A or anti-B in persons with ABO blood type = incompatible liver transplantation (n = 23). In our department, we have performed 822 liver transplantations at present. Of those cases, 183 were selected wherein apheresis was performed around the time of the operation. In all cases, transplantation with sufficient apheresis was performed before the surgical operation, however, 22 patients (48.9%) died after undergoing surgery. Among the patients who underwent the postoperative apheresis, those in the nonsurvivor group had lower grafted liver weights compared to those of the survivor group. The kidney was the organ that most frequently failed due to postoperative complications. In cases of ABO blood type-incompatible liver transplantations, patients with high preoperative anti-A/B IgM antibody titers sustained bile duct complications, patients with high preoperative anti-IgG antibody titers sustained hepatic necrosis, and patients with high postoperative anti-A/B IgM and anti-IgG antibody titers sustained hepatic necrosis most frequently.

DOI： 10.1046/j.1526-0968.2002.00460.x

Web of Science

PubMed

Language：Japanese  

CiNii Research

Language：English   Publisher：ELSEVIER SCIENCE INC  

DOI： 10.1016/S0041-1345(02)02980-9

Web of Science

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

The mucosal layer is the initial site of small bowel (SB) graft injury sustained during cold storage. Vascular administration of preservation solutions alone is unable to prevent ischemic injury of this layer during clinically relevant storage periods. The SB is unique in that it possesses both a vascular and a luminal route by which preservation solutions can be administered. We hypothesized that addition of a luminal-delivered solution, formulated on amino acid requirements for energy- and non-energy-related reactions, would provide site-specific preservation of mucosal energetics, barrier function and morphology throughout an extended period of cold storage. Of the three luminal solutions containing amino acids which were tested (UWG, AA1, AA2), only the two groups (AA1, AA2), containing glutamine plus 18 other amino acids, +/- osmotic agent (lactobionate) and buffer (BES), exhibited significant improvements in energetics, barrier function, and histology compared to the clinical standard of isolated vascular University of Wisconsin (UW) solution. Although the AA1 and AA2 groups preserved barrier function and morphology up to 24h better than all other solutions tested, AA2 proved to be the only luminal solution with values of permeability, conductance, and short-circuit current not significantly different from freshly isolated tissues. Furthermore, the greatest reduction in histologic injury was effected by AA2 treatment (median grade 2 compared to control, UW(v), grade 8). This study documents that a luminal-delivered solution, formulated on physiologic SB requirements, provides targeted preservation of the SB mucosa.

PubMed

Language：Japanese   Publisher：一般社団法人日本消化器外科学会  

CiNii Research

Language：Japanese   Publisher：特定非営利活動法人 日本小児外科学会  

DOI： 10.11164/jjsps.35.3_574_1

CiNii Research

Language：Japanese   Publisher：特定非営利活動法人 日本小児外科学会  

DOI： 10.11164/jjsps.34.5_949_1

CiNii Research

Language：Japanese   Publisher：特定非営利活動法人 日本小児外科学会  

DOI： 10.11164/jjsps.33.3_575_2

CiNii Research

Language：Japanese   Publisher：特定非営利活動法人 日本小児外科学会  

DOI： 10.11164/jjsps.31.3_527_1

CiNii Research

Language：Japanese   Publisher：(一社)日本肝胆膵外科学会  

Language：English   Publisher：(一社)日本肝胆膵外科学会  

Language：Japanese   Publisher：(一社)日本移植学会  

Language：English   Publisher：(一社)日本外科学会  

Language：Japanese   Publisher：(一社)日本移植学会  

Language：Japanese   Publisher：(一社)日本消化器外科学会  

Language：Japanese   Publisher：(一社)日本消化器外科学会  

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