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We assessed whether or not covalently closed circular DNA (cccDNA) levels in the background liver influence the recurrence of hepatocellular carcinoma (HCC) in patients with resolved hepatitis B virus (HBV) infection.Among 425 patients who underwent initial hepatectomy for HCC between 2010 and 2018, a retrospective review was performed in 44 with resolved HBV infection. The clinicopathologic characteristics were analyzed for correlation with tumor recurrence. The HBV cccDNA levels were tested via a droplet digital polymerase chain reaction assay.HBV cccDNA was detected in 27 of 44 patients (61%), and the median level was 1.0 copies/1000 ng (range, 0-931.3 copies/1000 ng). Anti-HBc ≥8.9 S/CO was associated with cccDNA detection (odds ratio, 11.08; 95% confidence interval [95% CI], 2.48-49.46; P = 0.002). Twenty-eight patients (64%) developed HCC recurrence after hepatectomy. The overall 3- and 5-year recurrence-free survival rates were 45.7% and 34.3%, respectively.19 HBV cccDNA levels was not significantly associated with HCC recurrence, while the presence of multiple tumors was an independent risk fact or (hazard ratio, 6.53; 95% CI, 2.48-17.19; P0.001.HBV cccDNA levels did not influence HCC recurrence after hepatectomy. Anti-HBc levels may be used as a surrogate marker for cccDNA.

The use of hepatitis B core antibody (anti-HBc)-positive grafts is one strategy for expanding the donor pool for liver transplantation (LT). The aim of this study was to determine the risk factors associated with hepatitis B virus (HBV) recurrence after living donor LT (LDLT) of anti-HBc-positive grafts. From January 1996 to December 2018, a total of 609 LDLT procedures were performed at our center. A retrospective review was performed for 31 patients (23 males and 8 females; median age = 47 years) who underwent LDLT for HBV-unrelated liver disease from anti-HBc-positive donors. The factors associated with HBV recurrence were evaluated and compared between the HBV recurrence and non-recurrence groups. The median follow-up period after LT was 135 months (range, 6-273 months). Four of 31 patients (12.9%) developed post-LT HBV recurrence. All four cases were HBV-naïve patients (anti-HBc-negative and Hepatitis B surface antibody-negative). The median interval between LDLT and HBV recurrence was 42 months (range, 20-51). The overall actuarial rates of HBV recurrence at 1, 3, 5, 10, and 20 years were 0%, 7.2%, 15.7%, 15.7%, and 15.7%, respectively. Although there were no significant differences between the HBV recurrence and non-recurrence groups, HBV recurrence tended to occur in HBV-naïve recipients (P = 0.093). HBV-naïve status may contribute to HBV recurrence after LDLT for HBV-unrelated liver disease from anti-HBc-positive donors. Careful monitoring for serological HBV markers is needed, particularly in this group.

Background & aims: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. Methods: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). Results: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10-4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10-6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028-1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09-1.26; P = 9.93 × 10-8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10-9; OR, 1.33; 95% CI, 1.21-1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). Conclusions: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.

The factors associated with hepatitis B virus (HBV) recurrence after living donor liver transplantation (LDLT) have not been fully clarified. The aim of this study was to determine the risk factors associated with HBV recurrence after LDLT. From January 1996 to December 2018, a total of 609 LDLT operations were performed at our center. A retrospective review was performed of 70 patients (male, n = 59; female, n = 11; median age = 54 years) who underwent LDLT for HBV-related liver disease. The virologic and biochemical data, tumor burden, antiviral and immunosuppressive therapy were evaluated and compared between the HBV recurrence and non-recurrence groups. Eleven of 70 patients (16%) developed post-LDLT HBV recurrence. The overall actuarial rates of HBV recurrence at 1, 3, 5, 10, and 20 years were 0%, 13%, 16.7%, 18.8%, and 18.8%, respectively. The median interval between LDLT and HBV recurrence was 57 months (range, 18-124 months). Based on the univariate and multivariate analyses, a serum HBV DNA level of ≥ 4 log copies/mL (hazard ratio [HR], 4.861; 95% confidence interval [95% CI], 1.172-20.165; P = 0.029), and hepatocellular carcinoma (HCC) beyond the Milan criteria (HR, 10.083; 95% CI, 2.749-36.982; P < 0.001) were independent risk factors for HBV recurrence after LDLT. In LDLT patients, high pre-LT HBV DNA levels and HCC beyond the Milan criteria were risk factors for HBV recurrence. With the current expansion of the LT criteria for HCC, we should remain cautious regarding the risk of HBV recurrence, particularly in these groups.

A Japanese woman with a history of Kasai operation for biliary atresia had living-donor liver transplantation at the age of 22. The first episode of refractory HE and late cellular rejection was treated by a high dose of methylprednisolone. The second episode of refractory HE was treated by balloon-occluded retrograde transvenous obliteration for a spleno-renal shunt. However, the third episode of refractory HE occurred 11 years after liver transplantation. The liver cirrhosis and hypersplenism were present with a Child-Pugh score of C-10. Although portal vein flow was hepatopetal, superior mesenteric vein flow regurgitated. We performed proximal total splenic artery embolization (TSAE). Superior mesenteric vein flow changed to a hepatopetal direction and she became clear. At a year after proximal TSAE, her spleen volume had decreased to 589 mL (20% decrease) on computed tomography. She is well and has a Child-Pugh score of 8 without overt HE. We report the first case of refractory HE treated by proximal TSAE that is a possible less invasive treatment option for a selected patient.

Background Only a few studies have reported the resection and reconstruction of major hepatic veins during hepatectomy. Here we present our strategy and techniques for venous reconstruction with cryopreserved homologous veins, and describe the surgical outcome. Methods Among 2387 hepatectomy patients, 39 patients who required hepatic venous reconstruction were reviewed retrospectively. Venous reconstruction was performed to secure a non-congested liver remnant volume of at least 40% of the total liver volume. Results There was no operative mortality, and the severe morbidity rate was 5% in this series. A total of 41 veins were reconstructed; 30 with homologous veins (73.2%) and 11 with autologous veins (26.8%), with the middle hepatic vein being the most frequent (n=23, 56%). Interposition grafting was performed more often (P=0.003), the length of the venous resection was longer (P=0.007), and pathologic wall infiltration of the vein was revealed more often (P=0.002) in the homologous graft group than in the autologous graft group. The 1-, 2-, and 3-year overall patency of the reconstructed veins was 55.4%, 46.3%, and 46.3%, respectively. Conclusions Aggressive venous reconstruction during hepatectomy using cryopreserved homologous veins is a feasible option with satisfactory short-term outcomes, and may be warranted to improve operative safety. This article is protected by copyright. All rights reserved.

Background There are several techniques for reconstructing the portal vein-superior mesenteric vein during pancreatoduodenectomy. The aim of the present study was to present our results with portal vein-superior mesenteric vein reconstruction using cryopreserved homologous veins during pancreatoduodenectomy for patients with pancreatic head cancer. Methods Patients who underwent pancreatoduodenectomy for pancreatic head cancer were reviewed retrospectively. In patients with portal vein-superior mesenteric vein resection, the detailed method of reconstruction and clinical outcomes were reviewed. Clinical characteristics, patient survival, and portal vein-superior mesenteric vein patency were compared between those with and without homologous vein grafts. Factors affecting the patency of reconstructed veins were assessed by univariate analysis. Results Among 144 patients undergoing pancreatoduodenectomy, portal vein-superior mesenteric vein resection was performed in 36 patients (25%); 18 (50%) underwent reconstruction with homologous veins, and the other 18 (50%) underwent reconstruction without homologous veins. The extent of portal vein-superior mesenteric vein involvement, operative time, duration of clamping of portal vein-superior mesenteric vein, intraoperative blood loss, and length of the venous resection were greater ( P ≤ .013 each) in those with homologous vein grafts. There was no significant difference in postoperative morbidity/mortality, patient survival, or portal vein-superior mesenteric vein patency. The 1- and 2-year overall patency of portal vein-superior mesenteric vein was 76% and 71%, respectively, while the 2-year patencies were 67% and 67% in those with homologous veins and 87% and 73% in those without homologous veins without difference between the groups. Circumferential resection and pathologic portal vein-superior mesenteric vein involvement were associated with the patency of the reconstructed vein ( P = .002 and P = .028, resp). Conclusion Use of homologous venous grafts for portal vein-superior mesenteric vein reconstruction are feasible alternatives during pancreatoduodenectomy for advanced pancreatic head cancer.

Administration of the selective arginine vasopressin V2 receptor antagonist tolvaptan to cirrhotic patients is controversial. There are no reports of tolvaptan use for patients with far-advanced end-stage liver disease (ESLD) and refractory ascites awaiting liver transplantation. Between 2013 and 2016, 64 patients awaiting adult-to-adult living donor liver transplantation (LDLT) were screened for enrollment. Patients with refractory ascites and on dual conventional diuretics (≥ 50 mg/day of spironolactone and ≥ 20 mg/day of a loop diuretic) were enrolled and assigned to the tolvaptan (TOL) group (n = 10), and low-dose tolvaptan, 3.75 mg/day, was started. The remaining patients who had no or little ascites on conventional diuretic therapy (CDT) were assigned to the CDT group (n = 23). The median model for end-stage liver disease and Child-Pugh scores were 16 (range 7-41) and 10 (7-15), respectively. The median dose of spironolactone in the TOL group was 88 mg (range 50-200) vs. 50 (0-100) in the CDT group (p < 0.01). The median dose of loop diuretics in the TOL group was 70 mg (20-120) vs. 20 (0-80) in the CDT group (p = 0.03). No significant liver damage was detected during tolvaptan therapy. Tolvaptan demonstrated favorable effects in 60% (6/10) of the patients, decreasing the body weight by at least 1.5 kg during the 7 day treatment. These findings suggest that low-dose of tolvaptan may be safe for patients having far-advanced ESLD patients with apparent and refractory ascites taking dual conventional diuretics for a short period before LDLT.

BACKGROUND Several clinical factors are reportedly correlated with acute cellular rejection (ACR) after liver transplantation. However, the factors that determine the response to rescue therapies remain unclear. METHODS A prospective database of 413 consecutive adult patients who underwent living donor liver transplantation (LDLT) was reviewed. RESULTS Ninety-nine (24%) patients developed ACR after LDLT. A multivariate analysis revealed that a positive T-lymphocytotoxic test (odds ratio [OR], 3.85; P=.017), HLA-DR mismatch (OR, 2.99; P=.013), autoimmune disease (OR, 2.61; P=.001), and a younger recipient age (OR, 0.60 for +10 years; P

Antiviral treatment in liver transplant recipients co-infected with hepatitis C virus (HCV) and HIV remains a challenge. We herein report a case of HCV recurrence that was successfully treated using interferon-free anti-HCV therapy with daclatasvir and asunaprevir. A 48-year-old man underwent antiviral therapy with a 24-week course of daclatasvir and asunaprevir for biopsy-proven recurrent HCV 15 months after living donor liver transplantation, following non-response to pre-emptive antiviral treatment with pegylated interferon plus ribavirin. Anti-HIV and immunosuppressive regimens were modified safely. Renal function was feasibly preserved. The anti-HCV effect was remarkable with an undetectable viral load confirmed within 2 weeks, and this patient achieved a sustained virological response after 12 weeks of post-transplantation treatment. No serious adverse events were observed. This case indicates that daclatasvir and asunaprevir for recurrent HCV in a HIV co-infected recipient after liver transplantation is safe and effective.

Aim The feasibility of vaccination in liver transplant recipients is highly controversial, and the present study aimed to investigate the efficacy of a 1-year extended, monthly vaccine prophylaxis protocol of a second-generation recombinant vaccine for transplant recipients. Methods The recombinant hepatitis B vaccine (10 µg) was administrated s.c. every month for 12 months as the vaccination protocol to 39 liver transplant recipients in stable condition, including those with hepatitis B-related chronic liver disease (n = 30), those with acute hepatitis B liver failure (hepatitis B surface antibody [HBsAb], n = 4), and those with hepatitis B core antibody positive grafts (n = 5). A fixed dose of hepatitis B immune globulin (HBIG) was administrated during the study based on the monoprophylaxis approach, and the increase in the hepatitis B surface antibody titer was measured to evaluate the efficacy of the vaccination. Results The vaccination protocol was initiated a mean of 54 months (range, 13–124) after liver transplantation, and all patients tolerated the vaccination well without adverse effects. The overall hepatitis B virus (HBV) recurrence rate was 5% (2/39) based on hepatitis B surface antigen positivity, and 2% (1/39) based on HBV DNA detectability. Six (15%) patients showed a good response to vaccination with an increase in the HBsAb titer greater than 100 IU/L at the end of vaccination, but only three (8%) maintained an adequate HBsAb level to spare HBIG during the 2-year observation period. Conclusion While a few patients demonstrated an adequate response to vaccination, the clinical indication for the HBV vaccination for liver transplant recipients is currently minimal.

Aim The clinical presentation of Primary biliary cirrhosis (PBC) at the time of liver transplantation (LT) may have changed, due to the long-term use of ursodeoxycholic acid (UDCA). The aim of this retrospective study was to investigate whether the clinical characteristics of LT recipients with PBC have changed over the years. Methods Of all 421 adults undergoing LT from 1997 to 2012 at our center, we included 85 recipients with PBC into the present study. The 85 recipients were divided into three groups according to the year LT was performed: group 1 (1997–2001, n = 29), group 2 (2002–2005, n = 29) and group 3 (2006–2012, n = 27). Results There were no significant differences in sex, recipient age, Model for End-Stage Liver Disease score, updated Mayo risk score for PBC, or liver-related complications except for esophageal varices among the three groups. Patients in group 1 were complicated with esophageal varices less frequently than those in the other two groups. In older cases, the ratio of explanted liver volume to standard liver volume (ELV/SLV) was significantly higher, and the duration of pre-LT UDCA treatment was significantly shorter. The duration of UDCA treatment was significantly correlated with ELV/SLV. Conclusion Recent LT patients were characterized by more frequent portal hypertension and more severe liver atrophy, with longer UDCA therapy prior to LT, which might have prevented the somewhat rapid progression of liver failure characterized by hepatomegaly with insignificant fibrosis or portal hypertension.

Aim The number of patients referred for liver transplantation (LT) with non-alcoholic steatohepatitis (NASH) continues to increase, but information about living donor liver transplantation (LDLT) for NASH is scarce. We conducted this study to document the details of LDLT for NASH in a Japanese LT center. Methods Among all LDLT recipients in our institution from March 1996 to March 2013 (n = 425), we identified seven patients that underwent LDLT for NASH. Results Of all the seven recipients, most of the patients (86%) were obese. The median follow-up period post-LDLT was 5.3 years. All were alive at the last follow-up. Recurrent NASH was detected in one patient (14%), and no recurrent hepatic steatosis was detected among the remaining six recipients on prospectively performed ultrasonography. No significant comorbidities were observed following donor surgery among the respective living donors during the follow-up period. We also retrospectively reviewed 22 patients with NASH-related end-stage liver disease (ESLD) who were evaluated but rejected for LDLT during the same period. The reasons for rejection for LDLT were presumably associated with the nature of NAFLD/NASH in either potential recipients or donors. Conclusion The post-transplant outcome of LDLT for NASH-related ESLD in our institution was feasible, although the sample size was small. Further studies in a larger patient cohort are warranted to investigate the long-term outcome of LDLT for NASH, both for recipients and living donors.

BACKGROUND Organ transplant recipients have an increased incidence of malignancy. Race differences in a variety of malignancies are observed among the general population, but de novo malignancies after adult-to-adult living-donor liver transplantation (LDLT) have not been compared with those from a Japanese population-based study. METHODS The subjects were 360 adult LDLT recipients who survived more than 1 year after transplantation. An annual medical checkup and screening examinations were performed as follows: abdominal computed tomography or magnetic resonance imaging, upper gastrointestinal endoscopy, and total colonoscopy and immunochemical fecal occult blood test every 1 to 2 years. Complete blood count, liver function tests, and several tumor markers were checked every 1 to 3 months after LDLT. RESULTS Mean follow-up period was 7.5±3.4 years. During the follow-up period, 27 de novo malignancies were diagnosed in 26 recipients. Colorectal cancer was the most commonly detected malignancy. The overall mortality of the recipients with de novo malignancies was similar to the findings of the Japanese general population-based study (standardized mortality ratio=0.9). Overall, the incidence of cancer was significantly higher in transplant recipients than in the Japanese general population (standardized incidence ratio=1.8). The 5-year estimated survival rate of recipients with de novo malignancies was 81% and those of recipients without malignancies was 93% (P

Aim Although alcoholic liver disease (ALD) is an accepted indication for liver transplantation (LT), there are several controversial issues. The aim of this study is to examine the applicability of the 6-month abstinence rule prior to LT and to evaluate the results in living donor LT for patients with ALD. Methods A retrospective study of 102 patients with ALD referred for LT was performed. Clinical data, including alcohol consumption history, were analyzed. A period of abstinence from drinking alcohol of at least 6 months was strictly required. Results Among 102 patients, 21 abstained from drinking for at least 6 months. Of these, 13 patients (12%) underwent LT, five patients (5%) recovered without LT and three patients (3%) were listed for deceased donor LT. LT was not indicated for the remaining 81 patients (80%). Eight patients died within 6 months of referral to our program. The Child–Pugh score was higher in these eight patients than in the 21 who achieved 6-month abstinence, although the alcohol consumption history variables did not significantly differ between the two groups. The 5-year overall survival rates after LT in 13 patients with ALD (91%) were similar to those in 387 non-ALD patients (83%). The rate of alcohol consumption relapse after LT was 8% (n = 1/13). Conclusion Living donor LT for patients with ALD who complied with the 6-month abstinence rule provides sufficient survival benefit with good compliance, compensating for the potential risks to the donors.

Although recent advances in preoperative imaging have enabled accurate estimation of the regional liver volume with venous occlusion, the extent of functional decrease in such regions remains unclear. In this study, the portal uptake function in postoperative veno-occlusive regions and non-veno-occlusive regions was evaluated by intraoperative fluorescent imaging after intravenous injection of indocyanine green (ICG).In 22 liver resection patients and 23 recipients and 18 donors of liver transplantation, fluorescent intensity on the remnant liver or the liver graft was evaluated in real time following intravenous injection of ICG (0.0025 mg per 1 ml of remnant liver volume).Plateau ICG concentrations were significantly lower in the veno-occlusive regions (C(VO)) than in the non-veno-occlusive regions (C(Non)) in liver resection patients (median [range], 0.75 [0.29-2.0]μg/ml vs. 3.0 [0.46-6.4]μg/ml, p0.001), donors (0.69 [0.29-1.9]μg/ml vs. 2.4 [0.46-6.4]μg/ml, p0.001), and recipients (0.75 [0.34-1.8]μg/ml vs. 1.8 [0.54-6.4]μg/ml, p0.001). Distributions of the C(VO)/C(Non) and the ratio of the hepatic uptake rate constant in the veno-occlusive regions to that in non-veno-occlusive regions were both around 40% (mean ± standard deviation, 0.36 ± 0.17 and 0.42 ± 0.16, respectively). When the functional remnant liver volume was calculated as a sum of non-veno-occlusive regions and veno-occlusive regions multiplied by C(VO)/C(Non), its ratio to the total liver volume was correlated with the improved postoperative/preoperative ratio of prothrombin time.Portal uptake function in veno-occlusive regions is approximately 40% of that in non-veno-occlusive regions. Intraoperative ICG-fluorescent imaging enables real-time evaluation of the extent of the functional decrease in veno-occlusive regions, enhancing accurate estimation of the hepatic functional reserve for determining the surgical indications and procedures.

BACKGROUND The aim of the present study was to investigate the pharmacokinetics of the once-daily tacrolimus formulation (QD form) in relation to polymorphisms of the donor cytochrome P450 family 3 sub-family A polypeptide 5 (CYP3A5) gene and recipient adenosine triphosphate-binding cassette sub-family B member 1 (ABCB1) gene. MATERIAL AND METHODS A total of 80 consecutive living-donor liver transplant (LDLT) recipients were started on the QD form of tacrolimus (day 1), and 60 patients were completely followed for 7 days early after liver transplantation in order to evaluate the pharmacokinetics. RESULTS The concentration/dose (C/D) ratio in recipients with the donor CYP3A5 *1 allele was significantly lower throughout the observation period compared with those with the CYP3A5 genotype *3/*3 (p

Nationwide surveys of acute liver failure (ALF) are conducted annually in Japan, and 20% of patients with ALF undergo liver transplantation (LT). We extracted data for 212 patients who underwent LT for ALF from the nationwide survey database of the Intractable Liver Diseases Study Group of Japan. After the exclusion of 3 patients who underwent deceased donor LT, 209 recipients of living donor liver transplantation (LDLT) were analyzed. ALF patients were placed into 3 subgroups according to the time from the onset of the disease to the occurrence of encephalopathy: patients who presented with encephalopathy within 10 days of the disease's onset were classified as having acute ALF, patients who presented within 11 to 56 days were classified as having subacute ALF, and patients who presented within 9 to 24 weeks were classified as having late-onset hepatic failure (LOHF). Long-term follow-up data were obtained from the registry of the Japanese Liver Transplantation Society. The 2 data sets were merged, and descriptive and survival data were analyzed. A Cox regression analysis was performed to define factors predicting overall mortality, short-term mortality (≤90 days after LT), and long-term mortality (>90 days after LT). One hundred ninety of the analyzed patients (91%) were adults (age ≥ 18 years); 70 patients (34%) were diagnosed with acute ALF, 124 (59%) were diagnosed with subacute ALF, and 15 (7%) were diagnosed with LOHF. Hepatitis B virus was the most common cause of acute ALF (61%), whereas autoimmune hepatitis (14%) and drug allergy–induced hepatitis (14%) were more frequent in patients with subacute ALF or LOHF. The cumulative patient survival rates 1, 5, and 10 years after LT were 79%, 74%, and 73%, respectively. Patient age was associated with short- and long-term mortality after LT, whereas ABO incompatibility affected short-term mortality, and donor age affected long-term mortality. In conclusion, the long-term outcomes of LDLT for ALF in this study were excellent, regardless of the etiology or classification. The majority of the donors were living donors. Increasing the deceased donor pool might be an urgent necessity. Liver Transpl, 2012. © 2012 AASLD.

Aim: Recurrent autoimmune hepatitis (AIH) following liver transplantation has been reported in 20–30% of cases, mainly of Western populations. The aim of this study was to review our experience of living-donor liver transplantation (LDLT) in Japanese patients with AIH. Methods: Among 375 adult (age ≥18 years) LDLT performed at our center between 1996 and 2010, 16 (4.2%) were for patients with AIH (n = 12) or AIH–primary biliary cirrhosis overlap syndrome (n = 4). The patient and donor characteristics and post-transplantation course were reviewed. Results: All recipients were female with a median age of 48 years (range, 21–58). Low-dose methylprednisolone and calcineurin inhibitors were continued in all patients. Acute cellular rejection occurred in 10 (63%), which was more frequent than in our overall series of 28.5% (107/375 cases). Overall survival rate was 81.2% at 5 years. At the end of the follow up (median, 6.0 years [range, 0.1–9.6]), 13 patients were alive with normal liver function tests (aspartate transaminase, 18 ± 5 IU/mL; alanine transaminase, 16 ± 8 IU/mL). None of the survivors exhibited liver function test results suspicious for recurrent AIH, which might indicate liver biopsy. Conclusion: Survival after LDLT for AIH and overlap syndrome was excellent and there was no evidence of clinical recurrence. The recurrence rate of AIH after liver transplantation may differ among countries, and requires further investigation.

The clinical features and perioperative management of liver transplant recipients who are already sensitized against human leukocyte antigen (HLA) prior to transplantation are not yet clear.Medical records of living donor liver transplant recipients were reviewed and clinical features of the patients possessing anti-HLA antibodies were studied.Among the 470 consecutive living donor liver transplant recipients, 6 patients (1.3%) had preformed anti-HLA antibodies. A review of the postoperative courses of these patients revealed that the problems included platelet transfusion refractoriness (PTR) due to immune-mediated destruction of platelet and thrombotic microangiopathy (TMA). PTR was observed in patients with anti-HLA class I antibodies and only HLA-matched platelet concentrate (HLA-matched PC) relieved thrombocytopenia. Intravenous gammaglobulin had an additive effect to HLA-matched PC in some cases, and platelet transfusion from close relatives might be a substitute for HLA-matched PC in life-threatening situations. Although the etiology of TMA is unremarkable, the incidence was high (67%, 4/6) compared with that in patients who were not sensitized against HLA (5.6%, 26/464; p0.01). Of the four patients, three were complicated with late-onset TMA.Considering these clinical features, careful preparation and postoperative management are needed for liver transplant candidates with anti-HLA antibodies.

Due to the organ shortage, many patients die without transplantation, even before completing an evaluation for candidacy. We analyzed outcomes after patient referral and factors associated with mortality both before and after listing for cadaveric donor liver transplantation.We analyzed 132 consecutive patients who were evaluated for candidacy for cadaveric donor liver transplantation between 2003 and 2010.The study included 69 men and 63 women of median age 49 years (range, 1-65). Etiologies of diseases were acute hepatic failure (n=19), liver cirrhosis due to hepatitis B or C (n=36), primary biliary cirrhosis (n=19), nonviral cirrhosis (n=14), hepatocellular carcinoma (n=13), or other causes (n=31). After evaluation for candidacy, we listed 68 (52%), subjects whereas 24 (18%) died before listing. Factors affecting death before listing were the levels of albumin (P.001), bilirubin (P.001), sodium (P.001), international normalized ratio (INR; P.001), Model for End-stage Liver Disease (MELD) score (P.001), MELD-Na score (P.001), and Child-Pugh-Turcotte (CPT) score (P.001). Based on multivariate Cox regression analysis, MELD score (hazard ratio [HR] 1.201, P=.017), MELD-Na score (HR 1.244, P=.014), CPT score (HR 1.468, P=.033), and INR (HR 0.491, P=.027) were independently associated with death before listing. Among 68 listed candidates, 11 (16%) underwent transplantation, whereas 29 (43%) died without transplantation. Based on multivariate Cox regression analysis, MELD score (HR 1.102, P=.001), MELD-Na score (HR 1.128, P=.001), and CPT score (HR 1.282, P=.038) independently predicted wait-list mortality. All 11 patients who underwent cadaveric liver transplantation were alive at 29 months (range, 1-55) after transplantation.Patients with a higher MELD, higher MELD-Na, and higher CPT score at referral were at greater risk for death without transplantation, especially before listing. Evaluation for transplantation candidacy is a time-consuming process. Therefore, earlier referral is mandatory to achieve successful listing for transplantation.

BACKGROUND Coinfection by Hepatitis B virus (HBV) and hepatitis C virus (HCV) has been reported to increase risk of graft failure for liver transplant recipients. But other studies have controverted that finding. The aim of this study was to determine whether-after adjustments for other important predictors-HBV/HCV coinfection was associated with worse liver graft survival than HBV or HCV mono-infection. METHODS A retrospective cohort study examined Organ Procurement and Transplantation Network/United Network Organ Sharing data for 48,654 deceased-donor primary liver-only transplants that were performed on adults between January 1, 1995, and August 31, 2009, and that included recipient and donor HBV/HCV status. Recipients were classified into four groups: the HBV/HCV coinfected [B+/C+]; HBV mono-infected [B+/C-]; HCV mono-infected [B-/C+]; and hepatitis uninfected [B-/C-]. Kaplan-Meier methods were used to calculate liver graft survival rates, Cox proportional hazard models were used to estimate the effect of hepatitis virus infection, and adjusted for potential confounders. RESULTS Graft survival rates were highest with B+/C-: 85.3% 1-year survival and 63.0% 10-year survival. Graft survival with B+/C+ was superior to survival with B-/C+: 83.5% 1-year survival and 53.6% 10-year survival vs. B-/C+: 82.9% 1-year survival and 46.1% 10-year survival. Survival with B-/C-: 83.6% 1-year survival and 56.6% 10-year survival was superior to survival with B+/C+ (shown above). After adjustment for confounders, and with the coinfected as reference, B-/C+ recipients had a higher risk of graft loss (hazard ratio, 1.35; 95% CI, 1.10-1.66); the other two groups had a lower risk. CONCLUSIONS Our results suggested-despite reports to the contrary-statistically better graft outcomes with HBV/HCV coinfection than with HCV mono-infection.

Summary In living donor liver transplantation (LDLT) for primary biliary cirrhosis (PBC), the majority of donors are genetically related to their recipients, leading to concerns of an earlier recurrence of PBC and a poorer prognosis due to genetic susceptibility. Totally 81 patients who underwent LDLT for PBC were the subjects of the present study. Immunosuppressive agents consisted of tacrolimus and methylprednisolone. In the outpatient clinic, when the aspartate and alanine aminotransferase level exceeded the upper limit of the normal range, the dose of methylprednisolone was increased from 4 to 6 mg/day for several months. Blood was examined every 2 weeks for 3 months and a liver biopsy was performed when aminotransferase levels did not decrease to the upper limit of the normal range after more than 3 months. Five-year survival and recurrence rates were estimated and the prognostic factors were analyzed. The mean observation period was 6.2 years. Five years after LDLT for PBC, the biopsy-proven PBC recurrence rate was 1%. The 5-year patient survival rate was 80%. The nonrelated or blood-related donor factor and number of human leukocyte antigen matches did not correlate with prognosis. PBC recurrence rate after LDLT in our series was lower than that in previous studies.

Aim: Although hepatocellular carcinoma (HCC)-specific serum tumor markers, α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP), are used in the screening for HCC, their utility in pre-transplantation evaluation is not well established. This study aimed to evaluate the accuracy of AFP and DCP measurement for the diagnosis of HCC in liver transplant candidates. Methods: A total of 315 consecutive adult patients (174 men and 141 women, mean age 52 years), who were to receive liver transplantation for end-stage liver diseases, were enrolled. The pre-transplant levels of AFP and DCP were compared with the histopathology of explanted liver. Results: Hepatocellular carcinoma was present in the explanted liver of 106 recipients (median number of nodules 2, mean diameter 2.5 cm). The area under receiver operating characteristic curve for the diagnosis of HCC was 0.83 (95% confidence interval, 0.78–0.88) for AFP and 0.47 (0.41–0.54) for DCP. With the cut-off value of 100 mAU/mL, 20/106 (18.9%) patients with HCC and 54/194 (27.8%) patients without HCC were positive for DCP. DCP positivity was associated with vascular invasion, tumor differentiation and size among patients with HCC, which was associated with albumin level among patients without HCC. Vitamin K was administered prior to transplantation to 20 patients who were positive for DCP (two with and 18 without HCC), resulting in a decrease in DCP levels in 19 of them. Conclusions: Serum DCP levels may be raised in end-stage liver disease patients without HCC, and cannot be used as a reliable marker for HCC among liver transplant candidates.

Hepatocellular carcinoma (HCC) recurrence after liver transplantation is associated with a poor prognosis; nonetheless, we report two cases of long-term survival after resection of pulmonary metastatic lesions following living donor liver transplantation (LDLT). The intervals between LDLT and pulmonary resection for the metastatic lesion were 24 months and 30 months, respectively. Regular checking of tumor markers and prompt workup for early detection may contribute to the resectability of such metastatic lesions. These cases suggest that resection of a solitary metastatic lesion in the lung from HCC after liver transplantation may be a feasible treatment for selected patients.

The skin of the toad Bufo bufo gargarizans Cantor is known to be rich in bufadienolides, peptides and alkaloids. It has been found to be a source of some extracts and biologically active compounds with antitumor activity. Cinobufacini (Huachansu), a Chinese medicine prepared from the dried toad skin, has been widely used in clinical therapy for various cancers in China. Bufadienolides, such as bufalin, cinobufagin, resibufogenin, and telocinobufagin, are the major active compounds derived from the toad skin. They are the maker biologically active compounds of cinobufagin while the antitumor activity of cinobufagin may be due to this kind of components. Experimental research has suggested that cinobufacini and its active compounds (e.g. bufalin and cinobufagin) exhibit significant antitumor activity, including inhibition of cell proliferation, induction of cell differentiation, induction of apoptosis, disruption of the cell cycle, inhibition of cancer angiogenesis, reversal of multi-drug resistance, and regulation of the immune response. Clinical data have indicated that cinobufacini may have effective anticancer activity with low toxicity and few side effects. Data to date suggest it may also enhance quality of life for patients with cancer. Thus, this review briefly summarizes recent studies on the anticancer activity of cinobufacini and some of its active compounds from the skin of the toad Bufo bufo gargarizans Cantor. This might provide additional evidence for further study of the extracts and active compounds from the toad skin in cancer treatment.

UNLABELLED Steroid bolus therapy for acute rejection after liver transplantation for hepatitis C virus (HCV) cirrhosis often results in graft loss due to adverse effects. The efficacy and safety of basiliximab for the treatment of acute cellular rejection (ACR) in adult liver transplantation has not been adequately evaluated. Three patients received basiliximab as rescue therapy for acute rejection. The outcome and biochemical parameters were recorded before and after treatment with basiliximab. These results were compared to 11 patients who received steroid therapy for ACR. The median time from transplantation to the development of ACR was 19 days (range, 9-49 days). The degree of ACR was mild or moderate. Resolution of rejection was obtained in all patients and the median time from the onset to resolution of ACR was 16 days (range, 6-41 days). A steroid resistant reaction occurred in 2 of 11 patients and OKT3 was used, and the rejection eventually resolved in all patients. Five patients died within 2 to 22 months after transplantation and four of them died from graft failure. In the basiliximab group, there were no significant immediate adverse effects. One patient died from pneumonia 8 months after transplantation. IN CONCLUSION Basiliximab can be safely used as rescue therapy for ACR without significant adverse effects in patients who underwent liver transplantation for HCV cirrhosis.

Treatment strategies against hepatocellular carcinoma have progressed remarkably over the past decade. In Asia, evidence-based guidelines for the management of hepatocellular carcinoma have evolved, including the option of liver transplantation. Due to severe organ shortage, however, living donor liver transplantation has become mainstream in Japan. Unlike deceased donor transplantation, living donor transplantation is not limited by the restrictions imposed by the nationwide allocation system. The decision for transplantation often depends on institutional or case-by-case considerations, balancing the will of the donor, the operative risk, and the overall survival benefit for the recipient. Cumulative data from the national multicenter registry analysis as well as individual center experience suggest that expansion of the Milan criteria is warranted.

It is unclear whether valganciclovir (VGCV) is effective compared with intravenous ganciclovir (GCV) for preemptive therapy of cytomegalovirus (CMV) infection in living donor liver transplantation (LDLT). A randomized trial was conducted to compare the efficacy of oral VGCV with intravenous GCV for preemptive treatment of CMV infection after LDLT. Patients who developed CMV infection within 6 months after LDLT at Tokyo University Hospital were randomly assigned to the VGCV or GCV group and received either oral VGCV 900 mg/day or intravenous GCV 5 mg/kg twice daily, respectively. The primary endpoint was the treatment success rate. Secondary endpoints were recurrence of CMV infection within 1 year after finishing the treatment, and safety and tolerability of the treatment. Twenty-two patients with CMV infection after LDLT fulfilled the inclusion criteria and were randomly assigned to the oral VGCV group (n = 11) or the intravenous GCV group (n = 11). Treatment success rates were 82% (9 of 11) and 91% (10 of 11) in the VGCV and GCV groups, respectively. One patient in the VGCV group developed recurrence, whereas no patients in the GCV group developed recurrence. All the patients completed the treatment protocol, and no patients in either group dropped out of the study. In conclusion, oral VGCV and intravenous GCV are safe, feasible options for preemptive treatment of CMV infection after LDLT.

Living donor liver transplantation (LDLT) is now a well established treatment modality for end-stage liver diseases, but the financial aspects of LDLT have not yet been fully investigated. The purpose of this study was to determine the overall direct cost of adult-adult LDLT in Japan and to identify the factors associated with the high cost.The direct cost of initial admission for LDLT was determined in a retrospective analysis of data from hospital charts and databases. The records for 100 consecutive adults who underwent LDLT from January 2004 to February 2006 at our center were reviewed, and clinical and financial data of all recipients and donors were analyzed.The median direct total cost for LDLT was $82,017 (range $51,189-438,295). Of this, the median cost for donors was $15,011 (range $12,354-23,251). A multivariate stepwise logistic regression model for overall cost of transplantation revealed that donor age [odds ratio (OR) = 1.1, p = 0.02], acute renal failure (OR = 24, p = 0.007), and posttransplant plasma exchange (OR = 72, p = 0.01) were associated with higher cost. When the models were repeated with preoperative patient and donor factors alone, donor age (OR 1.1, p = 0.008) and model for end stage liver disease score (OR 1.2, p = 0.003) were associated with higher cost.Donor age, acute renal failure, and posttransplant plasma exchange were independent risk factors for the high cost of LDLT in Japan.

Kyoden Y, Tamura S, Sugawara Y, Matsui Y, Togashi J, Kaneko J, Kokudo N, Makuuchi M. Incidence and management of biliary complications after adult-to-adult living donor liver transplantation. Clin Transplant 2010: 24: 535–542. © 2009 John Wiley & Sons A/S. Abstract: Background: There are few detailed reports of biliary complications in a large adult living donor liver transplantation (LDLT) series. Patient and methods: Biliary complications, treatment modalities, and outcomes in these patients were retrospectively analyzed in 310 adult LDLT. Results: One patient underwent retransplantation. Duct-to-duct anastomosis was primarily performed in 223 patients (72%). During the observation period (median 43 months), biliary complications were observed in 111 patients (36%); 53 patients (17%) had bile leakage, 70 patients (23%) had bile duct stenosis, and 12 patients (4%) had bile leakage followed by stenosis. A biliary anastomotic stent tube was placed in 266 patients (86%) at the time of transplantation. Univariate analysis of various clinical factors revealed duct-to-duct anastomosis as the single significant risk factor (p = 0.009) for biliary complications. The three-yr and five-yr overall patient survival rates were 88% and 85% in those with biliary complications, and 85% and 83%, respectively, in those without biliary complications (p = 0.59). Conclusion: Biliary complications are a major cause of morbidity following LDLT. Duct-to-duct anastomosis carried a higher risk for bile duct stenosis. With appropriate management, however, there was little influence on overall survival.

Aim: Recurrence of hepatocellular carcinoma (HCC) after liver transplantation decreases patient survival. The usefulness of post-transplant surveillance with tumor markers, however, is not clear. We evaluated our cumulative experience with recurrent HCC detected during post-transplant surveillance. Methods: We analyzed 100 patients with HCC detected in the explanted liver. Monthly to bimonthly measurement of tumor markers and yearly computed tomography were scheduled postoperatively. Results: Preoperatively, 82 met the Milan criteria. The histological findings indicated that 61 fulfilled the Milan criteria. In nine patients, HCC recurred 10 months (2–29) after liver transplantation in the graft (n = 1), lung (n = 2), bone (n = 3) and multiple organs (n = 3). In all nine recipients, HCC was first suspected based on an increase in tumor marker levels. Recurrent HCC was confirmed by computed tomography (n = 7) or magnetic resonance imaging (n = 2) within 4 months (0–6) after first identifying an increase in the tumor marker levels. Six cases were treated surgically, two of which achieved prolonged survival of 16 and 38 months. Conclusion: Frequent measurement of α-fetoprotein and des-γ carboxy prothrombin was useful for detecting recurrent HCC and may be useful long-term follow-up markers for post-transplant surveillance.

Summary Reports of large series in living donor liver transplantation (LDLT) for hepatitis C virus infection (HCV) are scarce. Between 1996 and 2008, 105 LDLTs were performed at the University of Tokyo for HCV. Rapid induction of antiviral treatment with interferon (IFN) and ribavirin (RBV) was attempted per protocol regardless of the clinical presentation of recurrent HCV (pre-emptive treatment approach). Treatment was continued for 12 months after serum HCV-RNA became negative (ETR: end-of-treatment response) and judged as a sustained viral response (SVR) after another 6 months of negative results without treatment. A fixed treatment period was not defined unless an ETR was achieved (no-stopping approach). Flexible dose adjustments were allowed. Ninety-five patients were eligible for pre-emptive therapy. Forty-three (45%) patients experienced an ETR, and 32 (34%) achieved SVR. Nonadherence to full-dose INF and RBV had little impact on the viral response. Evaluation using the Kaplan–Meier method to incorporate the cumulative time-dependent nature of the no-stopping approach estimated SVR rate at 53% by the fifth year. Survival rate at 5 years was 79% for the HCV recipients and did not differ significantly from our non-HCV series. In LDLT for HCV, pre-emptive IFN–RBV-based treatment with the application of no-stopping approach is feasible and effective.

Objectives. Pseudomonas aeruginosa infection is a major cause of bacterial infection after deceased-donor liver transplantation. The incidence and risk factors of P. aeruginosa infection after living-donor liver transplantation (LDLT), however, are not known. Methods. We retrospectively reviewed the data from 170 adult patients who underwent LDLT at the University of Tokyo Hospital. The microbiologic and medical records of the patients from admission to 3 months after LDLT were reviewed. Uni- and multivariate analyses were performed to identify the independent risk factors for postoperative P. aeruginosa infection. Result. Preoperative P. aeruginosa carriage was identified in 15 (9%) patients. Only 2 of the 15 patients later presented with postoperative P. aeruginosa infection. Postoperative P. aeruginosa infection occurred in 27 (16%) of 170 patients by median postoperative day 38. Among those 27 patients, surgical site infections were recorded in 8 (30%) and intra-abdominal infections in 14 (52%). In 5 of the 27 (19%) patients, P. aeruginosa isolates were multiple antimicrobial resistant. Postoperative bile leakage independently predicted postoperative P. aeruginosa infection. Conclusion. P. aeruginosa infections were frequently detected after LDLT, including those by multiple antimicrobial-resistant isolates. Postoperative bile leakage predisposed patients to P. aeruginosa infection. Surveillance culture should be checked periodically after LDLT to ensure that appropriate antimicrobials can be administered for postoperative infection.

Early after liver transplantation, patients are in a hypercoagulable state because of an imbalance between coagulation and fibrinolysis because of the slow recovery of depleted anticoagulant proteins. Antithrombin (AT) is used in anticoagulant protocols to prevent thrombosis. The subjects of the present study were 17 men and eight women that underwent living donor liver transplantation. The initial 15 cases were administered AT concentrate (1500 U/day) on postoperative days (POD) 1 through 3 (AT group) and the following 10 consecutive cases were not administered AT (control). AT, thrombin-AT complex, plasmin-alpha2 plasmin inhibitor complex, thrombomodulin, fibrin degradation product D-dimer (FDP-DD) level, prothrombin time international normalized ratio, activated partial thromboplastin time, and platelet counts were measured. In the AT group, AT activity was maintained at levels >80% for 5 days after transplantation. In the control group, AT activity did not return to normal during the first 2 weeks after the operation. FDP-DD levels were significantly higher in the control group than in the AT group (P < 0.05). Six patients in the control group and three patients in the AT group required transfusions with platelet concentrate (P < 0.05). AT supplementation might reduce FDP-DD levels and prevent decreased platelet counts in the early stages after liver transplantation.

Recurrence of hepatitis and progression of fibrosis are major problems in liver transplantation (LT) for patients with hepatitis C. Liver stiffness measurement (LSM) by transient elastography correlates well with histologic liver fibrosis stages in chronic liver diseases. The aim of this study was to evaluate the usefulness of transient elastography for the assessment of fibrosis in patients after living donor LT.Seventy-nine patients who visited our institution, and in whom LSM was successfully evaluated, were enrolled in the study. The patients were divided into three groups according to positivity for hepatitis C antibody and hepatitis B surface antigen as the hepatitis C virus (HCV) group (n=37), the hepatitis B virus (HBV) group (n=10), and the NBNC (negative for both hepatitis B and C) group (n=32). The correlation between LSM and histologic fibrosis stage was assessed in 36 patients. LSM was also compared with regard to the effect of interferon therapy in HCV patients.The median value for liver stiffness was 6.8 kPa and the median time from LT was 3.1 years. In patients who underwent liver biopsy, stiffness was significantly correlated with the stages of fibrosis (p0.001, rho = 0.848). In patients who received interferon therapy after LT, the LSM decreased over time in those with a sustained virological response, whereas LSM increased in patients without a response.Transient elastography may be an appropriate non-invasive procedure to sequentially assess the progression of liver fibrosis in patients after LT.

Background/Aims: The influence of lymphocytotoxic crossmatch on survival or acute rejection in liver transplantation remains controversial. Data regarding graft survival and acute rejection of living donor liver transplantation (LDLT) are limited. Methods: We retrospectively examined the influence of a positive T or B lymphocytotoxic crossmatch on survival and acute rejection in patients using a database of 414 consecutive LDLT cases. Results: The rejection-free rate at 90 days after LDLT was lower in patients that were T crossmatch-positive compared to patients that were both T and B crossmatch-negative (52 vs. 74%, p = 0.03). No patients with a positive lymphocytotoxic crossmatch died due to immunologic causes. The crossmatch results had no effect on graft survival. Conclusion: In the positive crossmatch groups, there was no acute rejection that was untreatable or that caused graft loss. These findings indicate that a positive crossmatch graft should not be considered a contraindication for LDLT.

Background. Methicillin-resistant Staphylococcus aureus (MRSA) infection frequently complicates the postoperative course in deceased-donor liver transplantation. The incidence and risk factors of MRSA infection after Living-donor Liver transplantation (LDLT), however, are unclear. Methods. We retrospectively reviewed the data from 242 adult patients who underwent LDLT at the University of Tokyo Hospital. The microbiologic and medical records of the patients from admission to 3 months after LDLT were reviewed. Uni- and multivariate analyses were performed to identify the independent risk factors for postoperative MRSA infection. Results. Postoperative MRSA infection occurred in 25 of 242 patients by median postoperative day 23. Preoperative MRSA colonization, preoperative use of antimicrobials, operation time (≥16 h), and postoperative apheresis independently predicted postoperative MRSA infection. Conclusion. Surveillance culture should be checked periodically after admission to identify patients at high risk for MRSA infection and to administer appropriate antimicrobials for perioperative infection. Postoperative apheresis, suggesting postoperative liver dysfunction, predisposed patients to MRSA infection.

Summary Biliary complications remain the most challenging issue in adult living donor liver transplantation (LDLT) and to the best of our knowledge, no study has focused on the biliary complications in LDLT with right lateral sector graft (RLSG), a graft consisting of segments VI and VII according to Couinaud’s nomenclature for liver segmentation. Between January 1996 and October 2006, 310 LDLTs were performed for adult recipients at our institution. Among them, 20 patients received RLSG. The incidence of biliary complications during follow-up in these patients with RLSG was retrospectively analyzed. Follow-up period after transplantation ranged from 1 to 87 months (median 58 months). The 3-year and 5-year graft survival rates following the use of RLSGs in LDLT were 90% and 90%, respectively. Biliary complications were encountered in altogether nine patients. Two patients (10%) were complicated with bile leakage requiring surgical intervention. Seven patients (35%) were complicated with bile duct stenosis, which occurred with a median interval of 26 months (range: 6–51 months) after LDLT. Four were treated surgically and the other three were treated by endoscopic approach. Outcomes of the interventions were satisfactory in all cases. The incidence and severity of biliary complications after LDLT using RLSG was within an acceptable range with excellent graft survival. Accordingly, it is concluded that RLSG is a technically feasible option that may effectively expand the donor pool. Further application of RLSG is warranted.

A significant proportion of patients with chronic hepatitis C virus (HCV) infection develop liver cirrhosis and complications of end-stage liver disease over periods of two to three decades and require liver transplantation, although re-infection is common and leads to further adverse events, given that such patients receive life-long immunosuppression. Because of the critical organ shortage worldwide, living-donor liver transplantation has an important role in many countries, especially in the Far East. Despite previous arguments, the results of recent well-designed studies suggest equivalent outcomes for deceased-donor and living-donor liver transplantation. No specific immunosuppression regimen has proven advantageous, but the general rule is "low and slow". Combined pegylated interferon and ribavirin therapy is the current standard treatment, but compared to this therapy in the immunocompetent population, its efficacy in clearing the virus remains low. Moreover, its general application is hindered by the high prevalence of intolerability, lowering its efficacy from the aspect of intention to treat. Retransplantation becomes an option when treatment for disease progression fails, but it should be considered at an earlier stage in patients with a lower MELD (model for end-stage liver disease) score compared to that used for primary transplantation, which is a great challenge with the current critical organ shortage. The need for new anti-HCV drugs to further delay disease progression or even to enhance viral clearance, presumably specific HCV life-cycle inhibitors, is urgent. The liver transplant community must maintain an open mind regarding the development of these drugs and focus on their availability for early clinical trials in liver transplant recipients.

There are no detailed studies on the prevalence or clinical magnitude of bloodstream infection (BSI) following living donor liver transplantation (LDLT). The study aimed to assess the incidence and analyze the risk factors for BSI after LDLT. Univariate and multivariate analyses were performed to identify the independent risk factors for postoperative BSI. Postoperatively, 26 episodes of BSI occurred in 21 of 242 studied adult patients by median postoperative d 35. Five patients had primary BSI. The source was unknown in 3 patients and an intravascular catheter in 2. The other 16 patients had secondary BSI. Secondary BSI was caused by surgical site infection in 8 patients, followed by intra-abdominal infection in 5, pneumonia in 2, and both surgical site infection and intra-abdominal infection in 1. The most frequent pathogen isolated was MRSA, which was detected in 4 patients. Surveillance culture detected the same isolates prior to BSI in 14 of 26 (50%) episodes. Diabetes mellitus and serum albumin level less than 2.4 g/dl independently predicted postoperative BSI. Perioperatively, screening for and taking actions against pathogen including MRSA should be performed in LDLT patients.

Hepatitis B surface antigen-negative and hepatitis B core antibody-positive grafts were considered unsuitable for transplantation. The number of potential recipients for liver transplantation now exceeds that of potential donor organs, which has led us to reevaluate the feasibility of these grafts. Several strategies involving prophylactic administration of hepatitis B immunoglobulin and/or lamivudine to transplant recipients have been proposed. At the University of Tokyo, we have continued to use hepatitis B immunoglobulin monoprophylaxis with zero recurrence. In this article we report our experience with the use of hepatitis B surface antigen-negative/hepatitis B core antibody-positive grafts with hepatitis B immunoglobulin monotherapy. We conducted a review of the literature regarding the feasibility of these grafts to reconfirm optimal prophylactic strategies for preventing de novo hepatitis B virus infection in transplant recipients.

Management of immunosuppression for human immunodeficiency virus/hepatitis C (HIV/HCV) in living-donor liver transplantation (LDLT) has not been established. We performed LDLT for two patients with HIV/HCV-co-infected end-stage liver disease. The immunosuppression protocol consisted of early calcineurin inhibitor-free and interleukin-2 receptor antagonist (IL2Ra) induction and methylprednisolone. Maintenance low-dose tacrolimus was started and anti-retroviral therapy for HIV was re-started 1 week after LDLT. Consecutively, pegylated interferon and ribavirin therapy were successfully added as pre-emptive therapy for HCV. HIV-RNA and HCV-RNA were undetectable on anti-retroviral therapy and HCV treatment at 17 and 8 months after LDLT, respectively, with normal liver function. This study is the first report of early calcineurin inhibitor-free and IL2Ra induction with methylprednisolone immunosuppression in LDLT for HIV/HCV-co-infected patients with a favorable outcome. Consecutive HIV/HCV treatment was well tolerated.