International consensus guidelines for surgery and the timing of intervention in chronic pancreatitis.

BACKGROUND/OBJECTIVES: Chronic pancreatitis (CP) is a complex inflammatory disease with pain as the predominant symptom. Pain relief can be achieved using invasive interventions such as endoscopy and surgery. This paper is part of the international consensus guidelines on CP and presents the consensus guideline for surgery and timing of intervention in CP. METHODS: An international working group with 15 experts on CP surgery from the major pancreas societies (IAP, APA, JPS, and EPC) evaluated 20 statements generated from evidence on 5 questions deemed to be the most clinically relevant in CP. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the level of evidence available for each statement. To determine the level of agreement, the working group voted on the 20 statements for strength of agreement, using a nine-point Likert scale in order to calculate Cronbach's alpha reliability coefficient. RESULTS: Strong consensus was obtained for the following statements: Surgery in CP is indicated as treatment of intractable pain and local complications of adjacent organs, and in case of suspicion of malignant (cystic) lesion; Early surgery is favored over surgery in a more advanced stage of disease to achieve optimal long-term pain relief; In patients with an enlarged pancreatic head, a combined drainage and resection procedure, such as the Frey, Beger, and Berne procedure, may be the treatment of choice; Pancreaticoduodenectomy is the most suitable surgical option for patients with groove pancreatitis; The risk of pancreatic carcinoma in patients with CP is too low (2% in 10 year) to recommend active screening or prophylactic surgery; Patients with hereditary CP have such a high risk of pancreatic cancer that prophylactic resection can be considered (lifetime risk of 40-55%). Weak agreement for procedure choice in patients with dilated duct and normal size pancreatic head: both the extended lateral pancreaticojejunostomy and Frey procedure seems to provide equivalent pain control in patients. CONCLUSIONS: This international expert consensus guideline provides evidenced-based statements concerning key aspects in surgery and timing of intervention in CP. It is meant to guide clinical practitioners and surgeons in the treatment of patients with CP.

Effect of portal haemodynamics on liver graft and intestinal mucosa after small-for-size liver transplantation in swine.

BACKGROUND: After small-for-size graft (SFSG) transplantation, elevated portal venous pressure (PVP) may lead to postoperative liver damage. Herein we evaluated the impact of portocaval shunt (PCS) to control PVP on liver grafts and intestine following SFSG transplantation. METHODS: Nineteen SFSG transplantations were performed with 30% of native liver in swine. Swine were divided into 3 groups: a high-flow shunt group (HS: n = 7), in which portal venous flow (PVF) was reduced with a 10-mm diameter PCS; a low-flow shunt group (LS: n = 6), in which PVF was reduced with a 5-mm diameter PCS, and a no-shunt group (NS: n = 6), in which no PCS was placed. RESULTS: Seven-day survivals were 83.3% in NS, 100% in LS and 0% in HS (p = 0.0088). PVP was significantly higher in the NS group (p = 0.0001; mean ± SEM NS/LS/HS: 20.5 ± 0.7/14.0 ± 1.2/11.6 ± 0.5 mm Hg). The LS group exhibited the highest compliance (PVF/PVP; NS/LS/HS 42.7 ± 10.9/44.6 ± 4.9/37.7 ± 8.3 ml/min/mm Hg; p = 0.009), the lowest aspartate aminotransferase (NS/LS/HS 562 ± 18/370 ± 55/720 ± 130 IU/l; p = 0.0493), and suppressed deleterious alternations of the hepatic parenchyma and intestinal mucosa. CONCLUSIONS: Portal hypertension after SFSG transplantation impaired liver and intestinal mucosa; however, inadequate portal flow impaired not only the liver, but also survival.

Protein C inhibitor regulates hepatocyte growth factor activator-mediated liver regeneration in mice.

BACKGROUND: We recently reported that human protein C inhibitor (PCI), a major inhibitor of activated protein C (APC), inhibits hepatocyte growth factor activator (HGFA) by forming HGFA-PCI complexes in vitro. In this study, we evaluated whether PCI regulates HGFA-mediated liver regeneration in a human PCI gene transgenic (hPCI-Tg) mouse model. METHODS AND RESULTS: After partial hepatectomy in hPCI-Tg and wild-type (WT) mice, the degree of liver regeneration, protein and mRNA expression of HGFA, proHGF activation, plasma levels of PCI and HGFA-PCI complex, and other markers were evaluated in the remnant liver. We also evaluated the effect of anti-human PCI antibody on liver regeneration, which significantly decreased in hPCI-Tg mice compared to WT mice. HGFA mRNA levels in naive and remnant livers after hepatectomy were the same in both WT and hPCI-Tg mice; however, plasma HGFA levels and HGF activation in the liver were lower in hPCI-Tg than in WT mice. There was no difference in plasma levels of transaminases and inflammatory cytokines. However, sinusoidal congestion and bleeding were detected and the serum hyaluronic acid level was elevated in hPCI-Tg mice, indicating that human PCI aggravates sinusoidal injury by inhibiting the cytoprotective effect of APC. APC decreased thrombin-induced IL-6 production in isolated hepatic nonparenchymal cells (NPCs) in vitro. This impaired liver regeneration was reversed by anti-human PCI antibody treatment in vivo. CONCLUSION: PCI regulates liver regeneration after hepatectomy by forming an HGFA-PCI complex and aggravates hepatic NPC injury by inhibiting the cytoprotective effect of APC. Anti-PCI antibody treatment may be a novel therapy for improving liver regeneration.

Feasibility and Outcomes of Direct Dual Portal Vein Anastomosis in Living Donor Liver Transplantation Using the Right Liver Graft With Anatomic Portal Vein Variations.

BACKGROUND: Portal vein (PV) reconstruction is a crucial factor in successful living donor liver transplantation (LDLT). In LDLT using the right liver grafts with anatomic PV variations, we sometimes encounter dual PV anastomosis. In this study we describe PV variations of donor liver in detail as well as our experiences with PV reconstruction in right liver grafts with PV variations. METHODS: We performed LDLT in 149 recipients between 2002 and 2016. PV variations of donor liver were classified into 3 major anatomic patterns, and we retrospectively analyzed the procedure and postoperative complications of PV anastomosis. RESULTS: PV variations in donor livers were classified as type A (normal type) in 125 patients, type B (trifurcation type) in 7 (4.7%), and type C (caudal origin of the right posterior branch) in 17 (11.4%). Among 75 right liver grafts, 10 (13.3%) had anatomic PV variations. In 9 of 10 recipients, dual PV of the graft were anastomosed to dual PV branches of the recipient in direct end-to-end fashion. In the remaining recipient, the posterior portal branch of the graft was anastomosed to the recipient portal trunk through the interposed venous graft in end-to-end fashion and the anterior portal branch of the graft was anastomosed to the side wall of the interposed venous graft. These 10 recipients did not develop any postoperative complications associated with PV anastomosis, although 3 of the 149 recipients (2.0%) developed complications associated with PV anastomosis, such as thrombosis and necrosis. CONCLUSION: Dual PV anastomosis of the right liver graft is safe and feasible in LDLT, even in anatomic PV variations.

Early Enteral Feeding of Daikenchuto Stimulates Early Bowel Movement With Increased Portal Venous Blood Flow After Living Donor Liver Transplantation.

Daikenchuto (DKT), a Japanese Kampo medicine, had been reported to increase small intestinal blood flow after liver resection. The aim of this study was to evaluate the effects of early enteral feeding of DKT on portal venous flow and early bowel movement after living donor liver transplantation (LDLT) in an attempt to clarify whether these effects on bowel motility can prevent bacterial and/or fungal translocation. MATERIALS AND METHODS: Our prospective study included the consecutive 16 LDLT recipients at Mie University Hospital between June 2006 and September 2009. Sixteen patients were divided into the 2 groups according to enteral feeding starting postoperative day (POD) 1: 8 patients in DKT (15 g/d) administration (DKT group, for 1 week) and 8 patients in tepid water administration (non-DKT group, for 1 week). Portal venous flow, portal venous pressure, presence of fungal infection (serum level of ß-D-glucan and fungal polymerase chain reaction assay), time to first food intake, and time to first defecation were serially examined. RESULTS: Portal venous flow (mean [SD] velocity) was significantly increased in DKT group compared with non-DKT group: 47.5 (12.9) vs 31.8 (15.4) (P = .04) on POD 1, 46.8 (11.5) vs 28.8 (12.5) (P = .03) on POD 3, and 42.3 (17.2) vs 25.2 (9.0) (P = .05) on POD 5. However, mean (SD) portal venous pressures did not significantly change between the 2 groups. Between the 2 groups (DKT vs non-DKT), the day of first oral intake was not significantly different: 6.9 (2.5) vs 11.3 (8.7) (P = .061), but the mean (SD) day of first defecation was significantly shorter in the DKT group: 3.9 (1.1) vs 5.5 (2.6) (P = .02). Although fungal polymerase chain reaction assay was not significantly different between the 2 groups (4 vs 4 positive cases), the mean (SD) serum levels of ß-D-glucan were significantly lower in the DKT group than in the non-DKT group: 9.0 (7.4) vs 18.4 (15.9) pg/mL (P = .04). CONCLUSION: Early enteral feeding of DKT after LDLT increased portal vein blood flow without increasing portal vein pressure and stimulated early bowel movement, which in turn might prevent fungal translocation.

De Novo Malignancy Following Adult-to-Adult Living Donor Liver Transplantation Focusing on Posttransplantation Lymphoproliferative Disorder.

OBJECTIVE: In patients with living donor liver transplantation (LDLT), late-onset complications sometimes develop because of long-term use of immunosuppressive drugs. One of the immunosuppressive drug-related complications is de novo malignancies resulting in reduced survival. PATIENTS AND METHODS: Among 153 patients undergoing LDLT, we retrospectively reviewed the medical records of 97 adult recipients (February 2002 to May 2017), who had been followed-up at our hospital for more than one year after LDLT. The median age was 52 years old (20-70) and the median observational period was 6.9 years (2.4-15.3). RESULTS: De novo malignancy after adult LDLT developed in 11.3% (11/97) of patients, including posttransplantation lymphoproliferative disorder (PTLD) (n = 4) (2 in the brain and 2 in abdominal lymph nodes), lung cancer (n = 1), pancreatic cancer (n = 1), gastric cancer (n = 1), laryngeal cancer (n = 1), lower gingival cancer (n = 1), bladder cancer (n = 1), and melanoma (n = 1). Age at cancer diagnosis ranged from 36 to 70 years old with an average age of 61 years. The interval from LDLT to cancer diagnosis was 8.3 years (3.9-12.2). Four patients (36.6%) including PTLD (n = 2), lung cancer (n = 1), and pancreatic cancer (n = 1) died of cancer and all of them were diagnosed with cancer within 10 years after LDLT. Six patients were diagnosed with cancer more than 10 years after LDLT and all of them survived after treatment of cancer. CONCLUSION: De novo malignancy was found in 11.3% of LDLT patients, and more than half of this population subset developed tumors 10 years after LDLT. Long-term close follow-up should be performed by taking any kinds of de novo malignancy into consideration.

Biliary Complications During and After Donor Hepatectomy in Living Donor Liver Transplantation Focusing on Characteristics of Biliary Leakage and Treatment for Intraoperative Bile Duct Injury.

BACKGROUND: Biliary complication is one of the major donor complications during and after hepatectomy in living donor liver transplantation (LDLT). We evaluated risk factors for donor biliary complication in adult-to-adult LDLT. PATIENTS AND METHODS: From March 2002 to November 2016, 126 consecutive patients who underwent donor hepatectomy in adult-to-adult LDLT were divided into 2 groups according to biliary compilations: nonbiliary complication (non-BC) group (n = 114) and biliary complication (BC) group (n = 12). RESULTS: Among 126 donor hepatectomies, 35 patients (28%) experienced perioperative complications, including 10 (7.9%) with Clavien-Dindo classification grade III. Biliary complications occurred in 12 patients (9.5%): bile leakage in 10 and intraoperative bile duct injury in 2. Additional computed tomography- and/or ultrasound-guided drainage or exchange of original drain was required in 7 patients. In comparison between BC and non-BC groups, future remnant liver volume was significantly higher in the BC group than in the non-BC group (63% vs 40%; P = .02). In multivariate analysis, larger future remnant liver volume (P = .005) and shorter operating time (P = .02) were identified as independent risk factors for biliary complications. We had 2 patients with intraoperative bile duct injury: both were successfully treated by duct-to-duct biliary anastomosis with insertion of biliary stent or T-tube. CONCLUSION: Large remnant liver volume was a significant risk factor for biliary complications, especially biliary leakage, after donor hepatectomy. For intraoperative bile duct injury, duct-to-duct anastomosis with biliary stent is a feasible method to recover.

Recombinant Human Soluble Thrombomodulin Attenuates Hepatic Ischemia and/or Reperfusion Injury by Inhibiting Leukocyte Accumulation in Mice With Normal and Fatty Liver.

In an attempt to increase the number of donor livers, there has been an increased use of marginal donor livers, such as steatotic (fatty) livers that increase susceptibility to ischemia and reperfusion injury (IRI). Inflammatory cell accumulation has a greater role in IRI in steatotic liver than in normal liver. Although the recombinant human soluble thrombomodulin (rhsTM) attracts attention as a new treatment for disseminated intravascular coagulation, the therapeutic efficacy of rhsTM in hepatic IRI remains uncertain, especially in fatty livers. We aimed to demonstrate the effect of rhsTM on hepatic IRI using well-established in vivo experimental models with steatotic liver. METHODS: C57/BL6 mice were divided into 2 groups: normal liver (NL) group and fatty liver (FL) group, in which the steatotic liver was induced by high-fat diet for 9 weeks. The mice in the NL and FL groups were premedicated with venous injection of rhsTM (TM) or saline (Control) as control groups. All 4 groups (NL-Control vs NL-TM, FL-Control vs FL-TM) were subjected to partial hepatic warm ischemia followed by reperfusion. RESULTS: rhsTM significantly attenuated liver injury in the FL group as well as the NL group, as evidenced by transaminase levels and histologic finding after hepatic IRI. rhsTM remarkably decreased the accumulation of inflammatory cells, such as macrophages and neutrophils, in both NL and FL tissue after IRI. Furthermore, rhsTM depressed mRNA and protein expressions of adhesion molecules such as intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 in both NL and FL groups after IRI. CONCLUSION: Our results demonstrate that rhsTM has a protective effect on fatty liver as well as normal liver after hepatic IRI. They also suggest that rhsTM contributes to attenuation of leukocyte accumulation caused by depressing expressions of adhesion molecules that facilitate accumulation of leukocytes in liver tissue in hepatic IRI.

Isolated Biliary Fistula After Donor Right Hepatectomy and Its Novel Interventional Treatment: Isolated Liver-Punctured Drainage.

Isolated biliary leakage is difficult to manage, and afflicted patients often develop refractory fistula. The present case was a 43-year-old male donor whose wife developed acute fulminant liver failure. Computed tomography (CT) volumetry showed that the estimated remnant liver volume was only 394 mL (31%) if his right lobe would be harvested. Since remnant liver volume was marginal, our proposed cut line for the right hepatectomy was set in order to preserve branches of the middle hepatic vein draining segments 4b+8 and 5. Right hepatectomy was performed, but on postoperative day 14, the donor developed fever and right back pain, and enhanced CT showed a 6 cm intra-abdominal abscess at the site of cutting, and we diagnosed it as an isolated biliary fistula since the isolated segment 5/8 was receiving arterial blood supply and exhibiting regrowth. A transabdominal abscess drainage was performed, after which the patient lost 30 to 50 mL of bile juice per day in drainage until 2 months after the drainage procedure. Ethanol injection, acetic acid injection, and transarterial or portal embolization for the isolated liver were proposed, but these all were impossible to carry out because there were no accessible routes. Thus, re-abscess drainage with a 7-French drainage catheter was performed through the isolated liver on postoperative day 53, and the isolated functional liver was punctured to induce liver atrophy. After this drainage, the isolated liver started to shrink and bile output had been stopped. In conclusion, our punctured-liver drainage could be effective for the treatment of isolated biliary fistula, allowing physicians to avoid an invasive additional liver resection or other invasive percutaneous approach using chemical reagents.

Intravenous Administration of Tacrolimus Stabilizes Control of Blood Concentration Regardless of CYP3A5 Polymorphism in Living Donor Liver Transplantation: Comparison of Intravenous Infusion and Oral Administration in Early Postoperative Period.

BACKGROUND: We compared achievement rate of sufficient tacrolimus blood concentration in the early postoperative period and incidence of acute cellular rejection within 1 month after living donor liver transplantation (LDLT) between tacrolimus intravenous (IV) and oral administration groups. METHODS: From October 2005 to November 2016, 61 LDLT patients administered tacrolimus, who could be genotyped for CYP3A5*3 and *1, were chosen from the electronic record database. The patients were then divided into the 2 groups (an IV group [n = 38] and an oral group [n = 23]). We defined patients with 1*1 or *1*3 as expressors and those with *3*3 as nonexpressors. Sufficient trough level tacrolimus blood concentration on postoperative day (POD) 3 was defined as 10-20 ng/mL. RESULTS: Comparable concentrations were seen between the 2 groups, with mean blood concentration 13.7 ± 8.5 ng/mL in the oral group and 15.2 ± 4.3 ng/mL in the IV group. Achievement rate of sufficient tacrolimus concentration on POD 3 was significantly higher in the IV group than in oral group: 97% (37 of 38) vs 65% (15 of 23), respectively (P = .001). When we focused on achievement rate in the oral group according to CYP3A5 polymorphism, the frequency of expressors (17%) was significantly lower than that of nonexpressors (82%) (P = .016). However, in the IV group this negative influence was totally eliminated, resulting in high achievement rates regardless of CYP3A5 polymorphism. In terms of incidence of acute cellular rejection, there was no significant difference between the 2 groups (IV 32% vs oral 17%, P = .250). CONCLUSION: IV administration of tacrolimus allowed us to obtain more stable control of blood concentration regardless of CYP3A5 genotype.

Percutaneous drainage of pancreatic fistula following pancreatectomy with CT-fluoroscopic guidance.

PURPOSE: To evaluate the clinical utility of percutaneous drainage of pancreatic fistula following pancreatectomy with real-time CT-fluoroscopic guidance. MATERIAL AND METHODS: During January 2007 through March 2013, of 295 patients who underwent pancreatectomy, 20 patients received percutaneous drainage of pancreatic fistula with real-time CT-fluoroscopic guidance. The mean diameter of pancreatic fluid collections was 8.1±2.7 (SD)cm (range: 3.5-15.0cm). Feasibility, safety, and clinical success were evaluated. Primary and secondary clinical successes were defined respectively as the resolution of pancreatic fistula by initial drainage alone, and after additional intervention. Factors affecting primary clinical success and the drainage period were also evaluated. RESULTS: Drainage catheters were placed in planned sites in all patients. No major complication occurred except in 1/20 patient (5%) who experienced endotoxin shock. Primary and secondary clinical success rates were, respectively, 50% (10/20) and 90% (18/20). An amylase level greater than 30,000IU/L in the fluid collection was a significant factor lowering the primary clinical success rate (P<0.02) and prolonging the drainage period (>30 days) (P<0.02). CONCLUSION: Real-time CT-fluoroscopic guided drainage is a feasible, safe, and useful therapeutic option for the management of pancreatic fistula after pancreatectomy. The fluid amylase level is a useful indicator to predict refractory pancreatic fistula.

Pretransplant Serum Hyaluronic Acid Can Be a Biomarker as a Prognostic Predictor in Adult-to-Adult Living Donor Liver Transplantation.

OBJECTIVE: The goal of this study was to evaluate whether pretransplant serum hyaluronic acid (HA) levels can predict outcomes after adult-to-adult living donor liver transplantation (LDLT). METHODS: In study I, 21 patients who underwent LDLT (March 2002-February 2004) were divided into 2 groups: the H-I group (HA ≥500 ng/mL; n = 12) and the L-I group (HA <500 ng/mL; n = 9). The influence of pretransplantation HA levels on short-term surgical outcome was investigated. In study II, 77 LDLT patients (May 2004-December 2014) were also divided into 2 groups: the H-II group (HA ≥500 ng/mL; n = 40) and the L-II group (HA <500 ng/mL; n = 37). We compared long-term survival and investigated prognostic factors. RESULTS: In study I, HA levels significantly decreased after LDLT, and those in the H-I group were significantly higher compared with the L-I group at 1, 3, 5, and 7 days after LDLT. There were significant differences in postoperative peak total bilirubin levels (H-I vs L-I, 17.2 vs 6.2 mg/dL; P = .013), peak ascitic fluid volume (1327 vs 697 mL/d; P = .005), and the hepatocyte growth factor levels at 3 days after LDLT (1879 vs 1092 pg/mL; P = .03). In study II, the 1- and 5-year survival rates were significantly lower in the H-II group than in the L-II group (H-II vs L-II, 65.0% and 48.5% vs 86.5% and 80.8%; P = .004). In multivariate analysis, significant prognostic factors were preoperative HA ≥500 ng/mL (P = .004) and graft to recipient body weight ratio <0.8 (P = .042). CONCLUSIONS: Preoperative HA level can be a prognostic risk factor. Patients with high HA levels are vulnerable and should be carefully managed after LDLT.

D-MELD, the Product of Donor Age and Preoperative MELD, Predicts Surgical Outcomes After Living Donor Liver Transplantation, Especially in the Recipients With HCV-positive and Smaller Grafts.

BACKGROUND: Appropriate donor-recipient match has not been explored well in living-donor liver transplantation (LDLT) unlike deceased-donor liver transplantation. In this study, we evaluate the donor-recipient match using D-MELD (donor age × recipient Modified for End-stage Liver Disease [MELD] score) as a predictor of surgical outcomes in LDLT, paying attention to graft size and hepatitis C virus (HCV) status. PATIENT AND METHODS: The 120 consecutive recipients who received adult-to-adult LDLT from March 2002 to December 2014 were divided into the two groups according to D-MELD score: D-MELD <1000 (low-D-MELD: n = 101) and D-MELD ≥1000 (high-D-MELD: n = 19). RESULTS: The 90-day mortality rate was significantly higher in the high-DM group than in low-DM group: 36.8% versus 14.9% (P = .046). In the HCV-positive recipients, the 90-day mortality rate was significantly higher in high-DM group (n = 6) than in low-DM group (n = 37): 66.7% versus 13.5% (P = .012), and the 3-year survival rate was significantly lower in high-DM group than in the low-DM group: 33.3% versus 56.8% (P = .01). In the recipients with left graft, the 90-day mortality rate was significantly higher in the high-DM group (n = 8) than in the low-DM group (n = 41): 50% versus 14.6% (P = .044), and total bilirubin level on postoperative day 14 was significantly higher in the high-DM group than in the low-DM group: 17.4 mg/dL versus 9.2 mg/dL (P = .018). CONCLUSIONS: It was clarified that D-MELD could predict early and long-term surgical outcomes in the recipients who were HCV-positive and who had smaller grafts.

Pre-operative Assessment of Psychological Characteristics and Mood States in Living Donor Kidney and Liver Transplantation.

BACKGROUND: Past studies have indicated that psychological problems in both transplant recipients and donors increase during the pre-operative period. However, few studies have evaluated the pre-operative psychological status of both the recipient and the donor. METHODS: This study included the donors and recipients of 36 adult living donor kidney transplants (LDKT) and 12 adult living donor liver transplants (LDLT) between January 2012 and December 2014. Their personalities were assessed using the Tokyo University Egogram (TEG) and the Yatabe-Guilford Personality Inventory (Y-G), while their mood states just before transplantation were evaluated via the Profile of Mood States (POMS). RESULTS: On the TEG, the mean Adapted Child (AC) score of the LDLT recipient group was significantly lower than that of the LDKT recipient group. On the Y-G, no differences in the distribution of the five personality types were recognized among the four groups. POMS depression scores in the LDLT recipient group were significantly higher compared with the other groups. CONCLUSION: LDLT recipients exhibited a depressive mood just before transplantation, and also had a low AC score. Therefore, clinicians should pay careful attention to potential medical non-adherence and post-operative depression in LDLT recipients. Based on these pre-operative assessments of personality and mood states, the transplant team should include post-operative care to support the quality of life of the recipients as well as the donors.

Long-Term Influence of CYP3A5 Gene Polymorphism on Pharmacokinetics of Tacrolimus and Patient Outcome After Living Donor Liver Transplantation.

BACKGROUND: We investigated a long-term association between donor/recipient CYP3A5 polymorphisms, pharmacokinetics of tacrolimus, and recipient outcomes in settings of living donor liver transplantation (LDLT). METHODS: From February 2002 to November 2009, 67 couples of donor/recipients with tacrolimus administration, who could be genotyped for CYP3A5*3 and *1, were eligible in this study. We compared the dose-adjusted trough levels (C/D ratio) and dose/weight ratio of tacrolimus at 1 to 36 months postoperatively and recipient prognosis according to donor/recipient CYP3A5 polymorphisms; *1*1 in 7, *1*3 in 15, and *3*3 in 45, based on recipient genotype, and *1*1 in 1, *1*3 in 28, and *3*3 in 38, based on donor genotype. RESULTS: On the basis of the data from C/D ratio and dose/weight ratio of tacrolimus, the recipients who had *1 allele and/or whose donor had *1allele required significantly high doses of tacrolimus with, compared with those without, all through 3 years after transplantation. These data allowed us to show the importance of not only recipient CYP3A5 polymorphisms but also donor polymorphisms to obtain the target tacrolimus blood concentration. The overall survival rates of the recipients with *1*1 (5-year survival rate: 28.6%) were significantly unfavorable, which might have been caused by over-immunosuppression, compared with those with *1*3 (5-year survival rate: 78.8%) and *3*3 genotype (5-year survival rate: 84.3%). CONCLUSIONS: Immune suppressive therapy with the use of tacrolimus should be tailored on the basis of CYP3A5 genotype, which may reduce the adverse effects and improve graft outcome.

Discontinuation of Hepatitis B Immunoglobulin by Long-term Hepatitis B Vaccine Inoculation in Preventing Hepatitis B Recurrence After Liver Transplantation.

INTRODUCTION: For the patients undergoing liver transplantation for hepatitis B virus (HBV)-related diseases, hepatitis B immunoglobulin (HBIG) should be administered to prevent reinfection. Because HBIG is highly expensive and a blood product, an alternative strategy using HBV vaccination has been made in an attempt to discontinue use of HBIG. The aim of this study was to evaluate the impact of long-term HBV vaccination for discontinuation of HBIG, paying attention to the status of active immunization using T-cell proliferation assay. PATIENTS AND METHODS: Among the 144 recipients who underwent liver transplantation in our hospital, 16 had HBV-related liver diseases; the 14 patients who had received vaccination were subjects in our study. To evaluate the status of active immunization, T-cell proliferation was examined by counting the number of T cells after adding HBV vaccine to the culture supernatant of T cells, and tumor necrosis factor α and interferon γ were measured in the culture supernatant. RESULTS: The ratio of male/female was 13/1 (median age: 55 years; range: 37 years to 67 years). The median follow-up time was 102 months (range: approximately 14 months to 148 months). All 14 patients were free of HBV recurrence. HBIG-free status could be achieved in 9 patients (64.3%) during the treatment period for more than 50 months after beginning of HBV vaccination, of whom 5 (35.7%) became HBV vaccine-free. T-cell proliferation was confirmed by fact that the stimulation index ranged from 2.34 to 5.2 in the patients who were HBIG-free. CONCLUSION: Long-term HBV vaccination after LT is a useful and effective treatment in preventing HBV recurrence, allowing the discontinuation of HBIG treatment.