[show abstract][hide abstract] ABSTRACT: For the identification of susceptibility loci for primary biliary cirrhosis (PBC), a genome-wide association study (GWAS) was performed in 963 Japanese individuals (487 PBC cases and 476 healthy controls) and in a subsequent replication study that included 1,402 other Japanese individuals (787 cases and 615 controls). In addition to the most significant susceptibility region, human leukocyte antigen (HLA), we identified two significant susceptibility loci, TNFSF15 (rs4979462) and POU2AF1 (rs4938534) (combined odds ratio [OR] = 1.56, p = 2.84 × 10(-14) for rs4979462, and combined OR = 1.39, p = 2.38 × 10(-8) for rs4938534). Among 21 non-HLA susceptibility loci for PBC identified in GWASs of individuals of European descent, three loci (IL7R, IKZF3, and CD80) showed significant associations (combined p = 3.66 × 10(-8), 3.66 × 10(-9), and 3.04 × 10(-9), respectively) and STAT4 and NFKB1 loci showed suggestive association with PBC (combined p = 1.11 × 10(-6) and 1.42 × 10(-7), respectively) in the Japanese population. These observations indicated the existence of ethnic differences in genetic susceptibility loci to PBC and the importance of TNF signaling and B cell differentiation for the development of PBC in individuals of European descent and Japanese individuals.
The American Journal of Human Genetics 10/2012; 91(4):721-728. · 11.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: Japan-China Joint Medical Workshop (2012) on standardization of perioperative management on hepato-biliary-pancreatic surgery was held by the Center for Medical Standards Research, IRCA-BSSA Group in Japan on April 15-16, 2012. Experts in the fields of surgery, anesthesia, pharmacy, and public health from 21 health institutions from Japan and China presented their research achievements and shared their medical experience of perioperative management on hepato-biliary-pancreatic surgery, which should facilitate building of guidelines for hepatocellular carcinoma and be expected to promote standardized management of liver cancer in Asia.
Drug discoveries & therapeutics. 04/2012; 6(2):108-11.
[show abstract][hide abstract] ABSTRACT: Recurrence following liver transplantation for hepatitis C virus (HCV), which is universal, affects long-term outcomes. Treatment with interferon (IFN) and ribavirin (RBV), the only widely available options at this time, have been faced with low tolerability and overall unsatisfactory results in deceased donor liver transplantation (DDLT). However, its place after living donor liver transplantation (LDLT) remains a matter of debate. Since most LDLT cases are performed in a planned manner at a lower Model for End-stage Liver Disease (MELD) score compared to DDLT, we have aggressively applied preemptive INF/RBV in our series.
We studied 122 adult recipients who underwent LDLT for HCV-related end-stage liver disease. The preemptive IFN/RBV protocol initiated treatment promptly after improvement in the patient's general condition with a low-dose IFN alpha2b and RBV (400 mg/d) followed by a gradual increase in the INFalpha2b dosage. Finally, we applied pegylated IFN (1.5 ug/kg/wk) and RBV (800 mg/d). The treatment was continued for 12 months after serum HCV-RNA became negative, which was defined as the end-of-treatment response (ETR). The response was considered to be a sustained viral response (SVR) if there were negative serologic results without antiviral treatment for another 6 months. Splenectomy was performed at the time of LDLT to improve tolerability to INF/RBV. The median age of the patients was 55 yrs (range = 23-66), with male dominance (87 males and 35 females). Median MELD score was 14 (range = 6-48). The series included 72 patients with hepatocellular carcinomas, and six with HIV coinfections. In 98 cases, HCV genotype was 1b.
Overall survival at 5 years was 79%. Cumulative response rates under the protocol were ETR 56% and SVR 44% at 5 years.
Preemptive IFN/RBV therapy after LDLT for HCV is feasible with acceptable outcomes.
[show abstract][hide abstract] ABSTRACT: 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.
[show abstract][hide abstract] ABSTRACT: Duodenal adenocarcinoma is a relatively rare malignancy and pancreaticoduodenectomy would be a standard procedure to achieve curative resection. We report a case of resection of the 2nd portion of the duodenum with nodal dissection preserving the pancreas. The patient was a 75-year-old man with right-sided paresis suffering from early cancer in the 2nd portion of the duodenum. Despite 3 times of endoscopic mucosal resections, mucosal local recurrence was found. The depth of the tumour involvement continued to be limited within the mucosal layer. We performed segmental duodenal resection with nodal dissection sacrificing the minor papilla, while preserving the pancreas and the major papilla. The pathological diagnosis was primary intramucosal adenocarcinoma; the surgical margin was negative for cancer and there was no nodal metastasis. This procedure can be an alternative to pancreaticoduodenectomy in patients with earlystage adenocarcinoma in the 2nd portion of the duodenum when the major papilla can be spared, especially in high-risk patients.
[show abstract][hide abstract] ABSTRACT: For the identification of susceptibility loci for primary biliary cirrhosis (PBC), a genome-wide association study (GWAS) was performed in 963 Japanese individuals (487 PBC cases and 476 healthy controls) and in a subsequent replication study that included 1,402 other Japanese individuals (787 cases and 615 controls). In addition to the most significant susceptibility region, human leukocyte antigen (HLA), we identified two significant susceptibility loci, TNFSF15 (rs4979462) and POU2AF1 (rs4938534) (combined odds ratio [OR] = 1.56, p = 2.84 x 10(-14) for rs4979462, and combined OR = 1.39, p = 2.38 x 10(-8) for rs4938534). Among 21 non-HLA susceptibility loci for PBC identified in GWASs of individuals of European descent, three loci (IL7R, IKZF3, and CD80) showed significant associations (combined p = 3.66 x 10(-8), 3.66 x 10(-9), and 3.04 x 10(-9), respectively) and STAT4 and NFKB1 loci showed suggestive association with PBC (combined p = 1.11 x 10(-6) and 1.42 x 10(-7), respectively) in the Japanese population. These observations indicated the existence of ethnic differences in genetic susceptibility loci to PBC and the importance of TNF signaling and B cell differentiation for the development of PBC in individuals of European descent and Japanese individuals.
[show abstract][hide abstract] ABSTRACT: Thrombotic microangiopathy (TMA) is an infrequent but severe life-threatening disorder in solid organ transplant recipients. Few studies of TMA in living donor liver transplant (LDLT) recipients, however, have been reported. We investigated the clinical characteristics and prognostic factors of TMA after LDLT. Among 393 adult LDLT recipients, 30 patients (7.6%) were identified to have TMA. The 1-, 3- and 5-year survival rates of these patients were lower (60.6%, 52.5% and 47.7%, respectively) than those of patients without TMA (93.0%, 89.0% and 87.3%, respectively). Multivariate analysis confirmed that reduced administration of fresh frozen plasma and sensitization against HLA are closely related with TMA (odds ratio [OR]: 2.6 and 16.1, respectively). However, a review of the cases revealed that individual responses to treatment varied considerably and the main etiologies were difficult to determine. A comparison of the clinical factors suggested that late onset (>30 days), poor response to treatment and delayed diagnosis and/or treatment are associated with a poor outcome. Because the prevention of TMA in LDLT patients is difficult, early diagnosis and initiation of intensive therapies may be crucial to improve the prognosis.
American Journal of Transplantation 11/2011; 12(3):728-36. · 6.19 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
[show abstract][hide abstract] ABSTRACT: Once-daily tacrolimus (denoted here simply as OD) is a recently developed extended release drug formulation. The purpose of the present study was to pharmacokinetically evaluate tacrolimus exposure and determine the feasibility of its de novo use in liver transplant recipients in the perioperative period. This was an open-label, single center study. Eligible patients were 18 to 65 years of age in the perioperative period after a liver transplant. Patients were initially treated with intravenous tacrolimus and then converted to the 10× milligram-for-milligram daily dose of OD administered once daily. Twenty-four hour pharmacokinetic profiles were obtained on day 7 after the conversion. Laboratory and safety parameters were also evaluated. A total of 9 patients received OD, were successfully converted, and provided pharmacokinetic profiles. Intravenous tacrolimus and OD resulted in similar areas under the curve for 24 h (AUC0-24) of tacrolimus. OD was well tolerated with a safety profile comparable to that of intravenous tacrolimus. The AUC0-24 correlated with the minimum concentration of OD (R = 0.49). Renal and liver functions remained stable. None of the patients experienced acute rejection during the observation period. OD and intravenous tacrolimus provide equivalent drug exposure, allowing conversion of selected liver transplant recipients from intravenous tacrolimus to OD in the peri-operative period.
[show abstract][hide abstract] ABSTRACT: 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.
[show abstract][hide abstract] ABSTRACT: In a 53-year-old male who received a right liver graft from his son, computed tomography 1 week before living donor liver transplantation (LDLT) revealed three hepatocellular carcinoma (HCC) tumors in the liver that met the Milan criteria. Resected specimen revealed four tumors and microscopically, one of four HCC tumors in the resected whole liver comprised a glandular structure with spindle-like cells indicative of a sarcomatous change in HCC. Two hundred and sixty days after LDLT, the patient complained of left meralgia, which was diagnosed as iliac bone metastasis from HCC. Over a period of 3 months, the iliac bone metastasis rapidly enlarged. The tumor aggressively extended into the patient's bone marrow, causing severe pancytopenia. The patient died 371 days after LDLT. This tumor was detected preoperatively by computed tomography but lack of enhancement. These findings indicate that pathologic evaluation of each tumor is a key to predicting an accurate prognosis.
[show abstract][hide abstract] ABSTRACT: The rate of chronic pancreas graft loss in simultaneous pancreas kidney transplantation has remained almost unchanged despite induction therapy. Since 1987, seven major immunosuppressive induction agents-basiliximab, daclizumab, ALG, eATG, OKT 3, alembuzumab, rATG-have been used as immunosuppressive induction agents. Those agents improved short-term survival by preventing acute rejection, but improvement of short-term survival has not translated into improved long-term graft survival. As with most solid organ transplants, there is a need for means to control chronic rejection to improve long-term graft survival.
[show abstract][hide abstract] ABSTRACT: 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.
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.
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.
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.
[show abstract][hide abstract] ABSTRACT: Unfractionated heparin sodium (UFH) or low-molecular weight heparin (LMWH) is used in anticoagulant protocols at several institutions to prevent thrombosis after liver transplantation. Heparin-induced thrombocytopenia (HIT) is an adverse immune-mediated reaction to heparin, resulting in platelet count decreases of more than 50%. The frequencies of HIT after liver transplantation and platelet factor 4/heparin-reactive antibody (HIT antibody) positivity in liver transplantation patients, however, are unknown.
The 32 men and 20 women underwent living donor liver transplantation. We started LMWH (25 IU/kg/h) on postoperative day (POD) 1, switching to UFH (5000 U/d) on POD 2 or 3. The dose of UFH was changed according to the activated clotting time level. HIT antibody levels were measured the day before surgery and on POD 7 and 14. Platelet count was measured daily for 3 weeks.
The average platelet counts preoperatively, and on POD 7, 14, and 21 were 65, 88, 149, and 169 x 10(9)/L, respectively. Two patients developed hepatic artery thrombosis on POD 11 and 19, respectively, although they were HIT antibody-negative and their platelet counts were stable. In 2 other patients, the platelet count decreased suddenly from 107 x 10(9)/L on POD 4 to 65 x 10(9)/L on POD 6 and from 76 x 10(9)/L on POD 7 to 33 x 10(9)/L on POD 9, respectively. The heparin-induced platelet aggregation test was negative in these patients. The percentage of HIT antibody-positive patients was 0.5% preoperatively, 5.6% on POD 7, and 5.6% on POD 14. None of the subjects/patients developed UFH-related HIT.
In our series, the occurrence of HIT after liver transplantation was uncommon.
[show abstract][hide abstract] ABSTRACT: 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.
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.
Postoperative MRSA infection occurred in 25 of 242 patients by median postoperative day 23. Preoperative MRSA colonization, preoperative use of antimicrobials, operation time (> or =16 h), and postoperative apheresis independently predicted postoperative MRSA infection.
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.
[show abstract][hide abstract] ABSTRACT: Preoperative carriage of methicillin-resistant Staphylococcus aureus (MRSA) is associated with an increased risk of MRSA infection after liver transplantation. It is not known, however, whether new MRSA carriage postoperatively also increases the risk of MRSA infection after liver transplantation.
We retrospectively reviewed the data from 242 adult patients who underwent living donor liver transplantation (LDLT) including microbiological and medical records from admission to 3 months after LDLT. Uni and multivariate analyses were performed to identify independent risk factors for postoperative MRSA infection among preoperative noncarriers of MRSA.
Postoperative MRSA infection occurred in 18 of 219 preoperative noncarriers of MRSA by median postoperative day 26. Operation time of at least 16 hours and postoperative colonization with MRSA independently predicted postoperative MRSA infection.
Postoperative surveillance cultures should be performed periodically after liver transplantation to identify high-risk candidates for postoperative MRSA infection, even among preoperative noncarriers of MRSA.
[show abstract][hide abstract] ABSTRACT: 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.
International Journal of Laboratory Hematology 01/2008; 31(1):81-6. · 1.29 Impact Factor