Yoshinori Azumi

Paradoxical impact of the remnant pancreatic volume and infectious complications on the development of nonalcoholic fatty liver disease after pancreaticoduodenectomy

The aim of the present study was to evaluate perioperative risk factors for development of nonalcoholic fatty liver disease (NAFLD) after pancreaticoduodenectomy (PD), paying special attention to remnant pancreatic volume (RPV) and postoperative infection.

Thrombomodulin Administration Attenuates Ischemia-Reperfusion Injury of the Remnant Liver After 70% Hepatectomy in Rats: Simulated Model of Small-for-size Graft in Living Donor Liver Transplantation

BACKGROUND Hepatic ischemia-reperfusion injury (IRI) is a serious complication affecting liver function and postoperative course after liver transplantation. Thrombomodulin (TM) has been known to have anticoagulant and anti-inflammatory activities exerting a cytoprotective effect. We evaluated the cytoprotective effect of recombinant human soluble TM (rhsTM) on the remnant liver exposed to IRI after 70% hepatectomy in rats, which was the simulated model of small-for-size graft in living donor liver transplantation. MATERIALS AND METHODS A Wistar rat underwent 70% hepatectomy followed by 20-minute IRI for the remnant liver. rhsTM (1 mg/kg) (TM group) or saline (control group) was intravenously administered 30 minutes before operation. RESULTS Alanine aminotransaminase levels were more significantly decreased during the 24 hours after operation in the TM group than in control group, especially at 6 hours. Intrahepatic infiltration of macrophages/monocytes (ED-1 immunohistochemical staining) at 6 hours was significantly decreased in the TM group compared to the control group. The number of proliferating cell nuclear antigen-positive cells at 12 hours (hepatocyte proliferation) was significantly higher in the TM group than in the control group; although liver weight 7 days after operation did not differ between the two groups. Hepatocyte apoptosis (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling, also known as TUNEL assay) at 24 hours was more significantly diminished in the TM group than in the control group. CONCLUSION These results suggest that rshTM attenuates hepatocyte injury through its anti-inflammatory effect, and promotes hepatocyte proliferation in the reduced-size liver exposed to hepatic IRI.

A New Surgical Technique of Pancreaticoduodenectomy with Splenic Artery Resection for Ductal Adenocarcinoma of the Pancreatic Head and/or Body Invading Splenic Artery: Impact of the Balance between Surgical Radicality and QOL to Avoid Total Pancreatectomy

For pancreatic ductal adenocarcinoma (PDAC) of the head and/or body invading the splenic artery (SA), we developed a new surgical technique of proximal subtotal pancreatectomy with splenic artery and vein resection, so-called pancreaticoduodenectomy with splenic artery resection (PD-SAR). We retrospectively reviewed a total of 84 patients with curative intent pancreaticoduodenectomy (PD) for PDAC of the head and/or body. These 84 patients were classified into the two groups: conventional PD (n = 66) and PD-SAR (n = 18). Most patients were treated by preoperative chemoradiotherapy (CRT). Postoperative MDCT clearly demonstrated enhancement of the remnant pancreas at 1 and 6 months in all patients examined. Overall survival rates were very similar between PD and PD-SAR (3-year OS: 23.7% versus 23.1%, P = 0.538), despite the fact that the tumor size and the percentages of UICC-T4 determined before treatment were higher in PD-SAR. Total daily insulin dose was significantly higher in PD-SAR than in PD at 1 month, while showing no significant differences between the two groups thereafter. PD-SAR with preoperative CRT seems to be promising surgical strategy for PDAC of head and/or body with invasion of the splenic artery, in regard to the balance between operative radicality and postoperative QOL.

Immunological aspects in late phase of living donor liver transplant patients: usefulness of monitoring peripheral blood CD4+ adenosine triphosphate activity.

Aim. To evaluate whether the combination of the peripheral blood CD4+ adenosine triphosphate activity (ATP) assay (ImmuKnow assay: IMK assay) and cytochrome P450 3A5 (CYP3A5) genotype assay is useful for monitoring of immunological aspects in the patient followup of more than one year after living donor liver transplantation (LDLT). Methods. Forty-nine patients, who underwent LDLT more than one year ago, were randomly screened by using IMK assay from January 2010 to December 2011, and the complete medical records of each patient were obtained. The CYP3A5 genotypes were examined in thirty-nine patients of them. Results. The mean ATP level of the IMK assay was significantly lower in the patients with infection including recurrence of hepatitis C (HCV) (n = 10) than in those without infection (n = 39): 185 versus 350 ng/mL (P < 0.001), while it was significantly higher in the patients with rejection (n = 4) than in those without rejection (n = 45): 663 versus 306 ng/mL (P < 0.001). The IMK assay showed favorable sensitivity/specificity for infection (0.909/0.842) as well as acute rejection (1.0/0.911). CYP3A5 genotypes in both recipient and donor did not affect incidence of infectious complications. Conclusions. In the late phase of LDLT patients, the IMK assay is very useful for monitoring immunological aspects including bacterial infection, recurrence of HCV, and rejection.

Combination assays for evaluation of immune function and CYP3A5 genotype to identify the risk of infectious complications and mortality in living donor liver transplant patients.

BACKGROUND The aim of this study is to evaluate whether the combination of the ImmuKnow assay (IMK) and cytochrome P450 3A5 (CYP3A5) genotype assay is useful for identifying the risk of morbidity and mortality in living donor liver transplantation (LDLT) patients, and also to investigate the optimal cutoff value of IMK level of immune status. MATERIAL AND METHODS Sixty six LDLT patients, who were randomly screened by using IMK between March 2002 and June 2011, were divided into 2 groups: patients in whom at least 1 IMK value was <175 ng/mL (Group A, n=16) and patients in whom all IMK values were >175 ng/mL (Group B, n=50). Both donors and recipients were evaluated for the CYP3A5 genotype. RESULTS The frequencies of cytomegalovirus and bacterial infection in Group A were significantly higher than those in Group B (P<0.001). The short term mortality was 4 (25.0%) in Group A and none in Group B, and the IMK level in all four cases became <100 ng/mL at least one time before death. The rate of CYP3A5*1 allele (expressors) among recipients was significantly higher in Group A than in Group B (63.6% vs. 22.2%, P=0.0147). The rates of CMV infection and bacterial infection, and the IMK levels was significantly higher in recipients with expressors (p=0.0216, p=0.0332, and p=0.0433, respectively). CONCLUSIONS The combination of the IMK and CYP3A5 genotype assay is useful for monitoring immune status after LDLT, and the IMK level <100 ng/ml might be the critical level to make a recovery from the severe immunesupressive condition.

Factor Analysis Influencing Postoperative Hospital Stay and Medical Costs for Patients with Definite, Suspected, or Unmatched Diagnosis of Acute Cholecystitis according to the Tokyo Guidelines 2013

Purpose. To identify significant independent preoperative factors influencing postoperative hospital stay (PHS) and medical costs (MC) in 171 patients who underwent cholecystectomy for benign gallbladder diseases and had definite, suspected, or unmatched acute cholecystitis (AC) diagnosis according to the Tokyo Guidelines 2013 (TG13). Methods. The 171 patients were classified according to the combination of diagnostic criteria including local signs of inflammation (A), systemic signs of inflammation (B), and imaging findings (C): A+ B+ C (definite diagnosis, n = 84), A+ B (suspected diagnosis, n = 25), (A or B) + C (n = 10), A (n = 41), and B (n = 11). Results. The A+ B + C and (A or B) + C groups had equivalent PHS and MC, suggesting that imaging findings were essential for AC diagnosis. PHS and MC were significantly increased in the order of severity grades based on TG13. Performance status (PS), white blood cell count, and severity grade were identified as preoperative factors influencing PHS by multivariate analysis, and significant independent preoperative factors influencing MC were age, PS, preoperative biliary drainage, hospital stay before surgery, albumin, and severity grade. Conclusion. PS and severity grade significantly influenced prolonged PHS and increased MC.

Clinicopathological factors affecting survival and recurrence after initial hepatectomy in non-B non-C hepatocellular carcinoma patients with comparison to hepatitis B or C virus.

We evaluated clinicopathological factors affecting survival and recurrence after initial hepatectomy in non-B non-C (NBNC) hepatocellular carcinoma (HCC) patients with comparison to hepatitis B or C virus, paying attention to relationship between alcohol consumption and histopathological findings. The medical records on the 201HCC patients who underwent initial hepatectomy between January 2000 and April 2013 were retrospectively reviewed. NBNC patients had higher prevalence of hypertension (47.4%), diabetes mellitus (35.5%), alcohol consumption (>20 g/day) (61.8%), and preserved liver function than hepatitis B or C patients. The 5-year survival rate of NBNC patients (74.1%) was significantly better than hepatitis B (49.1%) or C (65.0%) patients (NBNC versus B, P = 0.031). Among the NBNC patients, there was no relationship between alcohol consumption and clinicopathological findings including nonalcoholic fatty liver disease activity score (NAS). However, the 5-year OS and RFS rates in the alcohol-unrelated NBNC patients tend to be better than in the alcohol-related. By multivariate analysis, independent factors for OS in NBNC patients were Child-Pugh B/C, intrahepatic metastasis (im), and extrahepatic recurrence. NBNC patients, who were highly associated with lifestyle-related disease and preserved liver function, had significantly better prognosis compared to hepatitis B/C patients; however, there was no association between alcohol consumption and histopathological findings.

Comparative Study on the Cytoprotective Effects of Activated Protein C Treatment in Nonsteatotic and Steatotic Livers under Ischemia-Reperfusion Injury

Activated protein C (APC) has cytoprotective effects on liver ischemia-reperfusion injury (IRI). However, it is unclear whether APC is beneficial in steatotic liver IRI. We compared the cytoprotective effects of APC in nonsteatotic and steatotic liver IRI. Methods. Mice fed either normal diets (ND mice) or high fat diets (HF mice), were treated with APC or saline (control) and were performed 60 min partial IRI. Moreover, primary steatotic hepatocytes were either untreated or treated with APC and then incubated with H2O2. Results. APC significantly reduced serum transaminase levels and the inflammatory cells infiltration compared with control at 4 h in ND mice and at 24 h in HF mice. APC inhibited sinusoidal endothelial injury in ND mice, but not in HF mice. In contrast, APC activated adenosine monophosphate-activated protein kinase (AMPK) phosphorylation in HF mice, but not in ND mice. In the in vitro study, APC significantly increased AMPK phosphorylation, ATP concentration, and survival rates of hepatocytes compared with control. Conclusion. During IRI in normal liver, APC attenuated initial damage by inhibiting inflammatory cell infiltration and sinusoidal endothelial injury, but not in steatotic liver. However, in steatotic liver, APC might attenuate late damage via activation of AMPK.

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.

A Novel Predictor of Posttransplant Portal Hypertension in Adult-To-Adult Living Donor Liver Transplantation: Increased Estimated Spleen/Graft Volume Ratio.

Background In adult living donor liver transplantation (ALDLT), graft-to-recipient weight ratio of less than 0.8 is incomplete for predicting portal hypertension (>20 mm Hg) after reperfusion. We aimed to identify preoperative factors contributing to portal venous pressure (PVP) after reperfusion and to predict portal hypertension, focusing on spleen volume-to-graft volume ratio (SVGVR). Methods In 73 recipients with ALDLT between 2002 and 2013, first we analyzed survival according to PVP of 20 mm Hg as the threshold, evaluating the efficacy of splenectomy. Second, we evaluated various preoperative factors contributing to portal hypertension after reperfusion. Results All of the recipients with PVP greater than 20 mm Hg (n = 19) underwent PVP modulation by splenectomy, and their overall survival was favorable compared with 54 recipients who did not need splenectomy (PVP ⩽ 20 mm Hg). Graft-to-recipient weight ratio had no correlation with PVP. Multivariate analysis revealed that estimated graft and spleen volume were significant factors contributing to PVP after reperfusion (P < 0.0001 and P < 0.0001, respectively). Furthermore, estimated SVGVR showed a significant negative correlation to PVP after reperfusion (R = 0.652), and the best cutoff value for portal hypertension was 0.95. Conclusions In ALDLT, preoperative assessment of SVGVR is a good predictor of portal hypertension after reperfusion can be used to indicate the need for splenectomy before reperfusion.