Tomoharu Yoshizumi

Beneficial effects of splenectomy on massive hepatectomy model in rats.

Aim:  Possible spleno‐hepatic relationships during hepatectomy remain unclear. The purpose of this study was to investigate the impact of splenectomy during massive hepatectomy in rats.

Role of thymidine phosphorylase and orotate phosphoribosyltransferase mRNA expression and its ratio to dihydropyrimidine dehydrogenase in the prognosis and clinicopathological features of patients with pancreatic cancer

BackgroundThymidine phosphorylase (TP), orotate phosphoribosyltransferase (OPRT), and dihydropyrimidine dehydrogenase (DPD) are important enzymes related to the metabolism of 5-fluorouracil and its derivatives. In this study, we analyzed the expression of these enzymes and evaluated the association between the expression of these enzymes and clinicopathological features and prognosis in patients with pancreatic cancer.MethodsTP, OPRT, and DPD mRNA expressions were detected using a real-time reverse transcriptional-polymerase chain reaction method or by immunohistochemistry, using surgical specimens obtained from 25 patients with pancreatic cancer.ResultsTP mRNA expression was lower in cases with an alpha infiltration growth pattern than in cases with other infiltration growth patterns (P < 0.05). OPRT mRNA expression was higher in poorly differentiated-type cases than in differentiated type cases (P < 0.05). TP-, OPRT-, and DPD-positive stainings were found in 15 of 24 cases (63%), 10 of 19 cases (53%), and 14 of 21 cases (67%), respectively. There were significant correlations or trends between the mRNA and protein expressions of TP, OPRT, and DPD. Patients with a low TP/DPD ratio survived significantly longer than those with a high ratio (P < 0.05). Multivariate analysis demonstrated a significantly poorer outcome in patients with a high TP/DPD ratio compared with in patients with a low ratio (P < 0.05).ConclusionThe TP/DPD ratio might be useful as a prognostic factor in patients with pancreatic cancer.

Liver‐enriched transcription factor expression relates to chronic hepatic failure in humans

The mechanisms by which the liver fails in end‐stage liver disease remain elusive. Disruption of the transcription factor network in hepatocytes has been suggested to mediate terminal liver failure in animals. However, this hypothesis remains unexplored in human subjects. To study the relevance of transcription factor expression in terminal stages of chronic liver failure in humans, we analyzed the expression of liver‐enriched transcription factors (LETFs) hepatocyte nuclear factor (HNF)4α, HNF1α, forkhead box protein A2 (FOXA2), CCAAT/enhancer‐binding protein (CEBP)α, and CEBPβ. We then selected downstream genes responsible for some hepatic functions (ornithine transcarbamylase [OTC], cytochrome P450 3A4 [CYP3A4], coagulation factor VII [F7], cadherin 1 [CDH1], phospho‐ezrin (Thr567)/radixin (Thr564)/moesin (Thr558) [p‐ERM], phospho‐myosin light chain [p‐MLC], low‐density lipoprotein receptor‐related protein 1 [LRP1]) in liver tissue from patients at different stages of decompensated liver function based upon Child‐Pugh classification, Model for End‐Stage Liver Disease score, and degree of inflammatory activity/fibrosis. We first examined differential expression of LETF and determined whether a relationship exists between transcript and protein expression, and liver function. We found HNF4α expression was down‐regulated and correlated well with the extent of liver dysfunction (P = 0.001), stage of fibrosis (P = 0.0005), and serum levels of total bilirubin (P = 0.009; r = 0.35), albumin (P < 0.001; r = 0.52), and prothrombin time activity (P = 0.002; r = 0.41). HNF4α expression also correlated with CYP3A4, OTC, and F7 as well as CDH1 RNA levels. The Rho/Rho‐associated protein kinase pathways, which have been implicated in the regulation of HNF4α, were also differentially expressed, in concert with LRP1, a reported upstream regulator of RhoA function. Conclusion: HNF4α and other members of the LETFs appear to be important regulators of hepatocyte function in patients with chronic hepatic failure. (Hepatology Communications 2018;2:582‐594)

Chapter 23 – Role of Autophagy in Liver Regeneration

Abstract Autophagy regulates protein and organelle turnover and produces adenosine 5′-triphosphate (ATP) by using the amino acids from degraded proteins. We generated liver-specific autophagy-related gene 5 (Atg5)-knockout (KO) mice to investigate the activity of autophagy-associated pathways in liver regeneration after partial hepatectomy (PHx). The proliferation of remnant liver in Atg5 KO mice was severely impaired by 70% PHx with a reduction in postoperative mitosis, but a compensating increase in hepatocyte size. PHx injured cellular mitochondria and induced the intracellular ATP and β-oxidation reduction. Besides, hepatic accumulation of p62 and ubiquitinated proteins were enhanced. These results indicated that the reorganization of intracellular proteins and organelles during autophagy was impaired in the regenerating liver in this setting. Upregulation of p21 was associated with hepatocyte senescence and irreversible growth arrest. In the results, autophagy plays a critical role in regenerating liver and in the preservation of cellular quality by preventing hepatocytes from becoming fully senescent and hypertrophic in liver regeneration.

Microvascular Hepatic Artery Reconstruction in Living Donor Liver Transplantation

Even with the recent technical advances in the surgical procedures used for living donor liver transplantation (LDLT), hepatic artery reconstruction is still one of the most difficult procedures in LDLT (Matsuda et al., 2006; Eguchi et al., 2008). Because hepatic artery complications in liver transplantation, such as hepatic artery thrombosis (HAT) or hepatic artery dissection (HAD), often lead to devastating consequences, such as graft loss or patient death (Yanaga et al., 1990a; Settmacher et al., 2000; Stange et al., 2003), hepatic artery reconstruction should be performed using the most reliable procedure. A graft hepatic artery to be reconstructed in LDLT usually has a narrower caliber and a shorter stump compared to the arteries used during cadaveric liver transplantation. We introduced microvascular surgery for hepatic artery reconstruction in LDLT at the beginning of our LDLT program (Uchiyama et al., 2002). The use of microvascular surgery in LDLT was first reported in 1992 (Mori et al., 1992). Thereafter, many transplant centers introduced this technique for hepatic artery reconstruction in LDLT and confirmed that its application to hepatic artery reconstruction in LDLT decreased the number of hepatic artery complications (Inomoto, et al., 1996; Millis et al., 2000; Wei et al., 2004; Takatsuki et al., 2006; Panossian et al., 2009). We performed 401 cases of LDLT between October 1996 and June 2011 and almost all hepatic artery reconstructions were performed by microvascular surgery under a microscope. Microvascular surgery for hepatic artery reconstruction has been performed by general surgeons in our department. In this chapter, we present our microvascular surgical techniques used for hepatic artery reconstructions in LDLT and the outcomes of these reconstructions in 401 LDLT cases.