Toshio Kokuryo

Nagoya University, Nagoya-shi, Aichi-ken, Japan

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Publications (37)99.67 Total impact

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    ABSTRACT: Objectives This randomized clinical trial was designed to investigate whether inchinkoto has a hepatoprotective effect on postoperative outcome after major hepatectomy.Methods Sixty-one patients scheduled for major hepatectomy were randomly assigned to one of two groups in which preoperative inchinkoto was (inchinkoto group, n = 30) or was not (non-inchinkoto group, n = 31) administered. Inchinkoto was administered for at least 7 days before surgery. The primary endpoint was the incidence of post-hepatectomy liver damage. The expression of nuclear factor E2-related factor 2 (Nrf2) and other oxygen stress-related markers in the liver were also determined.ResultsThere was no significant difference in clinical characteristics between the inchinkoto and non-inchinkoto groups. Serum levels in liver function tests and incidences of post-hepatectomy liver failure did not differ significantly between the two groups. However, there was a significantly higher induction of antioxidant factors in the liver, such as Nrf2 protein and heme oxygenase-1 mRNA, after hepatectomy in the inchinkoto group than in the non-inchinkoto group.Conclusions The preoperative administration of inchinkoto did not have a significant impact on the overall outcome of major hepatectomy. However, inchinkoto induced the expression of Nrf2 during hepatectomy and may have exerted an antioxidative effect on the liver.
    HPB 02/2015; · 2.05 Impact Factor
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    ABSTRACT: Although an aggressive surgical approach to perihilar cholangiocarcinoma (PHC) has improved survival, a prognosis of advanced PHC remains unsatisfactory. The overexpression of mesenchymal-epithelial transition factor (MET) and recepteur d'origine nantais (RON) has been shown to be associated with poor prognosis in some types of cancer. One hundred sixty-nine patients who underwent histologically curative resection for PHC were subjected to immunohistochemical analysis for MET and RON. The association between a positive expression of MET or RON and clinicopathologic features as well as the patients' prognosis were analyzed. There were 27 patients (16 %) who had a positive expression for both MET and RON. Although clinicopathologic features in the either MET- or RON-negative group were not significantly different compared to the both MET- and RON-positive group, the prognosis tended to be worse in the patients with both MET and RON positivity. When the analysis was limited to patients with advanced-stage disease (stage III and IVa), a multivariate analysis revealed that both MET and RON positivity and lymph node metastasis were identified as independent poor prognostic factors. The overall survival rate for patients with both MET and RON positivity was worse than that with either MET or RON negativity in patients with advanced PHC. The poor prognosis in these patients was not associated with unfavorable clinicopathologic features. The examination of MET and RON expression in PHC may enable a tailored method for patient classification that could not otherwise be achieved using the conventional pathologic classification system.
    Annals of Surgical Oncology 01/2015; · 3.94 Impact Factor
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    ABSTRACT: RNA splicing is a fundamental process for protein synthesis. Recent studies have reported that drugs that inhibit splicing have cytotoxic effects on various tumor cell lines. In this report, we demonstrate that depletion of SNW1, a component of the spliceosome, induces apoptosis in breast cancer cells. Proteomics and biochemical analyses revealed that SNW1 directly associates with other spliceosome components, including EFTUD2 (Snu114) and SNRNP200 (Brr2). The SKIP region of SNW1 interacted with the N-terminus of EFTUD2 as well as two independent regions in the C-terminus of SNRNP200. Similar to SNW1 depletion, knockdown of EFTUD2 increased the numbers of apoptotic cells. Furthermore, we demonstrate that exogenous expression of either the SKIP region of SNW1 or the N-terminus region of EFTUD2 significantly promoted cellular apoptosis. Our results suggest that the inhibition of SNW1 or its associating proteins may be a novel therapeutic strategy for cancer treatment. © 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
    Cancer Medicine 12/2014;
  • Gan to kagaku ryoho. Cancer & chemotherapy 10/2014; 41(10):1212-5.
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    ABSTRACT: Hilar cholangiocarcinoma is clinically characterized by biliary obstruction in the porta hepatis. Because the boundary between the intrahepatic and extrahepatic bile duct is unclear, hilar cholangiocarcinoma can potentially arise from both ducts. Therefore, the definition of hilar cholangiocarcinoma remains under debate. In November 2013, the 6th edition of the General Rules for Clinical and Pathological Studies on Cancer of the Biliary Tract was released, following the American Joint Committee on Cancer (AJCC) or International Union Against Cancer (UICC) TNM system. In that edition, as an alternative to "hilar cholangiocarcinoma," the new term "perihilar cholangiocarcinoma" is defined as cholangiocarcinoma involving the perihilar bile duct, despite the presence or absence of a significant liver mass component. This definition clearly indicates that some intrahepatic as well as extrahepatic perihilar tumors are involved in the perihilar tumor category. From the clinical point of view, there is no need for a differential diagnosis between intrahepatic or extrahepatic tumors therefore, the new definition is readily applicable in multidisciplinary team management. Japanese clinicians were previously required to distinguish between the proper use of the AJCC/UICC and the Japanese staging systems, but now the current revision will allow the more convenient use of a single, globally standardized staging system in daily practice.
    Nihon Geka Gakkai zasshi. 07/2014; 115(4):201-5.
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    ABSTRACT: The objective of this study was to elucidate the role of toll-like receptor 4 (TLR4) in liver injury induced by biliary obstruction and subsequent intraportal lipopolysaccharide (LPS) infusion in rats. Biliary obstruction often leads to the development of bacterial translocation. Rats were subjected to either a sham operation (Sham group) or bile duct ligation for 7 days (BDL group). Seven days after each operation, LPS (0.5 μg) was injected through the ileocecal vein. In other experiments, rats that had undergone BDL were pretreated, prior to LPS challenge, with internal biliary drainage (Drainage group); intravenous TAK-242, a TLR4 inhibitor (TAK group); or intravenous GdCl3, a Kupffer cell deactivator (GdCl3 group). The expression of the TLR4 protein as well as the number of Kupffer cells in the liver were significantly increased in the BDL group compared with the Sham group. These changes were normalized after biliary drainage. The expression of TLR4 co-localized with Kupffer cells, which was confirmed by double immunostaining. Serum levels of liver enzymes and proinflammatory cytokines after intraportal LPS injection were significantly higher in the BDL group than in the Sham group. However, pretreatment with TAK-242 or GdCl3 strongly attenuated these changes to levels similar to those seen with biliary drainage.These results imply that blocking TLR4 signaling effectively attenuates liver damage to the same level as that observed with biliary drainage in rats with BDL and subsequent intraportal LPS infusion. TAK-242 treatment may be used for patients who are susceptible to liver damage by biliary obstruction and endotoxemia.
    AJP Gastrointestinal and Liver Physiology 12/2013; · 3.65 Impact Factor
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    ABSTRACT: In patients with luminal-type breast cancer (positive for ER and/or PgR), a complete consensus on the threshold indication for a combination of chemotherapy and endocrine therapy has not been achieved, especially for patients with HER2-negative luminal type (HNLT). Girdin, an actin-binding Akt substrate, plays a crucial role in the migration of cancer cells. This study examined the expression of Girdin in relation to clinicopathological features and other immunohistochemical markers (HER2, Ki-67), especially in patients with HNLT breast cancer. One hundred one breast cancer patients who underwent surgery were evaluated. Immunohistochemical staining was performed for Girdin and other biomarkers, such as ER, PgR, HER2, and Ki-67. Positive expression of Girdin was observed in 26 patients. The expression of Girdin was significantly associated with the incidence of lymph node metastases (p = 0.001). Among the other examined biomarkers, positive expression of Ki-67 also showed a significant association with the incidence of lymph node metastases (p = 0.04). In the HNLT breast cancer patients (n = 73), the 5-year recurrence-free survival rate was significantly lower (57 %) in patients with positive expression of both Girdin and Ki-67 than the rate in other patients (92 %) (p = 0.002). This study demonstrated that the expression of Girdin in invasive breast cancer is strongly associated with lymph node metastasis. The expression status of Girdin and Ki-67 can be a useful biomarker in stratifying patients with HNLT breast cancer into those with high risk of recurrence and the need for additional chemotherapy.
    Breast Cancer 10/2013; · 1.51 Impact Factor
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    ABSTRACT: The International Study Group of Liver Surgery (ISGLS) has defined bile leakage as a drain fluid-to-serum total bilirubin concentration (TBC) ratio (the bilirubin ratio) ≥3.0. The aim of the present study was to determine the clinical significance of this definition, and to outline characteristics of bile leakage in complex hepatectomy. The TBCs of the serum and drain fluid were measured on postoperative days (POD) 1, 3, and 7 in 241 patients who had undergone hepatobiliary resection. The validation of the bilirubin ratio and predictors of bile leakage were retrospectively assessed. Grade A, B, or C bile leakage was found in 23 (9.5 %), 66 (27.4 %), and 0 patients, respectively. The median duration of drainage was 27 days in grade B bile leakage. The sensitivity and specificity of the bilirubin ratio for detecting grade B bile leakage were 59 and 87 %, respectively. The area under the receiver operating characteristics curve of the drain fluid TBC on POD 3 had the highest predictive value: 68 % sensitivity and 76 % specificity for a drain fluid TBC of 3.7 mg/dL. The multivariate analysis demonstrated that operative time, left trisectionectomy, bilirubin ratio, and TBC of the drain fluid on POD 3 were independent predictors of grade B bile leakage. In complex hepatectomy, bile leakage develops most frequently after left trisectionectomy and often results in a refractory clinical course. The ISGLS biochemical definition is valid, and a combination of bilirubin ratio and drain fluid TBC may enhance risk prediction for grade B bile leakage.
    World Journal of Surgery 10/2013; · 2.35 Impact Factor
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    ABSTRACT: Inchinkoto (ICKT) is one of the most commonly used herbal medicines and is a hepatoprotective agent. Among the numerous chemical compounds included in ICKT, geniposide is the most abundant component. After oral intake, geniposide is converted into the active metabolite genipin by intestinal bacteria and absorbed in the portal circulation. The biological properties of ICKT and its major active ingredient genipin have been studied in numerous experiments using cells and animals. ICKT or genipin administration exerts a choleretic effect through upregulation of multidrug resistance-associated protein 2 in hepatocytes. ICKT also exerts antiapoptoic activity by inhibiting the transforming growth factor beta 1- or tumor necrosis factor alpha-dependent signaling pathway. The excessive inflammatory response induced by various forms of hepatic stress is also attenuated by ICKT preadministration. Proinflammatory cytokine-induced upregulation of inducible nitric oxide synthase is strongly attenuated by ICKT in both in vivo and in vitro experiments. Moreover, ICKT enhances antioxidant enzymes in the liver under oxidative stress. These experimental results clearly indicate the effects of ICKT on hepatic stress. To date, however, clinical data on the benefits of ICKT for liver disease are very rare. To extend the clinical applications of ICKT in humans, it is crucial to design and perform a rigorous clinical trial. In this review article, recent evidence relating to the hepatoprotective effects of ICKT in the field of basic and clinical science is summarized and discussed.
    Nippon Geka Gakkai zasshi 09/2013; 114(5):256-60.
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    ABSTRACT: BACKGROUND: The aim of this study was to determine the intrahepatic kinetics of different types of nitric oxide (NO) synthase, such as endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS), during repeated ischemia/reperfusion (I/R). METHODS: Three different protocols of hepatic I/R in rats were designed as follows: 60 min of ischemia and 30 min of reperfusion (I/R 60/30); 5 min of ischemia and 5 min of reperfusion (I/R 5/5); and repeating 15 min of ischemia and 5 min of reperfusion for four cycles (I/R 15/5 × 4). Intrahepatic NO levels were measured using a selective NO sensor. Changes in hepatic microcirculation during I/R 5/5 were investigated using intravital microscopy. Hepatic expression of eNOS, phospho-eNOS, and iNOS were evaluated during repeated I/R by Western blot, reverse transcription polymerase chain reaction, and immunohistochemistry. RESULTS: During I/R 60/30, intrahepatic NO levels gradually increased and then reached a plateau approximately 15 min after starting ischemia. During I/R 5/5, the sinusoids after 5 min reperfusion were dilated compared with the sinusoids before ischemia. The expression of phospho-eNOS during I/R 15/5 × 4 markedly increased during the first ischemia, and then the levels attenuated during the subsequent repeating I/R cycles; however, the expression of iNOS gradually increased, as observed by Western blot, reverse transcription polymerase chain reaction, and immunohistochemical analysis. An impact of NO production by phospho-eNOS activation during the superacute phase of I/R was also confirmed using pharmacologic NOS inhibitors. CONCLUSION: Our results firstly demonstrated an altered activation of the phospho-eNOS system and iNOS over the course of repeated hepatic I/R.
    Journal of Surgical Research 02/2013; · 2.12 Impact Factor
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    ABSTRACT: Objective: We determined whether there is a protective effect of branched-chain amino acid (BCAA) on hepatic ischemia/reperfusion (IR)-induced acute liver injury. Methods: Wister rats were divided into four groups: simple laparotomy with vehicle; simple laparotomy with BCAA (1 g/kg of body weight orally); IR (30 min clamp) with vehicle; and IR with BCAA. Serum liver function tests and the gene expression of adhesion molecules (ICAM and VCAM) and vasoconstrictor-related genes (endothelin-1) in the liver were examined. In the in vivo study, portal venous pressure, leukocyte adhesion, and hepatic microcirculation were evaluated. Furthermore, Kupffer cells were isolated and cultured with various concentrations of BCAA in the presence or absence of lipopolysaccharide (LPS). Results: Increased levels of liver function tests following IR were significantly attenuated by BCAA treatment. The increased expression of adhesion molecules and endothelin-1 were also significantly attenuated by BCAA treatment. Moreover, increased portal venous pressure, enhanced leukocyte adhesion, and deteriorated hepatic microcirculation following IR were all improved by BCAA treatment. In the experiment using isolated Kupffer cells, the expression of interleukin-6, interleukin-1β, and endothelin-1 in response to LPS stimulation was attenuated by BCAA in a dose-dependent fashion. Conclusions: These results indicate that perioperative oral administration of BCAA has excellent therapeutic potential to reduce IR-induced liver injury. These beneficial effects may result from the direct attenuation of Kupffer cell activation under stressful conditions.
    AJP Gastrointestinal and Liver Physiology 12/2012; · 3.65 Impact Factor
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    ABSTRACT: OBJECTIVE: To investigate the expression of calcitonin gene-related peptide (CGRP) and its role in the liver regeneration process after 70% hepatectomy (Hx). MATERIALS AND METHODS: Wistar rats were divided into eight groups based on time after Hx. Remnant liver samples were collected serially 0 h, 1 h, 6 h, 12 h, 1 d, 2 d, 7 d, and 14 d after Hx (n = 6 for each time point). The expression level of the calcitonin/CGRP gene in the remnant liver was measured. Western bolts and immunohistochemistry were performed to determine the levels of CGRP in the regenerating liver. Furthermore, CGRP8-37 (a CGRP receptor antagonist) was used to examine the role of CGRP during liver regeneration. RESULTS: A marked upregulation of the calcitonin/CGRP gene was observed immediately after Hx, and the protein levels of CGRP in the liver, which were measured by western blot and immunohistochemistry, also rapidly increased after Hx. The liver regeneration rate was significantly attenuated by an administration of CGRP8-37 2 d after Hx. The mitotic index was evaluated by histologic examination 1 and 2 d after Hx and was also significantly lower in the CGRP8-37 group. In addition, CGRP8-37 treatment inhibited the phosphorylation of extracellular-signal regulated kinase 1/2. The levels of early response genes, such as c-fos, c-jun, and c-myc, were also downregulated by CGRP8-37. CONCLUSION: The calcitonin/CGRP gene may have an important role in the early phase of liver regeneration after Hx.
    Journal of Surgical Research 12/2012; · 2.12 Impact Factor
  • Gan to kagaku ryoho. Cancer & chemotherapy 10/2012; 39(10):1483-5.
  • Toshio Kokuryo, Yukihiro Yokoyama, Masato Nagino
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    ABSTRACT: Cancer stem cells have been identified as cells with the capacity to self-renew and differentiate into multiple lineages of human malignancies. Cholangiocarcinoma is one of the most difficult intra-abdominal malignancies that can be treated using a surgical approach. Chemotherapy in addition to surgery is necessary to improve patient survival. However, its clinical benefit is limited, and, to date, no other effective anticancer drug is available for this disease. Several reports have shown the existence of cholangiocarcinoma stem cells. Cell surface antigens such as CD133, CD24, EpCAM, CD44, and others have been used to isolate cholangiocarcinoma stem cells. In general, enhanced expression of these markers in resected specimens of cholangiocarcinoma was associated with malignant potential. Distinct and specific pathways are expected to be present in cancer stem cells compared to other cancer cells that have no stem cell properties. To date, reports showing possible signaling pathways in cholangiocarcinoma stem cells are limited. More research is anticipated. Targeting therapies for surface molecular markers or specific signaling pathways of cholangiocarcinoma stem cells may be important in order to change the clinical outcome of patients with this disease. However, no clinical trial has been performed so far. This review will focus on the markers and signaling pathways used to define cholangiocarcinoma stem cells. A novel therapeutic approach of targeting cholangiocarcinoma stem cells will also be discussed.
    Journal of hepato-biliary-pancreatic sciences. 08/2012;
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    ABSTRACT: Hepatic ischaemia-reperfusion (IR) injury may lead to liver damage during liver surgery, and intrahepatic nitric oxide (NO) levels may play a role in this context. The aim of this study was to demonstrate real-time changes in intrahepatic NO concentration during IR and to correlate potential hepatic NO production with liver damage using a selective NO sensor. Wistar rats were exposed to 15 min of hepatic ischaemia followed by reperfusion, after which changes in intrahepatic NO levels were measured using an NO sensor. Additionally, rats were exposed to five successive periods of IR, each consisting of 15 min ischaemia followed by 5 or 15 min reperfusion, and hepatic damage was evaluated by blood tests and histological examination. Hepatic expression of Akt, phosphorylated Akt, endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS was examined at different time points during and after IR by western blot and immunohistochemical analysis. During ischaemia, intrahepatic NO levels increased and reached a plateau at approximately 10 min. Repeated 15 min ischaemia-5 min reperfusion cycles reduced the maximum amount of NO produced during ischaemia gradually, and almost no NO production was observed during the fifth period of ischaemia. NO production following repeated ischaemia was proportional to the degree of hepatic viability. Phosphorylated eNOS was upregulated and correlated with the level of NO production during hepatic ischaemia. Intrahepatic NO levels decrease during repeated IR in rats. Real-time monitoring of intrahepatic NO levels is useful for the prediction of IR-related liver injury during experimental liver surgery.
    British Journal of Surgery 05/2012; 99(8):1120-8. · 4.84 Impact Factor
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    ABSTRACT: Adipose tissue-derived mesenchymal stem cells (ADSCs) are an attractive source for regenerative medicine because they are easily accessible through minimally invasive methods. We investigated the efficacy of ADSC transplantation on outcome after hepatic ischemia-reperfusion and subsequent hepatectomy in rats. ADSCs were isolated from subcutaneous adipose tissue of rats. After clamping the hepatoduodenal ligament for 15 min, the rats were subjected to a 70% partial hepatectomy. After releasing the clamp, 2 × 10(6) ADSCs per rat were injected through the penile vein. Phosphate buffered saline was injected as a control. The parameters of hepatic regeneration, such as hepatic regeneration rate, mitotic index, and anti-proliferating cell nuclear antigen levels, were examined. Furthermore, the expression of hepatic regeneration-associated proteins and genes in the regenerating liver was determined. The hepatic regeneration rate 2 d after hepatectomy was significantly greater in the ADSC transplanted group compared with the sham group. Mitotic index, anti-proliferating cell nuclear antigen levels, and other regeneration-associated proteins in the liver were significantly higher in the ADSC transplanted group than the sham group on 1 d after hepatectomy. A number of hepatic regeneration-associated genes also were significantly upregulated in the ADSC transplanted group. These results indicate that ADSC transplantation may provide beneficial effects in the process of liver regeneration after hepatic ischemia-reperfusion and subsequent hepatectomy.
    Journal of Surgical Research 03/2012; 178(1):63-70. · 2.12 Impact Factor
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    ABSTRACT: The survival benefit of extended surgery for advanced pancreatic cancer has been denied by four randomized controlled trials. However, there still is confusion and conflict over the definition and effective treatment strategy for so-called locally advanced or borderline resectable pancreatic cancer. Although there are a number of reports that showed outcomes of preoperative chemotherapy or chemoradiotherapy for this disease, the definitions and treatment regimens described in these studies vary. Moreover, all of the studies were Phase I / II trials or retrospective analysis, and there is no Phase III trial currently focused on this issue. It is urgently necessary to establish an international consensus on the definition of borderline resectable pancreatic cancer. The usefulness of neoadjuvant treatment for this disease should also be elucidated in future clinical trials. In this review article, we discuss the current understanding and definition of borderline resectable pancreatic cancer, and the value of neoadjuvant treatment strategy for treating it.
    Gan to kagaku ryoho. Cancer & chemotherapy 03/2012; 39(3):337-41.
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    ABSTRACT: In the present study, we investigated whether α-bisabolol, a sesquiterpene alcohol present in essential oils derived from a variety of plants, has antitumor effects against pancreatic cancer. α-Bisabolol induced a decrease in cell proliferation and viability in pancreatic cancer cell lines (KLM1, KP4, Panc1, MIA Paca2), but not in pancreatic epithelial cells (ACBRI515). α-Bisabolol treatment induced apoptosis and suppressed Akt activation in pancreatic cancer cell lines. Furthermore, α-bisabolol treatment induced the overexpression of early growth response-1 (EGR1), whereas EGR1 siRNA decreased the α-bisabolol-induced cell death of KLM1 cells. Tumor growth in both subcutaneous and peritoneal xenograft nude mouse models was significantly inhibited by intragastric administration of 1000 mg/kg of α-bisabolol, once a week for three weeks. The results indicate that α-bisabolol could be a novel therapeutic option for the treatment of pancreatic cancer.
    Cancer Science 08/2011; 102(12):2199-205. · 3.53 Impact Factor
  • Cancer Research 01/2011; 70(8 Supplement):1571-1571. · 9.28 Impact Factor
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    ABSTRACT: Patients with hilar cholangiocarcinoma or hepatolithiasis often develop segmental cholangitis (SC), but it is unclear whether hepatectomy for patients with SC can be performed safely. Rats were subjected to segmental bile duct ligation (SBDL) with LPS (SC group) or a saline (Sham group) infusion into the bile duct of the ligated lobes. The rats were sacrificed at 3, 24 and 48 h after the SBDL. For another experiment, the rats were subjected to partial hepatectomy (PHx) for the ligated lobes. Hepatic regeneration rates and the expression of regeneration-associated genes were evaluated. In the SC group, severe parenchymal damage was observed in the acute phase (3 h). Altered gene expression in the liver in response to biliary infection occurred not only in the infected lobes but also in the non-infected lobes. In the rats of the SC group, both the hepatic regeneration rate and serum HGF levels were significantly lower than in the Sham group. These results clearly demonstrate that SC impairs the regeneration capacity of the contralateral remnant liver. Therefore, hepatectomy should be avoided for patients with SC even if it occurs in the part of the liver to be resected.
    HPB 12/2010; 12(10):664-73. · 2.05 Impact Factor