Acta Medica Okayama542013CD14 upregulation as a distinct feature of non-alcoholic fatty liver disease after pancreatoduodenectomy189195ENDaisukeSatohTakahitoYagiTakeshiNagasakaSusumuShinouraYuzoUmedaRyuichiYoshidaMasashiUtsumiTakehiroTanakaHiroshiSadamoriToshiyoshiFujiwaraAIM: To investigate the pathogenesis of non-alcoholic fatty liver disease (NAFLD) after pancreatoduodenectomy (PD).
METHODS: A cohort of 82 patients who underwent PD at Okayama University Hospital between 2003 and 2009 was enrolled and the clinicopathological features were compared between patients with and without NAFLD after PD. Computed tomography (CT) images were evaluated every 6 mo after PD for follow-up. Hepatic steatosis was diagnosed on CT when hepatic attenuation values were 40 Hounsfield units. Liver biopsy was performed for 4 of 30 patients with NAFLD after PD who consented to undergo biopsies. To compare NAFLD after PD with NAFLD associated with metabolic syndrome, liver samples were obtained from 10 patients with NAFLD associated with metabolic syndrome [fatty liver, n = 5; non-alcoholic steatohepatitis (NASH), n = 5] by percutaneous ultrasonography-guided liver biopsy. Double-fluorescence immunohistochemistry was applied to examine CD14 expression as a marker of lipopolysaccharide (LPS)-sensitized macrophage cells (Kupffer cells) in liver biopsy specimens.
RESULTS: The incidence of postoperative NAFLD was 36.6% (30/82). Univariate analysis identified cancer of the pancreatic head, sex, diameter of the main pancreatic duct, and dissection of the nerve plexus as factors associated with the development of NAFLD after PD. Those patients who developed NAFLD after PD demonstrated significantly decreased levels of serum albumin, total protein, cholesterol and triglycerides compared to patients without NAFLD after PD, but no glucose intolerance or insulin resistance. Liver biopsy was performed in four patients with NAFLD after PD. All four patients showed moderate-to-severe steatosis and NASH was diagnosed in two. Numbers of cells positive for CD68 (a marker of Kupffer cells) and CD14 (a marker of LPS-sensitized Kupffer cells) were counted in all biopsy specimens. The number of CD68+ cells in specimens of NAFLD after PD was significantly increased from that in specimens of NAFLD associated with metabolic syndrome specimens, which indicated the presence of significantly more Kupffer cells in NAFLD after PD than in NAFLD associated with metabolic syndrome. Similarly, more CD14+ cells, namely, LPS-sensitized Kupffer cells, were observed in NAFLD after PD than in NAFLD associated with metabolic syndrome. Regarding NASH, more CD68+ cells and CD14+ cells were observed in NASH after PD specimens than in NASH associated with metabolic syndrome. This showed that more Kupffer cells and more LPS-sensitized Kupffer cells were present in NASH after PD than in NASH associated with metabolic syndrome. These observations suggest that after PD, Kupffer cells and LPS-sensitized Kupffer cells were significantly upregulated, not only in NASH, but also in simple fatty liver.
CONCLUSION: NAFLD after PD is characterized by both malnutrition and the up-regulation of CD14 on Kupffer cells. Gut-derived endotoxin appears central to the development of NAFLD after PD.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0340-70046242013Intratumoral peptide injection enhances tumor cell antigenicity recognized by cytotoxic T lymphocytes: a potential option for improvement in antigen-specific cancer immunotherapy639652ENDaisukeNobuokaToshiakiYoshikawaMariTakahashiTatsuakiIwamaKazutakaHorieManamiShimomuraShiroSuzukiNorikoSakemuraMunehideNakatsugawaHiroshiSadamoriTakahitoYagiToshiyoshiFujiwaraTetsuyaNakatsuraAntigen-specific cancer immunotherapy is a promising strategy for improving cancer treatment. Recently, many tumor-associated antigens and their epitopes recognized by cytotoxic T lymphocytes (CTLs) have been identified. However, the density of endogenously presented antigen-derived peptides on tumor cells is generally sparse, resulting in the inability of antigen-specific CTLs to work effectively. We hypothesize that increasing the density of an antigen-derived peptide would enhance antigen-specific cancer immunotherapy. Here, we demonstrated that intratumoral peptide injection leads to additional peptide loading onto major histocompatibility complex class I molecules of tumor cells, enhancing tumor cell recognition by antigen-specific CTLs. In in vitro studies, human leukocyte antigen (HLA)-A*02:01-restricted glypican-3(144-152) (FVGEFFTDV) and cytomegalovirus(495-503) (NLVPMVATV) peptide-specific CTLs showed strong activity against all peptide-pulsed cell lines, regardless of whether the tumor cells expressed the antigen. In in vivo studies using immunodeficient mice, glypican-3(144-152) and cytomegalovirus(495-503) peptides injected into a solid mass were loaded onto HLA class I molecules of tumor cells. In a peptide vaccine model and an adoptive cell transfer model using C57BL/6 mice, intratumoral injection of ovalbumin(257-264) peptide (SIINFEKL) was effective for tumor growth inhibition and survival against ovalbumin-negative tumors without adverse reactions. Moreover, we demonstrated an antigen-spreading effect that occurred after intratumoral peptide injection. Intratumoral peptide injection enhances tumor cell antigenicity and may be a useful option for improvement in antigen-specific cancer immunotherapy against solid tumors.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6722013Living Donor Liver Transplantation to a Survivor of LiverResection for Hepatocellular Carcinoma with Major Portal Vein Invasion117121ENHiroshiSadamoriTakahitoYagiSusumuShinouraYuzoUmedaRyuichiYoshidaDaisukeSatoDaisukeNobuokaMasashiUtsumiToshiyoshiFujiwaraCase Report10.18926/AMO/49671We present a case of living donor liver transplantation to a 3-year disease-free survivor of liver resection for hepatocellular carcinoma (HCC) with major portal vein invasion. A 48-year-old man had HCC in the right lobe with a portal venous tumor thrombus extending into the left portal vein. An extended right lobectomy with thrombectomy was performed to remove the thrombus. Three years after liver resection, the patient experienced liver failure, with massive ascites and jaundice due to the formation of a thrombus in the main and left portal veins. During the 3 years after liver resection, no metastasis or recurrence of HCC had been detected, and tumor markers had been within normal ranges. The portal venous thrombus did not show any arterial enhancement under contrast-enhanced computed tomography, suggesting that the co-existence of any HCC component in the portal venous thrombus may have been negative. Based on these findings, living donor liver transplantation was performed using a right lobe graft from the patientʼs son. The patient is alive at 87 months after the transplantation, with no evidence of HCC recurrence.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6622012Resection of Metachronous Lymph Node Metastases from Hepatocellular Carcinoma after Hepatectomy: Report of Four Cases177182ENMasashiUtsumiHiroakiMatsudaHiroshiSadamoriSusumuShinouraYuzoUmedaRyuichiYoshidaDaisukeSatohMasaakiHashimotoTakahitoYagiToshiyoshiFujiwaraCase Report10.18926/AMO/48268We report 4 cases of surgical resection of metachronous lymph node (LN) metastases from hepatocellular
carcinoma (HCC) following hepatectomy. Clinicopathological features and results of LN dissection
were investigated in the 4 patients. One patient was found to have a single metastasis in the mediastinal LNs, another had multiple metastases in the mediastinal and abdominal LNs, and the other 2 had single metastases in the abdominal LN. The locations of the abdominal LN metastases were behind the pancreas head in 2 patients and around the abdominal aorta in 1 patient. They all underwent surgical resection of metastatic LNs and had no postoperative complications. The 3 patients whose LN metastases were solitary have been alive for more than 2 years after LN resection, and one of them is free from recurrence. The patient with multiple LN metastases died 13 months after LN resection due to carcinomatosis. With the expectation of long-term survival, a single metachronous LN metastasis from HCC after hepatectomy should be resected in patients without uncontrollable intrahepatic or extrahepatic tumors.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812412012膵炎を伴った胃異所性膵の1切除例5962ENSusumuShinouraTakahitoYagiHiroshiSadamoriHiroakiMatsudaYuzoUmedaRyuichiYoshidaDaisukeSatohMasashiUtsumiNaosukeYokomichiTakashiKuiseToshiyoshiFujiwaraWe experienced a case of gastric aberrant pancreas with acute pancreatitis. The patient was a 42-year-old man. He was referred to our hospital because of epigastric pain. A CT scan and endoscopic examination revealed a gastric submucosal tumor with inflammation. His serum amylase level was high at 222 IU/l. Endoscopic ultrasonography revealed a hypoechoic mass lesion, 3 cm in diameter, at the body of his stomach. Endoscopic ultrasoundscopy-guided fine needle aspiration was performed. Pathological examination showed pancreatic tissue. So, he underwent partial gastrectomy due to gastric aberrant pancreas with pancreatitis. There are very few cases of gastric aberrant pancreas with pancreatitis on record.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812332011多発肝内転移を伴う進行肝細胞癌に対して減量手術を含めた集学的治療が奏功した一例213216ENDaisukeSatohTakahitoYagiHiroshiSadamoriYuzoUmedaToshiyoshiFujiwaraWe report a case of advanced HCC with multiple intrahepatic metastases who obtained long-term survival by reductive hepatic resection as part of a multidisciplinary treatment. The patient was a 75-year-old man who had HCC, 13.5 cm in diameter in the right lobe of the liver with multiple intrahepatic metastases around the main tumor and 7 intrahepatic metastases in the left lobe of the liver. The large main tumor and intrahepatic metastases around the main tumor were initially resected by right lobectomy as reduction surgery. Transcatheter arterial chemoembolization (TACE) with epirubicin for intrahepatic metastases in the remnant liver was started 1 month after initial hepatectomy and repeated every 3 months. Twelve months after initial hepatectomy, lung metastases appeared, so we started systemic chemotherapy with 5-fluorouracil (5-FU) and cisplatin (CDDP). In addition, we changed epirubicin to CDDP for TACE. Despite this combination therapy, 20 months after the initial hepatectomy, the lung metastases showed an increase in size. We decided to discontinue systemic chemotherapy and administer sorafenib. The patient was alive without progression of intrahepatic metastasis and lung metastasis more than 26 months after the initial hepatectomy.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812332011脾動脈結紮を伴う生体肝移植後に脾動脈症候群を呈した一例207211ENDaisukeSatohTakahitoYagiHiroshiSadamoriHiroakiMatsudaSusumuShinouraYuzoUmedaRyuichiYoshidaTakashiUtsumiToshiyoshiFujiwaraAfter orthotopic liver transplantation, splenic artery syndrome (SAS), a phenomenon by which the main blood flow of the impaired hepatic artery is shifted to the splenic artery or gastroduodenal artery despite the absence of a structural lesion involving the anastomosis, has occasionally been observed. We report a 20-year-old women who developed SAS with pancytopenia and refractory ascites after living donor liver transplantation despite intraoperative ligation of the splenic artery as a prophylactic treatment for SAS. In this case SAS was diagnosed by digital subtraction angiography (DSA). A celiac trunk angiogram showed relative hypoperfusion of the hepatic artery together with augmentation of the blood flow toward the spleen with the unique collateral circulation through the left gastric artery, stomach and short gastric artery, and distal splenic artery. Embolization of one of the two left gastric arteries was performed. After embolization the hepatic artery perfusion showed significant improvement, but reduced again the next day. We ultimately conducted splenectomy. This case showed portal hyperperfusion and portal hypertension, consistent with previous reports that have described an association of SAS with portal hyperperfusion. After splenectomy, there was significant improvement in the hepatic artery perfusion, ascites disappeared promptly, and pancytopenia was significantly improved.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X5752003Annexin V assay-proven anti-apoptotic effect of ascorbic acid 2-glucoside after cold ischemia/reperfusion injury in rat liver transplantation.209216ENJieLiuTakahitoYagiHiroshiSadamoriHiroyoshiMatsukawaDong-ShengSunNaoshiMitsuokaMasaoYamamuraJunjiMatsuokaZaishunJinItaruYamamotoNoriakiTanakaArticle10.18926/AMO/32828<p>Controversy exists over whether the predominant cell death of hepatocytes is due to apoptosis or necrosis after ischemia/reperfusion injury. In this study we investigated the predominant cell death of hepatocytes after cold ischemia/reperfusion injury using the Annexin V-based assay, and evaluated the anti-apoptotic effect of ascorbic acid 2-glucoside (AA-2G) added to the University of Wisconsin solution (UW solution) in rat liver transplantation. The retrieved liver was preserved in 4 UW solution for 24 h, and then transplanted orthotopically to the syngeneic Wistar recipient. The animals were divided into 2 groups, a control group (n=10), in which liver grafts were preserved in UW solution (4), and an AA-2G group (n=10), in which liver grafts were preserved in UW solution (4) with AA-2G (100 ug/ml). The serum AST level 4 h after reperfusion in the control group was significantly suppressed in the AA-2G group, and the bile production of the liver graft in the AA-2G group was well recovered. The mean survival time in the AA-2G group was significantly improved compared with that in the control group. Annexin-V and Propidium iodide staining 4 h after reperfusion showed a significantly higher percentage of viable hepatocytes in the AA-2G group compared with the control group (93.4 +/- 2.0 vs. 80.3 +- 2.1%, P<0.05). In the control group, the main cell death of hepatocytes was apoptosis (early apoptosis: 10.0 +- 4.7%, late apoptosis: 6.4 +/- 1.7%). The addition of AA-2G to the UW solution significantly inhibited both early and late apoptotic cell death 4 h after reperfusion (early apoptosis: 0.98 +/- 0.88%, late apoptosis: 2.2 +/- 1.1%). The expression of caspase 9 in the immunostaining of the liver graft was suppressed in the AA-2G group compared with in the control group. Our study using the Annexin V-based assay provided evidence that the predominant cell death of hepatocytes was apoptosis after 24 h cold ischemia/reperfusion injury in rat liver transplantation. The addition of AA-2G to the UW solution attenuated 24 h cold ischemia/reperfusion injury by inhibiting the apoptosis of hepatocytes.</p>
No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X5452000Calcineurin antagonists inhibit interferon-gamma production by downregulation of interleukin-18 in human mixed lymphocyte reactions.201209ENMasahikoKuinoseHiromiIwagakiYoshinoriMorimotoHideoKohkaKentaKobashiHiroshiSadamoriMasaruInagakiNaotoUrushiharaTakahitoYagiNoriakiTanakaArticle10.18926/AMO/32294<p>Tacrolimus (FK-506) and cyclosporin A (CsA) are calcineurin antagonists used widely as T-cell immunosuppressants; however, their relative efficacy on the production of interleukin-18 (IL-18) remains undefined. We have examined the effects of FK-506 and CsA on the cytokine generation of human peripheral blood mononuclear cells (PBMCs) in mixed lymphocyte reaction (MLR) with lipopolysaccharide (LPS). We studied the levels of interleukin-18 (IL-18), IL-12, IL-10, IL-6, IL-2 and interferon-gamma (IFN-gamma) in the supernatant in allo-MLR by ELISA assay. Supernatant levels of IFN-gamma, IL-2, IL-6, IL-10 and IL-12 were detected 12 h after MLR and markedly increased thereafter. In contrast, production of IL-18 was detected at 12 h, reached a near maximum level at 24 h and decreased at 72 h. These results suggested that IFN-gamma production depended on IL-18, IL-12 and IL-2 in the early phase of MLR and depended mainly on IL-12 and IL-2 in the late phase. Both calcineurin antagonists inhibit the generation of IL-18, which plays a large role in allogeneic cell interactions, in macrophages and they also promote an equivalent down-regulation of T helper 1 (Th1) and Th2 responses in a concentration-dependent manner. About 90% of IFN-gamma production induced by MLR was inhibited by an anti-IL-18 antibody, showing that IL-18 can trigger IFN-gamma production in MLR. These results suggest that dual signaling consisting of antigen-driven nuclear factor of activated T cells (NFAT) activation and LPS-mediated NF-kappaB activation is crucial for IL-18 production in macrophages, and that IL-18 can trigger IFN-gamma production in T-cells by MLR.</p>
No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-15581101-61998原発性胆汁性肝硬変に対する成人生体部分肝移植の1例18ENTakahitoYagiNaotoUrushiharaMasahiroOishiHiroyoshiMatsukawaMasanobuMoriHiromuTsugeNorihisaTakakuraNoriakiTanakaToshihiroHigashiTakaoTsujiMasaruInagakiHiroshiSadamoriYasuakiKamikawaA 49-year-old female received a living related liver transplantation from her son. She had a 13-years history of primary biliary cirrhosis (PBC). The preoperative 1-year survival rate and mortality after 6 months were calculated to be 6.5% and 99.3%, respectively. The graft included left bisegments weighing 435g, and was equal to 43% of the calculated standard liver volume. Massive ascites were sustained due to accompanied portal hypertension. On Postoperative day 7, she manifested massive tarry stool by portal-hypertensive colonopathy. The CT scan revealed a right subphrenic abscess on the postoparative day 14. After drainage of the abscess, the serum total billirubin level decreased to the norman range. She was descharged with extracorptreal tube dainage. On the postoperative day 169, she was readmitted due to acute elevation of the serum bilirubin level. Echography revealed selective dilatation of the hepatic bile duct in the segment 2, and suggested the presence of insufficiency of hepatico-jejunostomy in the early postoperative phase. Despite emergent PTCD, jaundice was sustained and responded poorly to steroid pulse therapy. According to tapering of oral prednisolone, the serum bilirubin level gradually decreased and reached a the plateau between 2 and 4mg/dl. The patient is currently completely free from oral steroid therapy and in receiving interventional hepaticoplasty using the YAG laser system. We concluded that living related liver transplantation is an effective transplantational option for adult end-stage liver disease.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama1996The Effects of Nutritional Repletion on Donors for Liver Transplantation in PigsENNo potential conflict of interest relevant to this article was reported.