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A rare case of primary gastric endocrine cell carcinoma in a 79-year-old man is reported. Upper gastrointestinal endoscopy showed a large Bormann’s type 2 tumour located in the middle of the stomach. On computed tomography, the gastric wall was thickened by the large tumour, and there were no distant metastases. Distal gastrectomy, lymph node dissection, and partial resection of the transverse colon were performed because the tumour involved the transverse mesocolon. The final pathological diagnosis was endocrine cell carcinoma, with tumour infiltration up to the subserous layer. Adjuvant chemotherapy was given, but metachronous remnant gastric cancer developed 2 years after surgery. Endoscopic submucosal dissection was performed for the early 0-IIc type gastric cancer, and the surgical margin was preserved. The patient has survived for 5 years after the primary surgery, remaining disease-free so far.

In living-donor liver transplantation (LDLT), biliary complications are recognized as a significant cause of post-transplantation morbidity. Eighty patients who underwent LDLT with duct-to-duct biliary reconstruction at Hiroshima University Hospital were enrolled in this study. The mean follow-up was 24 months (range, 3–72 months). Eighteen patients underwent the basiliximab-based immunosuppressive therapy, and 62 patients underwent non-basiliximab-based immunosuppressive therapy. The development of biliary complications after LDLT was retrospectively analyzed. Biliary complications were initially treated by endoscopic or radiological modalities. Biliary leakages and strictures occurred in 12 (15%) and 20 (25%) of the 80 patients, respectively. Stepwise multivariate analysis demonstrated bile leakage to be an independent risk factor for the development of biliary stricture (p = 0.001) and basiliximab-based immunosuppressive therapy to be an independent protective factor for postoperative biliary leakage (p = 0.005). The 1-week total doses of steroids were significantly lower in the basiliximab-based immunosuppressive regimes (mean dose: 573mg) than in the non-basiliximab-based ones (mean dose: 1,121mg) (p = 0.01). All patients with biliary leakage were successfully treated with endoscopic or radiological modalities, except one patient who was treated by surgical treatment. Endoscopic or radiological modalities were successful as primary treatment modalities in 12 (60%) of 20 patients with biliary strictures. Lastly, six patients were treated surgically with long-term success, except for one patient with chronic cholangitis who died after 16 months. Steroid-sparing basiliximab-based immunosuppressive therapy reduced the incidence of biliary leakage, and biliary leakage was the independent factor for biliary stricture. The non-surgical and surgical treatments for biliary complications were satisfactory.

A portal venous injection of allogeneic donor cells is known to prolong the survival of subsequently transplanted allografts. In this study, we investigated the role of liver sinusoidal endothelial cells (LSECs) in immunosuppressive effects induced by a portal injection of allogeneic cells on T cells with indirect allospecificity. To eliminate the direct CD4+ T cell response, C57BL/6 (B6) MHC class II-deficient C2tatm1Ccum (C2D) mice were used as donors. After portal injection of irradiated B6 C2D splenocytes into BALB/c mice, the host LSECs that endocytosed the irradiated allogeneic splenocytes showed enhanced expression of MHC class II molecules, CD80, and Fas ligand (FasL). Due to transmigration across the LSECs from BALB/c mice treated with a portal injection of B6 C2D splenocytes, the naive BALB/c CD4+ T cells lost their responsiveness to stimulus of BALB/c splenic APCs that endocytose donor-type B6 C2D alloantigens, while maintaining a normal response to stimulus of BALB/c splenic APCs that endocytose third-party C3H alloantigens. Similar results were not observed for naive BALB/c CD4+ T cells that transmigrated across the LSECs from BALB/c FasL-deficient mice treated with a portal injection of B6 C2D splenocytes. Adaptive transfer of BALB/c LSECs that had endocytosed B6 C2D splenocytes into BALB/c mice via the portal vein prolonged the survival of subsequently transplanted B6 C2D hearts; however, a similar effect was not observed for BALB/c FasL-deficient LSECs. These findings indicate that LSECs that had endocytosed allogeneic splenocytes have immunosuppressive effects on T cells with indirect allospecificity, at least partially via the Fas/FasL pathway.

Near-infrared spectroscopy (NIRS), which enables non-destructive evaluation of hemoglobin (Hb) oxygenation and the redox state of cytochromeoxidase (Cyt.aa3) in living tissues, has been employed during surgery to detect possible impairment of hemodynamics and mitochondrial respiration in the anterior segment of a right lobe liver graft in living-donor liver transplantation (LDLT). Thirty-six patients undergoing LDLT using a right lobe graft without the middle hepatic vein (MHV) were enrolled in this study. During the course of harvesting and implantation, NIRS measurements were performed on the anterior segments of the liver grafts. In two recipients of liver grafts with Hb residue over 70% in the anterior segment after ex vivo flushing, the MHV tributary was reconstructed, while it was not reconstructed in the other 34 recipients. Of those 34 recipients, 16 recipients of liver graft with 40-70% Hb residue showed transient increase of transaminase levels after LDLT. Of those 16 recipients, six recipients who showed reduction in oxidized Cyt.aa3 in the anterior segment suffered from persistent hyperbilirubinemia after LDLT. In patients showing impairment of mitochondrial redox associated with congestion caused by deprivation of the MHV tributaries, reconstruction of the MHV tributaries might have a beneficial effect.

Although livers transplanted across MHC barriers in mice are normally accepted without recipient immune suppression, the underlying mechanisms remain to be clarified. To identify the cell type that contributes to induction of such a tolerance state, we established a mixed hepatic constituent cell-lymphocyte reaction (MHLR) assay. Irradiated C57BL/6 (B6) or BALB/c mouse hepatic constituent cells (HCs) and CFSE-labeled B6 splenocytes were cocultured. In allogeneic MHLR, whole HCs did not promote T cell proliferation. When liver sinusoidal endothelial cells (LSECs) were depleted from HC stimulators, allogeneic MHLR resulted in marked proliferation of reactive CD4+ and CD8+ T cells. To test the tolerizing capacity of the LSECs toward alloreactive T cells, B6 splenocytes that had transmigrated through monolayers of B6, BALB/c, or SJL/j LSECs were restimulated with irradiated BALB/c splenocytes. Nonresponsiveness of T cells that had transmigrated through allogeneic BALB/c LSECs and marked proliferation of T cells transmigrated through syngeneic B6 or third-party SJL/j LSECs were observed after the restimulation. Transmigration across the Fas ligand-deficient BALB/c LSECs failed to render CD4+ T cells tolerant. Thus, we demonstrate that Fas ligand expressed on naive LSECs can impart tolerogenic potential upon alloantigen recognition via the direct pathway. This presents a novel relevant mechanism of liver allograft tolerance. In conclusion, LSECs are capable of regulating a polyclonal population of T cells with direct allospecificity, and the Fas/Fas ligand pathway is involved in such LSEC-mediated T cell regulation.

Background. To monitor antidonor alloreactivity for accurate diagnosis of acute rejection after living-donor liver transplantation (LDLT), we used a mixed lymphocyte reaction (MLR) assay using an intracellular fluorescent dye carboxyfluorescein diacetate succimidyl ester (CFSE)-labeling technique (CFSE-MLR) in 29 consecutive patients who underwent adult-to-adult LDLT. Methods. For patients who developed moderate or severe disorders in liver function, CFSE-MLR was performed together with needle biopsy of the liver allografts immediately after liver dysfunction had occurred. CFSE-labeled peripheral blood mononuclear cells (PBMC) from recipients and irradiated autologous, donor, or third-party PBMC were cultured, and then proliferation and CD25 expression in each of the CD4 + and CD8 + T cell subsets were analyzed by flow cytometry. Results. Twelve (41.4%) of the 29 patients developed moderate or severe disorders in liver function within 6 months after LDLT. Eight ofthe 12 patients (overall incidence of 27.6%) suffering from liver function disorder were diagnosed on the basis of liver biopsy results as having mild or moderate acute rejection. However, only 4 of the 12 patients (overall incidence of 13.8%) showed remarkable proliferation of CD8 + T cells in association with CD25 expression on antidonor CFSE-MLR. The other eight patients were eventually diagnosed as having recurrence of original hepatitis, drug-induced hepatotoxicity, or congestion of the anterior segment of the liver allograft by further extensive examinations or in retrospect. Conclusions. The results of CFSE-MLR assays, which could be used for rigorously monitoring rejection, provided evidence of low incidence of acute rejection after LDLT.

Although it is known that activation of natural killer (NK) cells causes liver injury, the mechanisms underlying NK cell-induced killing of self-hepatocytes are not clear. We demonstrated that liver NK cells have cytotoxicity against normal syngeneic hepatocytes in mice. Polyinosinic-polycytidylic acid (poly I:C) treatment enhanced hepatocyte toxicity of liver NK cells but not that of spleen NK cells. Unlike NK cells in other tissues, approximately 30%-40% of liver NK cells constitutively express tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). An in vitro NK cell cytotoxic assay revealed that hepatocyte toxicity of liver NK cells from both naïve and poly I:C-treated mice was inhibited partially by an anti-TRAIL monoclonal antibody (mAb) alone and completely by the combination with anti-Fas ligand (FasL) mAb and a perforin inhibitor, concanamycin A, indicating contribution of TRAIL to NK cell-mediated hepatocyte toxicity. The majority of TRAIL(+) NK cells lacked expression of Ly-49 inhibitory receptors recognizing self-major histocompatibility complex class I, indicating a propensity to targeting self-hepatocytes. Poly I:C treatment significantly upregulated the expression of Ly-49 receptors on TRAIL(-) NK cells. This might be a compensatory mechanism to protect self-class I-expressing cells from activated NK cell-mediated killing. However, such compensatory alteration was not seen at all in the TRAIL(+) NK cell fraction. Thus, liver TRAIL(+) NK cells have less capacity for self-recognition, and this might be involved in NK cell-dependent self-hepatocyte toxicity. In conclusion, our findings are consistent with a model in which TRAIL-expressing NK cells play a critical role in self-hepatocyte killing through poor recognition of MHC.

Background. This study was performed to determine the usefulness of intraoperative near-infrared spectroscopy (NIRS) for evaluating the extent of congestion in the anterior segment of the graft after living-donor liver transplantation using right lobe grafts that do not have the middle hepatic vein.

胸腔鏡下あるいは開胸下に生検を施行した術前診断未確定の肺腫瘤性病変47例について検討した.腫瘤径は5～45mmで, 平均18.1mm.発見契機のほとんどは検診または他疾患に対する定期検査での異常陰影であった.生検・手術に至った理由は画像上悪性を疑ったものが33例, 悪性を否定できなかったものが5例, 腫瘤の増大を認めたものが9例であった.最終診断は, 原発性肺癌が33例, 転移性腫瘍が4例, 結核腫が5例, 肺炎が2例, リンパ節, 肉芽腫, 過誤腫が各1例であった.原発性肺癌33症例のうち25例がstageIAであったが, stageIB症例が4例, stageIIA以上の症例が4例含まれていた.また, 腫瘤径別に悪性病変の頻度を見てみると, 10mm以下の小腫瘤であってもその60%は悪性であった.早期肺癌の発見のために, 小腫瘤であっても, 悪性を疑う所見のある病変に対しては, 積極的な胸腔鏡下肺生検が有用であると思われた.

Gasless hand-assisted surgery, an alternative technique for colorectal cancer, is described. The abdomen is lifted by two metal disks especially designed for this procedure. The gasless condition evokes no hazard from pneumoperitoneum, and the procedure is greatly simplified by the hand assistance.

The purpose of this study was to ascertain the usefulness of preoperative evaluations of donors by computed tomography (CT) volumetry and CT cholangiography for prevention of unexpected liver failure and biliary complications after donor right hepatectomy for adult-to-adult living donor liver transplantation. Fifty-two donors who underwent right hepatectomy without the middle hepatic vein were enrolled in this study. The values of graft weight (GW) were significantly correlated with those of estimated graft volume (GV; P0.0001). GW was predicted by the following formula: GW = 155.25 + 0.658 x GV; r(2) = 0.489. CT cholangiography revealed anatomical variants of biliary structure in one-third of the donors and also clearly showed one or two small biliary branches from the caudate lobe to the right hepatic ducts or the confluence in 58% of the donors. Biliary leakage, which was treated by conservative therapy, occurred in only one donor (1.9%). No donors received homologous blood transfusion. Hyperbilirubinemia (serum total bilirubin5 mg/dl) occurred in 5.8% of the donors during their early postoperative periods. Precise evaluations of liver remnant volume by CT volumetry and biliary variation by CT cholangiography are essential for performing safe donor hepatectomy, preventing hepatic insufficiency and minimizing the risk of biliary tract complications.

In rodents, liver natural killer (NK) cells have been shown to mediate higher cytotoxic activity against tumor cells than do peripheral blood (PB) NK cells. However, such differences between liver and PB NK cells have not been extensively investigated in humans. The phenotypical and functional properties of NK cells extracted from liver perfusates at the time of living donor liver transplantation were investigated. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a critical molecule for NK cell-mediated anti-tumor cell killing, was not expressed by freshly isolated PB NK cells or by liver NK cells. Stimulation with interleukin (IL)-2, significantly up-regulated the expression of TRAIL on liver NK cells, but this effect was barely observed on PB NK cells. Donor liver NK cells showed the most vigorous cytotoxicity against HepG2, a hepatocellular carcinoma (HCC) cell line, after IL-2 stimulation (90.5% +/- 2.2% at E: T = 10:1), compared with donor and recipient PB NK cells and recipient liver NK cells (64.8% +/- 8.2%, 56.1% +/- 8.9%, and 34.6% +/- 7.5%, respectively). IL-2 stimulation resulted in an increased expression of killing inhibitory receptors on liver NK cells in parallel with TRAIL expression. Consistently, the cytotoxicities of IL-2-stimulated donor liver NK cells against self and recipient lymphoblasts were negligible. In conclusion, adoptive transfer of IL-2-stimulated NK cells extracted from donor liver graft perfusate could mount an anti-tumor response without causing toxicity against 1-haplotype identical recipient intact tissues. These findings present a concept to prevent recurrence of HCC after liver transplantation.

Background Portal vein reconstruction is still a crucial problem in living-donor liver transplantation. Vascular closure staples (VCS) have been applied for small peripheral and large vessels because of the technical ease with which they can be employed. We describe here our experience with portal vein reconstruction in living donor-liver transplantation and compare VCS with conventional sutures in portal vein reconstruction. Methods The anastomosis between the donor portal vein and recipient portal vein or the right external iliac vein graft was created using either VCS or conventional sutures. Results The stenotic ratios were .51 ± .15 and .79 ± .25 for the conventional sutures and VCS, respectively. The stenotic ratio was significantly lower in VCS compared with conventional sutures. Conclusions VCS compared with conventional sutures has the advantage of low risk of anastomotic stenosis.

Although major or extended hepatectomy may result in drastic alterations in the hemodynamics and oxygen metabolism of the residual livers, this issue remains to be elucidated in detail.In this study, in vivo near-infrared spectroscopy (NIRs) was performed to determine oxy-/deoxy-hemoglobin (Hb) and oxidized/reduced cytochrome oxidase (Cyt.aa3) contents in hepatic tissues in a rat 70% hepatectomy model. We also investigated the effectiveness of Pringle occlusion for minimizing bleeding and the therapeutic effects of prostaglandin E1 (PGE1) on haemodynamics alteration after hepatectomy.After 70% hepatectomy, total Hb (oxy-Hb + deoxy-Hb) content was persistently elevated in the residual hepatic tissues, indicating congestion probably caused by surplus portal inflow. Oxidized Cyt.aa3 contents were elevated after hepatectomy, whereas reduced Cyt.aa3 contents were not significantly altered, indicating that mitochondrial respiration was not impaired. Pringle occlusion before hepatectomy per se did not cause deterioration of the hemodynamics or oxygen metabolism of the residual livers. The congestion of the residual liver after 70% hepatectomy was significantly improved by continuous injection of PGE1 (1.0 mg/kg/min) via the portal vein.The alteration of hemodynamics and oxygen metabolism in the liver after extended hepatectomy has been quantitatively evaluated using the NIRs.

This study was performed to determine the usefulness of intraoperative near-infrared spectroscopy (NIRS) for evaluating the extent of congestion in the anterior segment of the graft after living-donor liver transplantation using right lobe grafts that do not have the middle hepatic vein.Fifteen patients undergoing living-donor liver transplantation using a right lobe graft without the middle hepatic vein were enrolled in this study. During the course of harvesting and implantation, in vivo NIRS was performed on the liver grafts to determine hemoglobin (Hb) and cytochrome oxidase content in the hepatic tissues.The 15 cases were divided into three groups according to the caliber of the middle hepatic vein tributaries in the right lobe grafts: the small group (4 mm), the intermediate group (4-7 mm), and the large group (7 mm). After implantation, congestion (increase in tissue Hb) in the anterior segment was more severe than that in the posterior segment in the intermediate and large groups. However, well-preserved mitochondrial cytochrome oxidase redox state was observed in both segments except for two cases in the large group with severe congestion in the anterior segment. The extent of postoperative congestion in the anterior segment was significantly correlated with the tissue content of remaining Hb in that segment after ex vivo flushing.Intraoperative NIRS enables quantification of the extent of congestion in the anterior segment after implantation of a right lobe liver graft and even enables prediction of such congestion at the phase of ex vivo perfusion.

カドミウムのグルタミン酸,およびアスパラギン酸錯イオンの水銀電極面における還元反応についてポーラログラフ法を用い解明を行ない,直流ポーラログラム半波電位のpH,グルタミン酸,またはアスパラギン酸の濃度に対する依存性から,これらの錯イオンの組成,および安定度定数を決定した。カドミウムは,pH>7.0の領域でこれらの配位子と錯形成するが,アスパラギン酸とは本実験の行なわれた条件のもとではCdX3-3なる1:3の組成をもつ錯イオンを形成せず,1:1,および1:2の組成をもつ錯イオンのみ形成する。しかし,グルタミン酸の場合は高いpH領域では1:1,1:2のグルタミン酸錯イオンのほかに,1:3なる組成をもつ錯イオンをつくることが明らかになった。一定pHにおける半波電位のアミノ酸の濃度による変化からDe-Ford-Humeの方法にしたがって解析した結果,錯イオンの安定度定数としては,それぞれグルタミン酸系については5.8×104,3.7×107,2.6×1010,アスパラギン酸系については,それぞれ7.0×105,1.2×108なる値が得られた。

The pathway leading to cell death in clinical liver transplantation is not known. Eight liver transplant recipients and eight donors were enrolled in this study. Postoperative serum levels of alanine transferase had significantly increased in the recipients compared with those in the donors. Mild centri-lobular necrosis was observed in only liver tissues taken from the recipients. Tumor necrosis factor (TNF)-R1 and death receptor 5 expression levels had increased in liver tissues taken from the recipients. There were no changes in the levels of Fas/Fas ligand expression in liver tissues from either the donors or recipients. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression was down-regulated in donor liver after hepatectomy and liver allograft after implantation. The results suggest that, although ischemic liver injury was not serious, due to the short ischemia time, TNF and TRAIL signals are associated with liver ischemic injury in live-donor liver transplantation but Fas signal is not.