Impact of Portal Hemodynamic Changes in Partial Liver Grafts on Short-Term Graft Regeneration in Living Donor Liver Transplantation.

BACKGROUND: Regeneration of partial liver grafts is critical for successful living donor liver transplantation (LDLT), especially in adult recipients. The purpose of this study was to investigate the intraoperative hemodynamic changes in partial liver grafts and characterize their potential impact on post-transplant liver regeneration in LDLT. METHODS: We examined the portal venous flow (PVF) and hepatic arterial flow (HAF) to partial liver grafts by means of ultrasonic transit time flowmeter of donors immediately before graft retrieval and of the corresponding recipients after vascular reconstruction in 48 LDLT cases. We evaluated post-transplant liver regeneration according to the changes in graft liver volume between the time of transplantation and the 7th post-transplant day. RESULTS: There was a significant increase in PVF to the partial liver grafts in recipients (rPVF) compared with that in donors. In contrast, graft HAF in recipients significantly decreased compared with that in donors. The rPVF inversely correlated with graft weight (GW)-recipient body weight ratio (GRWR), whereas HAF volume showed no significant correlation. The rPVF/GW positively correlated with the rate of liver regeneration (GRR), which inversely correlated with GRWR. The rPVF/GW was significantly higher, and GRR tended to be larger in the small graft group than in the non-small graft group. CONCLUSIONS: Intraoperative portal hemodynamic changes in partial liver grafts strongly affect their post-transplant regeneration. In particular, in small liver grafts, an immediate and remarkable increase in graft PVF may contribute to rapid liver regeneration after LDLT if the increased PVF remains within a safe range.

Adult living-donor liver transplantation for a recipient with a high preoperative 1,3-beta-D-glucan level and positive test result for Aspergillus antigen.

The patient was a 45-year-old man with underlying alcoholic liver cirrhosis. Two years prior, he was repeatedly hospitalized for liver failure symptoms and requested a living-donor liver transplantation (LDLT) because of end-stage cirrhosis. A pretransplantation blood test revealed a high 1,3-beta-d-glucan (BDG) value of 102.0 pg/mL (reference value <20.0 pg/mL) and a high blood Aspergillus antigen (AsAg) value of 1.6 cutoff index (COI; reference value <0.5 COI). Contrast-enhanced thoracoabdominal-pelvic computed tomography (CT) and cranial magnetic resonance imaging revealed no fungal infection. However, latent fungal infection could not be ruled out, hence preoperative antifungal agent treatment was administered. BDG and AsAg levels showed a decreasing trend after treatment initiation. However, normalization did not occur; the BDG and AsAg levels were 25.8 pg/mL and 1.0 COI, respectively. Although the possibility of latent fungal infection was judged low, we prophylactically administered antifungal agents after LDLT. The BDG level consistently increased at 35-39 pg/mL until postoperative day 5 but subsequently normalized. The AsAg level was higher than the limit of detection at 5.0 COI on postoperative day 3 but normalized to 0.2 COI on postoperative day 5 and did not subsequently increase. The postoperative course was uneventful despite bacterial pneumonia and the patient was discharged on postoperative day 35. A histopathologic examination (Grocott methenamine silver staining) and a fungal polymerase chain reaction assay were performed for the resected liver, but the results of both were negative. At 9 postoperative months, the patient was making ambulatory follow-up visits. Currently, the BDG and AsAg values remain normal and clinical progress is favorable. We found no reports of LDLT for a recipient with a high preoperative BDG level and positive test result for AsAg. Thus, we report on such a case with a discussion of the literature on the causes of high preoperative BDG and AsAg values.

Analysis of histologic changes during early rejection after renal transplantation by performing protocol biopsy at 1 year after kidney transplantation.

BACKGROUND: In this retrospective study, we analyzed histologic changes identified through protocol biopsy (PB) at 1 year after kidney transplantation (KT). We focused on the pathologic changes observed in patients with a history of treatment for graft rejection within 1 year of transplantation. METHODS: Between January 2008 and December 2011, 56 patients underwent KT at our center. We assessed the histologic findings observed at 1 year after renal transplantation using the Banff 2007 classification. At our center, PBs are performed immediately after or at 1 hour after transplantation, and at 1 year after KT. PBs were performed in 39 patients; PBs could not be performed in 17 patients because of various causes. Of the 39 patients, 29 stabilized without clinical rejection and without treatment (the NTx group); 10 patients showed pathologic changes or clinical rejection after steroid pulse therapy within 1 year (the Tx group). We compared these 2 groups with respect to baseline data, renal function, and pathologic scores. RESULTS: The interstitial fibrosis ("ci") score, according to the Banff classification, was significantly greater in the NTx group (0.89) than in the Tx group (0.50) at 1 year after transplantation. CONCLUSIONS: The currently applied early steroid withdrawal regimen may be not be ideal for preventing pathologic changes occurring after KT. In addition to the PB performed 1 year after KT, PB should be performed within 1 year of renal transplantation to identify early signs of rejection and to provide access to appropriate treatment regimes.

Correlation between post kidney transplant anemia and kidney graft function.

BACKGROUND: Posttransplant anemia (PTA) influences kidney graft function and prognosis; however, there is no consensus regarding target hemoglobin (Hb) levels. METHODS: We examined several cases of PTA to identify any correlation between Hb levels and graft function. We evaluated 84 kidney transplant recipients (50 men and 34 women; mean age, 46.7 years) who were treated at our department between February 2004 and March 2012 and were available for a 2-year post-transplant follow-up. RESULTS: Hb levels and serum creatinine levels before transplantation and at 1, 3, 6, 12, and 24 months after transplantation were compared. We examined the correlation between the degree of anemia and renal function among the patients. Data were analyzed using Spearman's rank correlation coefficient and Friedman tests. The mean pretransplantation Hb level was 10.4 g/dL, whereas Hb levels at 6, 12, and 24 months after transplantation were significantly increased to 11.6, 12.2, and 12.4 g/dL, respectively, suggesting an improvement in anemia after the transplantation. Correlation analysis between anemia and kidney graft dysfunction revealed significant correlations at 1, 3, 12, and 24 months after transplantation. Subjects were stratified for correlation analysis according to Hb level at 24 months after transplantation: <10, 10-10.9, 11.0-11.9, 12.0-12.9, and ≥ 13.0 g/dL. A significant improvement in kidney graft function was noted in patients with an Hb level ≥ 11 g/dL at 2 years after transplantation. Anemia improved significantly by 3 months after transplantation. CONCLUSIONS: A significant correlation between PTA and kidney graft function was apparent, and the prognosis for kidney graft function was poor in patients with Hb levels ≤ 11 g/dL.

Pharmacokinetics of mizoribine in adult living donor liver transplantation.

We investigated the pharmacokinetics of mizoribine in the acute phase after adult living donor liver transplantation (LDLT). Between February 2004 and October 2009, 16 recipients received immunosuppressive therapy that included mizoribine (100 to 200 mg/d) after undergoing LDLT. We determined the serum levels of mizoribine before (C0) and 3 (C3), 4 (C4), and 10 (C10) hours after administration on postoperative days 3, 7, and 21. We assessed area under the concentration time curve (AUC) (hour · µg/mL), normalized serum concentration (NSC) at C0 [concentration (µg/mL)/dose (mg/kg body weight)], and estimated glomerular filtration rate (eGFR). The mizoribine concentration showed increases at C3 and C4 followed by a decrease at C10 on all days. AUC was 4.3, 5.9, and 8.3 in the 200-mg/d dose group on days 3, 7, and 21, respectively. NSC at C0 increased for 3 weeks after LDLT. There was a significant correlation between the NSC at C0 and eGFR on day 21, but not on days 3 and 7. There were no correlations between the NSC at C0 and either aspartate aminotransferase, total bilirubin, albumin, trough cyclosporine, or trough tacrolimus on any day. The pharmacokinetics of mizoribine in the acute phase after LDLT seems to be affected by postoperative day and renal function.

Interstitial fibrosis and tubular atrophy on protocol biopsies at 1 year after renal transplantation.

BACKGROUND: Advancements in immunosuppressive therapy have enabled control of early acute rejection and improved long-term kidney transplantation (KT) survival. Chronic histopathologic changes influence graft survival rate. We examined tubulointerstitial changes at 1 year after KT, focusing on the progression of interstitial fibrosis and/or tubular atrophy (IF/TA). METHODS: Using the Banff' 07 classification, we assessed the histological findings obtained at 1 year after transplantation of 38 patients who underwent the procedure between January 2008, and March 2010. In 24 cases, we obtained scores for interstitial fibrosis (ci) >1 and/or tubular atrophy (ct) > 1. We classified the patients into two groups, namely, less than borderline changes (BCs) (t0, i0, or i1; group A) versus BCs and above (t > 1, i2, or i3; group B). We compared their baseline data, renal function, and pathological scores. RESULTS: The mean serum creatinine levels were 1.06 mg/dL for group A and 1.32 mg/dL for group B. The "ct" grading according to the Banff' 07 classification was 0.83 for group A and 1.50 for group B (both P < .05). No significant difference was observed with respect to the percentage of patients with IF/TA (Banff category 5). CONCLUSION: Patients more within 1 year after KT with BCs who show irreversible tubular atrophy by biopsy experience impaired renal function. The presence of BC at the first year may not be associated with IF/TA.

Long-term recurrence-free survival after liver transplantation from an ABO-incompatible living donor for treatment of hepatocellular carcinoma exceeding Milano criteria in a patient with hepatitis B virus cirrhosis: a case report.

The early results of liver transplantations (OLT) in patients with advanced hepatocellular carcinoma (HCC) were poor because of frequent tumor recurrence. However, OLT has significant, theoretical advantage that it removes both the tumor and the organ that is at a risk of malignancy. The Japanese law on organ transplantation limited the availability of cadaveric liver donors until its revision on July 17, 2011. ABO-incompatible OLT was formerly contraindicated because performed anti-A/B antibodies on recipient endothelial cells raised the risk of antibody-mediated humoral graft rejection. We have herein described four successful cases of steroid withdrawal among adult patients who underwent living donor OLT from ABO-incompatible donors. In addition, we transplanted a liver from a living donor into an ABO-incompatible recipient on August 9, 2004. The 55-year-old man with HCC due to hepatitis B virus (HBV) a cirrhosis had a Child-Pugh score of C, and Model for End-stage Liver Disease score of 22. Two tumors greater than 5 cm, exceeded the Milan criteria. His des-gamma-carboxy prothrombin level was 6 mAu/mL, and alpha-fetoprotein, 18.78 ng/mL. Antirejection therapy included multiple perioperative plasmaphereses and splenectomy; with an immunosuppressive regimen consisting of tacrolimus, methylprednisolone, and mycophenolate mofetil. The maintenance dose of immunosuppression did not differ from that of ABO-identical cases. After transplantation, we used intrahepatic arterial infusion therapy with prostaglandin E1 (PG E1). The patient had complications of portal vein thrombosis, hepatic artery thrombosis, and acute myocardial infarction, which were treated by interventional radiology in the posttransplantation period. We controlled the HBsAb titer by administering hepatitis B immunoglobulin and lamivudine (200 IU/L doses) for 1 year after OLT and 100 IU/L doses thereafter. As a result, the patient achieved long-term, disease-free graft survival without steroids. He currently has good liver function and leads a normal lifestyle. Our results suggested the feasibility of controlling antibody-mediated humoral rejection and other complications in living donor liver transplantations into ABO-incompatible adults via intrahepatic arterial PG E1 infusion splenectomy, and plasmapheresis with regular immunosuppression. Withdrawal of steroids, HBV vaccination, and lamivudine, an nucleoside analog reverse transcriptase inhibitor, have achieved long-term (7 years) survival without recurrent HBV infection or tumor.

Safety and efficacy of conversion from twice-daily tacrolimus (prograf) to once-daily prolonged-release tacrolimus (graceptor) in stable kidney transplant recipients.

BACKGROUND: Graceptor is a new modified-release once-daily formulation of tacrolimus with an efficacy and safety profile similar to twice-daily tacrolimus (Prograf), as identified by clinical trials, offering a more convenient dosing regimen to improve adherence. The aim of this study was to analyze the safety of a 1:1 dose conversion from twice-daily Prograf to once-daily Graceptor in stable kidney transplant recipients. METHODS: We switched 33 Japanese patients who had undergone kidney transplantation ≥1 years before from twice-daily Prograf to once-daily Graceptor. The dose conversion ratio between Prograf and Graceptor was 1:1. We compared the following parameters: minimum tacrolimus concentration (C(min)); concentration dose per weight (CDW); serum creatinine (sCr); blood urea nitrogen (BUN); total cholesterol (TC); high-density lipoprotein cholesterol (HDL-C); uric acid (UA); fasting blood sugar (FBS). Time points for measurements were 1 month before study start and 1 and 2 months afterward. RESULTS: The mean age of the subjects in this study was 46.5 ± 13.1 years. Mean C(min) decreased from 4.55 ± 1.79 to 3.20 ± 1.22 ng/dL. The mean CDW also decreased, from 99.8 ± 69.5 to 75.0 ± 55.1 mg/dL/kg over the 2 months. There were no significant changes in sCR, BUN, UA, and FBS. Mean TC increased from 187.5 ± 51.4 to 194.3 ± 43.4 mg/dL, and mean HDL-C changed from 53.7 ± 12.0 to 56.1 ± 11 mg/dL. There were no episodes of rejection or infection. CONCLUSIONS: We conclude that switching from Prograf to Graceptor is safe and has the advantage of improving adherence. It could also have a beneficial effect in controlling glycemic levels and the adverse effects of tacrolimus. In many cases (25%-30%), the minimum concentration of tacrolimus decreased after changing tablets. With Graceptor, the ratio of area under trough level to area under the curve (AUC) is low compared with Prograf, resulting in low C(min) values of 1-2 ng/mL, and the AUC for Graceptor is very similar to that for Prograf.

Falsely abnormally elevated blood trough concentration of tacrolimus measured by antibody-conjugated magnetic immunoassay in a renal transplant recipient: a case report.

This report presents a falsely abnormally elevated blood trough concentration (C(t)) of tacrolimus measured by antibody-conjugated magnetic immunoassay (ACMIA) methods in a renal transplant recipient. Because the C(t) of tacrolimus was 78.5 ng/mL at day 2 after a 52-year-old man underwent renal transplantation, we stopped the tacrolimus extended-release formulation. However, because the abnormally elevated blood C(t) continued in the range of 41.1-59.1 ng/mL, we then measured the tacrolimus concentration in a stored blood sample before renal transplantation, it was 43 ng/mL. Consequently, the day-7 blood sample was measured with both ACMIA and enzyme-linked immunoassay, showing C(t) values of 42.8 ng/mL and 0.89 ng/mL, respectively. Because the abnormally elevated C(t) was falsely measured by the ACMIA method, we restarted tacrolimus However, the calcineurin inhibitor was subsequently converted to cyclosporine at day 21 after renal transplantation. Although cyclosporine was also measured by ACMIA, there was not an abnormally elevated C(t). Subsequently, the tacrolimus concentration ratio in plasma and whole blood (P/B-tacrolimus concentration ratio) was measured by ACMIA in a posttacrolimus blood sample. The P/B-tacrolimus concentration ratio was 100%. In contrast, the P/B-tacrolimus concentration ratio was <30% in 2 control patients administered tacrolimus. It has been reported recently that there were cases showing falsely slightly elevated C(t) of tacrolimus within the therapeutic range of concentrations. Therefore, we must be careful not to reduce the tacrolimus dose falsely. We consider confirmatory methods for a falsely abnormally elevated C(t) of tacrolimus measured by ACMIA to (1) measure P/B-tacrolimus concentration ratio, (2) compare ACMIA with another measurement, and (3) evaluate a blood sample stored before tacrolimus administration.

Early steroid withdrawal in adult kidney transplantation at a single center.

BACKGROUND: Beneficial effects of protocols using minimal steroid exposure have been recently reported. The purpose of this study was to evaluate the outcomes of kidney transplantation recipients who received immunosuppression protocols with early steroid withdrawal (ESW) at our center. METHODS: We retrospectively studied 84 kidney transplant recipients who had received ESW immunosuppressive protocols at our center from March 2005 to December 2010. The immunosuppressive regimen was a combination of calcineurin inhibitors (tacrolimus/cyclosporine), methylprednisolone, which was tapered and discontinued within 2 months, mycophenolate mofetil, and basiliximab (postoperative days 0 and 4). We compared the outcomes of our ESW recipients with those of a historical control group (February 2003 to January 2005; n = 18). RESULTS: Clinical acute rejection episodes were observed in 15 (17.9%) and 5 (27.8%) cases in the ESW and control groups, respectively. Cytomegalovirus infection occurred in 12 (14.3%) and 5 (27.8%) cases in the ESW and control groups, respectively. The creatinine levels at 1 year after transplantation were 1.3 ± 0.4 mg/dL and 1.3 ± 0.5 mg/dL in the ESW and control groups, respectively. In the ESW group of 84 recipients, actuarial patient survival at 1 year was 94.0%. In the historical group of 18 recipients, the actuarial patient survival at 1 year was 100% (P = .76). In the ESW group the graft survival rate at 1 year was 95.2%. In the historical group, graft survival rate at 1 year was 100% (P = .65). There were no significant differences in the parameters between the groups. CONCLUSIONS: The outcomes from this study were considered to be acceptable; however, the possibility of improving the protocols exists.

Correlation of motility and neuronal integrity with a focus on the grade of intestinal allograft rejection.

Intestinal graft motility after small bowel transplantation (SBT) is poorly characterized. The aim of this study was to compare motor patterns with myenteric neuronal cell population as a parameter of graft viability at various degrees of acute cellular rejection (ACR). Three grades of ACR were achieved in orthotopic allografts. Syngeneic transplants and allografts with immunosuppression served as controls. Motor activities were recorded using strain gauge force transducers and analyzed visually. Quantifications of myenteric neurons in whole mounts of intestinal grafts were used to evaluate neuronal population. A typical migrating motor complex (MMC) was found in syngeneic and allogenic transplants with immunosuppression. A high prevalence of discrete clustered contractions (DCC) and nonpropagating contractions (NPC) without MMC was seen in moderately and severely rejected allografts. Neuronal cell loss in the allografts, which could be one of the causes of motor dysfunction, was noted in moderate rejection (19.3%) and progressed until severe rejection (60.1%). Monitoring motility patterns in SBT could be an effective tool for assessing intestinal rejection. Allograft dysmotility, such as absence of MMC and high prevalence of DCC or NPC, could be useful markers of progression of acute rejection and help guide treatment decisions.

Discontinuation of living donor liver transplantation for PSC due to histological abnormalities in intraoperative donor liver biopsy.

Liver transplantation is the only curative treatment known to date for end-stage liver disease occurring as a result of primary sclerosing cholangitis (PSC). Here, we report a case in which living donor liver transplantation (LDLT) for PSC was cancelled because of histological abnormalities in intraoperative biopsy of the donor liver. The donor was the mother of the recipient, and her preoperative evaluation revealed no abnormalities. In the donor operation, the donor liver biopsy revealed expansion of the portal zone with lymphocytic infiltration and dense concentric fibrosis developed around a bile duct. These histological findings were identical to those of early-stage PSC; therefore, the LDLT was called off. The experience in this case suggests that preoperative liver biopsy may be useful to exclude first-degree relative donors with potential PSC prior to LDLT for PSC.

Various costimulatory pathways are essential for induction of regulatory cells by intratracheal delivery of alloantigen.

BACKGROUND: We previously reported that intratracheal delivery of alloantigen induced regulatory cells in a mouse heart transplantation model. We investigated the roles of costimulatory pathways in the induction of regulatory cells by intratracheal delivery of alloantigen. METHODS: CBA (H-2k) mice were pretreated with intratracheal delivery of splenocytes (1 x 10(7)) from C57BL/10 (H-2b) mice and administration of monoclonal antibodies (mAb) specific for programmed death (PD)-1 and its ligands, programmed death-ligand (PD-L)1 and PD-L2, CD70, CD134 ligand (CD134L), CD153, CD137L, or receptor activator of nuclear factor-kappaB (NF-kappaB) (RANK). Seven days later, naive CBA mice underwent adoptive transfer of splenocytes (5 x 10(7)) from the pretreated CBA mice and transplantation of C57BL/10 heart. RESULTS: Adoptive transfer of splenocytes from CBA mice that had been pretreated with intratracheal delivery of C57BL/10 splenocytes significantly prolonged the survival of C57BL/10 allograft (median survival time [MST], 68 days) as compared with adoptive transfer from untreated CBA mice (MST, 12 days). Concomitant administration of control immunoglobulin (Ig)G, anti-PD-L2 mAb, or anti-CD137L along with intratracheal delivery did not significantly affect the prolongation (MST, 72, 68, and 65 days, respectively). In contrast, anti-PD-1, anti-PD-L1, anti-CD70, anti-CD134L, anti-CD153, or anti-RANK mAb abrogated the prolongation induced by adoptive transfer from the pretreated mice with intratracheal delivery (MST, 18, 17, 16, 14, 10, and 18 days, respectively). CONCLUSION: The PD-1/PD-L1, CD27/CD70, CD134/CD134L, CD30/CD153, and tumor necrosis factor (TNF)-related activation-induced cytokine (TRANCE)/RANK interactions are independently required for generation of regulatory cells by intratracheal delivery of alloantigen.

Syenergistic effect of 15-deoxyspergualin with costimulation blockade on alloimmune response.

INTRODUCTION: A virally induced alloreactive memory seems to represent a potent barrier to tolerance induction but the combination of 15-deoxyspergualin (DSG), an inhibitor of NFkB translocation, with costimulation blockade (CB)-based chimerism as an induction regimen can overcome a preformed anti-donor memory response. In this study, we investigate the ability of DSG with CB to inhibit a naive alloimmune responses. METHODS: A BALB/c (H-2d) skin or heart was transplanted into a C57BL/6 (H-2b) recipient treated with anti-CD154 mAb (MR1; 500 mcg/d on days 0, 2, 4, 6) alone, DSG (5 mg/kg/d, days 0 to 7) alone, or both agents. Proliferation of alloreactive T cells after each treatment was also examined using a graft-versus-host disease (GvHD) model using the fluorescent dye CFSE. RESULTS: Treatment with DSG alone induced prolonged survival of the cardiac allografts (median survival time [MST]: 97.5 days). MR1 alone induced indefinite survival of cardiac allografts, although at 150 days after transplantation, the histology showed changes characteristic of chronic rejection, including interstitial fibrosis, infiltration of mononuclear cells, and intimal hyperplasia in coronary vessels. Combined treatment with DSG and MR1 induced donor-specific unresponsiveness in all recipients, graft histology showed only minimal infiltration. Treatment with DSG and MR1 also significantly prolonged the survival of skin allografts (MST: 31 days) compared with that of DSG or MR1 alone (MST: 17 and 14 days, respectively). In the GvHD model assessed with CFSE, the combined treatment was the more effective to suppress proliferation of alloreactive T cells while DSG alone inhibited proliferation more than MR1 alone. CONCLUSION: DSG potentiates anti-CD154 therapy to suppress the alloimmune response.

Simultaneous degradation of organophosphorus pesticides and p-nitrophenol by a genetically engineered Moraxella sp. with surface-expressed organophosphorus hydrolase.

Moraxella sp., a native soil organism that grows on p-nitrophenol (PNP), was genetically engineered for the simultaneous degradation of organophosphorus (OP) pesticides and p-nitrophenol (PNP). The truncated ice nucleation protein (INPNC) anchor was used to target the pesticide-hydrolyzing enzyme, organophosphorus hydrolase (OPH), onto the surface of Moraxella sp., alleviating the potential substrate uptake limitation. A shuttle vector, pPNCO33, coding for INPNC-OPH was constructed and the translocation, surface display, and functionality of OPH were demonstrated in both E. coli and Moraxella sp. However, whole cell activity was 70-fold higher in Moraxella sp. than E. coli. The resulting Moraxella sp. degraded organophosphates as well as PNP rapidly, all within 10 h. The initial hydrolysis rate was 0.6 micromol/h/mg dry weight, 1.5 micromol/h/mg dry weight, and 9.0 micromol/h/mg dry weight for methyl parathion, parathion, and paraoxon, respectively. The possibility of rapidly degrading OP pesticides and their byproducts should open up new opportunities for improved remediation of OP nerve agents in the future.

[En bloc resection of the hepatoduodenal ligament for advanced carcinoma of the biliary tract].

Theoretically, en bloc resection of the hepatoduodenal ligament is considered to be the most radical procedure for advanced carcinoma of the biliary tract. However, this procedure involves perioperative difficulties such as hepatic ischemia, portal congestion, patency of reconstructed vessels, and high incidence of operative mortality, moreover, when it is combined with resection of the liver and/or pancreas. We developed several tactics in vascular reconstruction, hepatic resection, and pancreatoduodenectomy in order to decrease the operative morbidity and mortality. We preferred to anastomose the portal vein and hepatic artery separately to avoid total hepatic ischemia, and used the porto-systemic bypass during prolonged portal reconstruction. We resected the liver without vascular clamping to minimize hepatic ischemia, and employed the simplified method of pancreatojejunostomy. To date, we performed 4 hepatoligamentectomies and 4 hepatoligament-pancreatoduodenectomies with no operative mortality, although long-term survivors were not encountered. This procedure should be evaluated with more clinical experiences after its safety and indication was established.

Silent mixed corticotroph and somatotroph macroadenomas presenting with pituitary apoplexy.

We discuss three unique cases of pituitary macroadenoma presenting with pituitary hemorrhage but without typical endocrine symptomatology. Immunohistochemical analysis indicated positive reactivity for adrenocorticotropic hormone (ACTH) and growth hormone (GH), and in situ hybridization indicated the expression of proopiomelanocortin (POMC) and GH mRNA. We designated these cases silent mixed corticotroph and somatotroph adenoma. Patient 1 was a 30-year-old man, patient 2 was a 29-year-old woman, and patient 3 was a 59-year-old woman. All patients presented with a headache of sudden onset and visual disturbance. The patients did not exhibit typical Cushing's or acromegalic features. Serum ACTH level was remarkably elevated in patient 1, and slightly elevated in patients 2 and 3. In all patients, serum GH levels were within normal range and magnetic resonance imaging revealed an intra- and suprasellar mass with pituitary hemorrhage. Transnasal pituitary surgery in the three patients disclosed a pituitary adenoma producing ACTH and GH. In patient 2, the residual adenoma reappeared along with an intratumoral hemorrhage, and was resected by secondary transnasal surgery. Silent mixed corticotroph and somatotroph adenomas are characterized by the following: no endocrine symptoms; presentation dominated by mass effect symptoms; macroadenoma presenting with acute pituitary hemorrhage; and production of both ACTH and GH.

Development of endoscopic surgery for the minimally invasive treatment of digestive and other diseases.

Minimally invasive surgery has rapidly changed the performance of surgical practice in a wide range of surgical specialities in the last decade of the 20th century. The marked progress in endoscopic surgery has been conducted especially in general and digestive surgery. The Department of Surgery, School of Medicine, Keio University has contributed to the development and establishment of endoscopic surgery in every subspeciality of general and digestive surgery. Our achievements include the development of original methods for laparoscopic wedge gastrectomy and endoscopic thyroidectomy, establishment of surgical techniques in endoscopic surgery for esophageal, gastric, colorectal and hepatobiliary diseases, and the introduction of robotics and tele-communicative technologies to endoscopic surgery.

Copper metabolism after living donor liver transplantation for hepatic failure of Wilson's disease from a gene mutated donor.

There is a genetic problem in living donor liver transplantation, involving Wilson's disease, because the majority of donors have a kinship relationship. Recently, it was reported that the serum ceruloplasmin level is insufficient in some persons with one allele mutation. The recipient was a 13-year-old male child, and the donor was a 22-year-old woman, who was his sister by a different father. The gene analysis for Wilson's disease (ATP7B gene) was preoperatively carried out by the amplification refractory mutation system-PCR. Homozygous and heterozygous deletion of 2871 cytosine (C) were detected in the recipient and donor, respectively, in the ATP7B gene. Serum ceruloplasmin level was sufficient in the donor. The right hepatic lobe graft was transplanted to the recipient. Immediately after the liver transplantation, the copper metabolism improved to increase the serum ceruloplasmin levels up to the normal range, and decrease the urinary copper excretion. However, the serum ceruloplasmin levels gradually decreased below the normal base line, although the urine copper levels continued to be low without any clinical symptoms. We should perform gene analyses and confirm the serum ceruloplasmin levels in donors before living donor liver transplantation for Wilson's disease, to screen for their impairment of copper metabolism. After living donor liver transplantation for Wilson's disease, we should carefully follow-up the transition of serum ceruloplasmin levels in the recipient.

The role of tumor necrosis factor-alpha and interleukin-1beta in ischemia-reperfusion injury of the rat small intestine.

BACKGROUND: To determine the role of tumor necrosis factor (TNF) and interleukin (IL)-1 in small-intestinal ischemia-reperfusion (I-R) injury, we investigated the effect of FR 167653, a specific IL-1 and TNF inhibitor, on warm I-R injury of the rat small intestine. MATERIALS AND METHODS: Male rats treated with either saline (NS group) or FR 167653 (FR group) underwent 150 min of warm small-intestinal ischemia by applying a vascular clip at the origin of the superior mesenteric artery. In addition to the survival analyses, we investigated plasma TNF-alpha and endotoxin levels, intestinal tissue TNF-alpha and IL-1beta levels, hematocrit values and the amount of exudates in the intestinal lumen, glutamic aspartate aminotransferase (AST), and histological findings up to 120 min after reperfusion. RESULTS: TNF-alpha and IL-1beta levels in the intestinal tissue, and plasma TNF-alpha and endotoxin levels, were significantly (P < 0.05) reduced in the FR group. Severe mucosal damage on histological findings (120 min after reperfusion) and a large amount of intraluminal exudates (60 min after reperfusion) were shown in the NS group, but these findings were significantly (P < 0.05) ameliorated in the FR group. Serum AST levels in the NS group increased 120 min after reperfusion, but this change was significantly (P<0.05) reduced in the FR group. The 30-day survival rate was 80% in the FR group and 30% in the NS group (P<0.05). CONCLUSIONS: Dual inhibition of TNF and IL-1 effectively alleviated intestinal I-R injury, suggesting the key role of TNF and IL-1 in this pathophysiology.