Kenji Wakayama

Long-Term Hepatic Allograft Acceptance Based on CD40 Blockade by ASKP1240 in Nonhuman Primates

Blockade of the CD40–CD154 costimulatory signal is an attractive strategy for immunosuppression and tolerance induction in organ transplantation. Treatment with anti‐CD154 monoclonal antibodies (mAbs) results in potent immunosuppression in nonhuman primates (NHPs). Despite plans for future clinical use, further development of these treatments was halted by complications. As an alternative approach, we have been focusing on the inhibition of the counter receptor, CD40 and have shown that a novel human anti‐CD40 mAb, ASKP1240, markedly prolongs renal allograft survival in NHPs, although allografts eventually underwent chronic allograft nephropathy. On the basis of our previous findings that a CD40–CD154 costimulation blockade induces tolerance to hepatic, but not cardiac, allografts in rodents, we tested here our hypothesis that a blockade of CD40 by ASKP1240 allows acceptance of hepatic allografts in NHPs. A 2‐week ASKP1240 induction treatment prolonged liver allograft survival in NHPs; however, the graft function deteriorated due to chronic rejection. In contrast, a 6‐month ASKP1240 maintenance monotherapy efficiently suppressed both cellular and humoral alloimmune responses and prevented rejection on the hepatic allograft. No serious side effects, including thromboembolic complications, were noted in the ASKP1240‐treated monkeys. We conclude that CD40 blockade by ASKP1240 would be a desirable immunosuppressant for clinical liver transplantation.

Surgical management of hepatocellular carcinoma with tumor thrombi in the inferior vena cava or right atrium

BackgroundThe prognosis for advanced hepatocellular carcinoma (HCC) with tumor thrombi in the inferior vena cava (IVC) or right atrium (RA) is poor, and there is no established effective treatment for this condition. Thus study aimed to evaluate the efficacy of surgical resection and prognosis after surgery for such cases.MethodsBetween January 1990 and December 2012, 891 patients underwent hepatectomy for HCC at our institution. Of these, 13 patients (1.5%) diagnosed with advanced HCC with tumor thrombi in the IVC or RA underwent hepatectomy and thrombectomy. Data detailing the surgical outcome were evaluated and recurrence-free and overall survival rates were calculated using the Kaplan-Meier method.ResultsSeven patients had an IVC thrombus and six had an RA thrombus. Extra-hepatic metastasis was diagnosed in 8 of 13 patients. Surgical procedures included three extended right lobectomies, three extended left lobectomies, five right lobectomies, and two sectionectomies. Right adrenal gland metastases were excised simultaneously in two patients. All IVC thrombi were removed under hepatic vascular exclusion and all RA thrombi were removed under cardiopulmonary bypass (CPB). Four patients (30.8%) experienced controllable postoperative complications, and there was no surgical mortality. The mean postoperative hospital stay for patients with IVC and RA thrombi was 23.6 ± 12.5 days and 21.2 ± 4.6 days, respectively. Curative resection was performed in 5 of 13 cases. The 1- and 3-year overall survival rates were 50.4%, and 21.0%, respectively, and the median survival duration was 15.3 months. The 1- and 3-year overall survival rates for patients who underwent curative surgical resection were 80.0% and 30.0%, respectively, with a median survival duration of 30.8 months. All patients who underwent curative resection developed postoperative recurrences, with a median recurrence-free survival duration of 3.8 months. The 1-year survival rate for patients who underwent noncurative surgery and had residual tumors was 29.2%, with a median survival duration of 10.5 months.ConclusionsAggressive surgical resection for HCC with tumor thrombi in the IVC or RA can be performed safely and may improve the prognoses of these patients. However, early recurrence and treatment for recurrent or metastatic tumors remain unresolved issues.

Risk factors for portal vein complications in pediatric living donor liver transplantation.

Shibasaki S, Taniguchi M, Shimamura T, Suzuki T, Yamashita K, Wakayama K, Hirokata G, Ohta M, Kamiyama T, Matsushita M, Furukawa H, Todo S. Risk factors for portal vein complications in pediatric living donor liver transplantation.
Clin Transplant 2010: 24: 550–556.
© 2009 John Wiley & Sons A/S.

Clinicopathological characteristics and prognostic factors in young patients after hepatectomy for hepatocellular carcinoma

BackgroundThe aim of this study was to analyze the clinicopathological characteristics and the prognostic factors for survival and recurrence of young patients who had undergone hepatectomy for hepatocellular carcinoma.MethodsBetween 1990 and 2010, 31 patients aged 40 years or younger (younger patient group) among 811 consecutive patients with hepatocellular carcinoma who had undergone primary hepatectomy were analyzed with regard to patient factors, including liver function, tumor factors and operative factors. The clinicopathological characteristics of the younger patients were compared with those of patients over the age of 40 (older patient group). Then the prognostic factors of the younger patients were analyzed. Continuous variables were expressed as the means ± standard deviation and compared using the χ2 test for categorical variables. Overall survival and recurrence-free survival rates were determined by the Kaplan-Meier method and analyzed by the log-rank test. The Cox proportional hazards model was used for multivariate analysis.ResultsIn the younger patients, the rates of HBs-antigen-positivity, high alpha-fetoprotein, portal invasion, intrahepatic metastasis, large tumors, low indocyanin green retention rate at 15 minutes, and anatomical resection were significantly higher than the same measures in the older patients. The five-year overall survival rate of the young patients was 49.6%. The prognostic factors of survival were HCV-antibody-positivity and low albumin status. Prognostic factors of recurrence were multiple tumors and the presence of portal invasion.ConclusionsIn younger patients, survival appeared to be primarily affected by liver function, while recurrence was affected by tumor factors. Young patients with hepatocellular carcinoma should be aggressively treated with hepatectomy due to their good pre-surgical liver function.

An intraductal papillary neoplasm of the bile duct mimicking a hemorrhagic hepatic cyst: a case report.

An intraductal papillary neoplasm of the bile duct is a biliary, epithelium-lined, cystic lesion that exhibits papillary proliferation and rarely causes large hemorrhagic cystic lesions. Here, we report a case of an intraductal papillary neoplasm of the bile duct mimicking a hemorrhagic hepatic cyst in a middle-aged man with large hemorrhagic hepatic cysts who experienced abdominal pain and repeated episodes of intracystic bleeding. Following portal vein embolization, extended right hepatic lobectomy was performed, and intraoperative cholangiography revealed communication between the intracystic space and the hepatic duct. Although histological studies revealed that the large hemorrhagic lesion was not lined with epithelium, the surrounding multilocular lesions contained biliary-derived epithelial cells that presented as papillary growths without ovarian-like stroma. A diagnosis of oncocytic-type intraductal papillary neoplasm of the bile duct was made, and we hypothesized that intracystic bleeding with denudation of the lining epithelial cells might occur as the cystically dilated bile duct increased in size. Differential diagnosis between a hemorrhagic cyst and a cyst-forming intraductal papillary neoplasm of the bile duct with bleeding is difficult. However, an intraductal papillary neoplasm of the bile duct could manifest as multilocular hemorrhagic lesions; therefore, complete resection should be performed for a better prognosis.

Hydrogen Gas Ameliorates Hepatic Reperfusion Injury After Prolonged Cold Preservation in Isolated Perfused Rat Liver

Hydrogen gas reduces ischemia and reperfusion injury (IRI) in the liver and other organs. However, the precise mechanism remains elusive. We investigated whether hydrogen gas ameliorated hepatic I/R injury after cold preservation. Rat liver was subjected to 48-h cold storage in University of Wisconsin solution. The graft was reperfused with oxygenated buffer with or without hydrogen at 37° for 90 min on an isolated perfusion apparatus, comprising the H2 (+) and H2 (-) groups, respectively. In the control group (CT), grafts were reperfused immediately without preservation. Graft function, injury, and circulatory status were assessed throughout the perfusion. Tissue samples at the end of perfusion were collected to determine histopathology, oxidative stress, and apoptosis. In the H2 (-) group, IRI was indicated by a higher aspartate aminotransferase (AST), alanine aminotransferase (ALT) leakage, portal resistance, 8-hydroxy-2-deoxyguanosine-positive cell rate, apoptotic index, and endothelial endothelin-1 expression, together with reduced bile production, oxygen consumption, and GSH/GSSG ratio (vs. CT). In the H2 (+) group, these harmful changes were significantly suppressed [vs. H2 (-)]. Hydrogen gas reduced hepatic reperfusion injury after prolonged cold preservation via the maintenance of portal flow, by protecting mitochondrial function during the early phase of reperfusion, and via the suppression of oxidative stress and inflammatory cascades thereafter.

Multiplication of alpha‐fetoprotein and protein induced by vitamin K absence‐II is a powerful predictor of prognosis and recurrence in hepatocellular carcinoma patients after a hepatectomy

To evaluate the oncological implications of multiplication of α‐fetoprotein (AFP) and protein induced by vitamin K absence or antagonists‐II (PIVKA‐II) in patients with hepatocellular carcinoma (HCC).

Portal vein stenosis after pancreatectomy following neoadjuvant chemoradiation therapy for pancreatic cancer.

Extrahepatic portal vein (PV) stenosis has various causes, such as tumor encasement, pancreatitis and as a post-surgical complication. With regard to post-pancreaticoduodenectomy, intraoperative radiation therapy with/without PV resection is reported to be associated with PV stenosis. However, there has been no report of PV stenosis after pancreatectomy following neoadjuvant chemoradiation therapy (NACRT). Here we report the cases of three patients with PV stenosis after pancreatectomy and PV resection following gemcitabine-based NACRT for pancreatic cancer and their successful treatment with stent placement. We have performed NACRT in 18 patients with borderline resectable pancreatic cancer since 2005. Of the 15 patients who completed NACRT, nine had undergone pancreatectomy. Combined portal resection was performed in eight of the nine patients. We report here three patients with PV stenosis, and thus the ratio of post-operative PV stenosis in patients with PV resection following NACRT is 37.5% in this series. We encountered no case of PV stenosis among 22 patients operated with PV resection for pancreatobiliary cancer without NACRT during the same period. A relationship between PV stenosis and NACRT is suspected, but further investigation is required to determine whether NACRT has relevance to PV stenosis.

Immunosuppressive effects of DTCM-G, a novel inhibitor of the mTOR downstream signaling pathway.

Background A newly developed compound, 3-[(dodecylthiocarbonyl)methyl]-glutarimide (DTCM-G), has been shown to inhibit nuclear translocation of c-Fos/c-Jun in a murine macrophage cell line. Herein, we studied the immunosuppressive properties and potency of DTCM-G. Methods Using purified mouse T cells, the in vitro effects of DTCM-G on activation, cytokine production, proliferation, and cell cycle progression were assessed, and a possible molecular target of DTCM-G was investigated. In a BALB/c (H-2d) to C57BL/6 (H-2b) mouse heart transplantation model, transplant recipients were administered DTCM-G, a calcineurin inhibitor (tacrolimus), and a nuclear factor-&kgr;B inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ). Treatment drugs were administered daily for 14 days after transplantation. Alloimmune responses were assessed in addition to graft survival time. Results After anti-CD3+anti-CD28 monoclonal antibody stimulation, DTCM-G significantly suppressed proliferation, interferon-&ggr; production, and cell cycle progression of activated T cells but not CD25 expression or interleukin-2 production. These effects were accompanied by inhibition of 70-kDa S6 protein kinase phosphorylation, a downstream kinase of the mammalian target of rapamycin. The addition of tacrolimus and DHMEQ to DTCM-G resulted in a robust inhibition of T-cell proliferation. In vivo combination therapy of DTCM-G plus either tacrolimus or DHMEQ significantly suppressed alloreactive interferon-&ggr;–producing precursors and markedly prolonged cardiac allograft survival. Furthermore, combination of all three agents markedly inhibited alloimmune responses and permitted long-term cardiac allograft survival. Conclusions DTCM-G inhibits T cells by suppressing the downstream signal of mammalian target of rapamycin. DTCM-G in combination with tacrolimus and DHMEQ induces a strong immunosuppressive effect in vivo.

Successful transplantation of rat hearts subjected to extended cold preservation with a novel preservation solution

Since prolonged cold preservation of the heart deteriorates the outcome of heart transplantation, a more protective preservation solution is required. We therefore developed a new solution, named Dsol, and examined whether Dsol, in comparison to UW, could better inhibit myocardial injury resulting from prolonged cold preservation. Syngeneic heterotopic heart transplantation in Lewis rats was performed after cold preservation with UW or Dsol for 24 or 36 h. In addition to graft survival, myocardial injury, ATP content, and Ca2+ ‐dependent proteases activity were assessed in the 24‐h preservation group. The cytosolic Ca2+ concentration of H9c2 cardiomyocytes after 24‐h cold preservation was assessed. Dsol significantly improved 7‐day graft survival after 36‐h preservation. After 24‐h preservation, Dsol was associated with significantly faster recovery of ATP content and less activation of calpain and caspase‐3 after reperfusion. Dsol diminished graft injury significantly, as revealed by the lower levels of infarction, apoptosis, serum LDH and AST release, and graft fibrosis at 7‐day. Dsol significantly inhibited Ca2+ overload during cold preservation. Dsol inhibited myocardial injury and improved graft survival by suppressing Ca2+ overload during the preservation and the activation of Ca2+ ‐dependent proteases. Dsol is therefore considered a better alternative to UW to ameliorate the outcome of heart transplantation.