Potent immunosuppressive drugs have significantly improved early patient survival after liver transplantation (LT). However, long-term results remain unsatisfactory because of adverse events that are largely associated with lifelong immunosuppression. To solve this problem, different strategies have been undertaken to induce operational tolerance, for example, maintenance of normal graft function and histology without immunosuppressive therapy, but have achieved limited success. In this pilot study, we aimed to induce tolerance using a novel regulatory T-cell-based cell therapy in living donor LT. Adoptive transfer of an ex vivo-generated regulatory T-cell-enriched cell product was conducted in 10 consecutive adult patients early post-LT. Cells were generated using a 2-week coculture of recipient lymphocytes with irradiated donor cells in the presence of anti-CD80/86 monoclonal antibodies. Immunosuppressive agents were tapered from 6 months, reduced every 3 months, and completely discontinued by 18 months. After the culture, the generated cells displayed cell-number-dependent donor-specific inhibition in the mixed lymphocyte reaction. Infusion of these cells caused no significant adverse events. Currently, all patients are well with normal graft function and histology. Seven patients have completed successful weaning and cessation of immunosuppressive agents. At present, they have been drug free for 16-33 months; 4 patients have been drug free for more than 24 months. The other 3 recipients with autoimmune liver diseases developed mild rejection during weaning and then resumed conventional low-dose immunotherapy. Conclusions: A cell therapy using an ex vivo-generated regulatory T-cell-enriched cell product is safe and effective for drug minimization and operational tolerance induction in living donor liver recipients with nonimmunological liver diseases. (HEPATOLOGY 2016;64:632-643) SEE EDITORIAL ON PAGE 347 E arly results after liver transplantation (LT) have been greatly improved by the evolution of potent antirejection agents. However, unfortunately, late outcomes remain unsatisfactory because of immunological and nonimmunological complications that are largely associated with lifelong immunosuppression (IS). They are infection, de novo malignancy, chronic rejection, and kidney, cardiovascular, and

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The Milan criteria should be used to recommend hepatectomy for patients with HCC; however, it is important to consider the high recurrence rate after hepatectomy and the possible requirement of salvage transplantation.

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.

Blockade of CD40-CD154 signaling pathway is an attractive strategy to induce potent immunosuppression and tolerance in organ transplantation. Due to its strong immunosuppressive effect shown in nonhuman primate experiments, anti-CD154 monoclonal antibodies (mAbs) have been tried in clinical settings, but it was interrupted by unexpected thromboembolic complications. Thus, inhibition of the counter molecule, CD40, has remained an alternative approach. In the previous preliminary study, we have shown that 4D11, a novel fully human anti-CD40 mAb, has a fairly potent immunosuppressive effect on kidney allograft in nonhuman primates. In this study, we aimed to confirm the efficacy and untoward events of the 2-week induction and 180-day maintenance 4D11 treatments. In both, 4D11 significantly suppressed T-cell-mediated alloimmune responses and prolonged allograft survival. Addition of weekly 4D11 administration after the induction treatment further enhanced graft survival. Complete inhibition of both donor-specific Ab and anti-4D11 Ab productions was obtained only with higherdose maintenance therapy. No serious side effect including thromboembolic complications was noted except for a transient reduction of hematocrit in one animal, and decrease of peripheral B-cell counts in all. These results indicate that the 4D11 appears to be a promising candidate for immunosuppression in clinical organ transplantation.

4D11 appears to be a promising agent for antirejection treatment in clinical organ transplantation.

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T he evolution of liver transplantation in Japan has been quite different from its evolution in Western countries. Traditional religious, emotional, and historical issues have presented long-standing obstacles to cadaveric liver transplantation. The first brain death law was approved in Japan only 2 1 ⁄2 years ago, and only 7 cadaveric liver transplantations have been performed to date. In the past, the difficulty of performing cadaveric liver transplantation in Japan forced many patients with end-stage liver disease to seek transplantation abroad. For this reason, living donor liver transplantation (LDLT) became the primary type of liver transplantation, especially for children. 1,2 LDLT is being used with increasing frequency in adult patients 3,4 (Fig. 1).In this report, we summarize the experience with 308 adult living donor liver transplant recipients who underwent transplantation at 20 centers in Japan. Patients and Methods PatientsThree hundred eight adult patients underwent LDLT from January 1991 through December 1999. There were 200 women with a mean age of 40.8 years (range, 18 to 68 years) and 108 men with a mean age of 38.2 years (range, 18 to 64 years). Indications for LDLT were cholestatic liver diseases (n ϭ 129; 42%); chronic parenchymal liver disease, mainly caused by viral hepatitis (n ϭ 62; 20%); fulminant liver failure (n ϭ 54; 17%); metabolic liver diseases (n ϭ 43; 14%); and hepatobiliary malignancy (n ϭ 21; 7%; Fig. 2). Patients were followed up for a minimum of 3 months posttransplantation; survival and causes of mortality and morbidity were analyzed. Types of liver grafts, right lobe versus left lobe, and donor demographics were also determined.