Tsuyoshi Shimamura

Efficacy and safety of preoperative percutaneous transhepatic portal embolization with absolute ethanol: A clinical study

BACKGROUND Preoperative portal embolization has been performed by using various thrombogenic substances to increase the safety and resectability of liver surgery. We evaluated the clinical safety and efficacy of using absolute ethanol in preoperative portal embolization. METHODS Our study included 19 patients who had undergone right hepatic lobectomy. According to our criteria for right lobectomy of the liver, seven patients were not appropriate for the operation because of a high risk in each of postoperative liver failure. Those patients received preoperative right portal embolization with 11 to 32 ml absolute ethanol. The remaining 12 patients satisfied our criteria and received no preoperative embolization. RESULTS Although alanine aminotransferase concentrations increased dramatically after the embolization, all serologic changes reverted within 3 weeks. The mean volume of the nonembolized lobe increased from 320 cm3 to 619 cm3 and 667 cm3 2 and 4 weeks, respectively, after embolization. The mean regeneration rate of this lobe was 21.3 cm3 per day for the first 2 weeks and 11.4 cm3 per day for the first 4 weeks after embolization. All patients underwent right lobectomy of the liver and survived; none of the patients had severe complications associated with embolization or surgery. The postoperative survival periods were not statistically significant between the patients with and without preoperative portal embolization. CONCLUSIONS According to our criteria for liver surgery, the seven patients should not have undergone major surgery, but each underwent right lobectomy of the liver and all survived, showing that portal embolization with absolute ethanol brings about compensatory hepatic hypertrophy for major surgery and that its extreme effect on liver regeneration could widen the range of patients appropriate for liver surgery.

Perioperative Management of Hepatic Resection Toward Zero Mortality and Morbidity: Analysis of 793 Consecutive Cases in a Single Institution

BACKGROUND The mortality rates associated with hepatectomy are still not zero. Our aim was to define the risk factors for complications and to evaluate our perioperative management. STUDY DESIGN Between 2001 and 2008, 793 consecutive patients (547 men and 246 women; mean age ± SD, 56.1 ± 14.9 years) underwent hepatectomy without gastrointestinal resection and choledocojejunostomy at our center. Of these patients, 354 (44.6%) were positive for the hepatitis B virus surface antigen and/or the hepatitis C virus antibody. We categorized 783 (98.7%) patients as Child-Pugh class A. Major resection (sectionectomy, hemihepatectomy, and extended hemihepatectomy), was performed in 535 patients (67.5%) and re-resection in 81 patients (10.2%). RESULTS The median operative time was 345.5 minutes and median blood loss was 360 mL. The rate of red blood cell transfusion was 6.8%. The morbidity rate was 15.6%. Reoperations were performed in 19 patients (2.4%). The mean postoperative hospital stay was 18.4 ± 10.4 days. The in-hospital mortality rate was 0.1% (1 of 793 patients; caused by hepatic failure). The independent relative risk for morbidity was influenced by an operative time of more than 360 minutes, blood loss of more than 400 mL, and serum albumin levels of less than 3.5 g/dL, as determined using multivariate logistic regression analysis. CONCLUSIONS Shorter operative times and reduced blood loss were obtained by improving the surgical technique and using new surgical devices and intraoperative management, including anesthesia. Additionally, decision making using our algorithm and perioperative management according to CDC guidelines reduced the morbidity and mortality associated with hepatectomy.

A Human Anti‐CD40 Monoclonal Antibody, 4D11, for Kidney Transplantation in Cynomolgus Monkeys: Induction and Maintenance Therapy

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 higher‐dose 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.

A pilot study of operational tolerance with a regulatory T‐cell‐based cell therapy in living donor liver transplantation

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)

Protective role of nitric oxide in ischemia and reperfusion injury of the liver

Abstract Background: The suppressed production of nitric oxide (NO), associated with endothelial dysfunction, is thought to be a cause of ischemia and reperfusion injury of the liver. But findings of the salutary effects of NO enhancement on such injury have been conflicting. In this study, we tested our hypothesis that NO enhancement would attenuate ischemic liver injury. For this purpose, an NO precursor, L-arginine, and a novel NO donor, FK409, were applied to a 2-hour total hepatic vascular exclusion model in dogs. Study Design: L-arginine was administered IV at a dose of 100 mg/kg twice (n = 5), while 300 mg/kg twice of FK409 was infused continuously into the portal vein (n = 5). The drugs were given to the animals for 30 and 60 minutes before and after ischemia, respectively. Nontreated animals were used as the control (n = 10). Two-week survival, systemic and hepatic hemodynamics indices, liver function tests, energy metabolism, and histopathology were analyzed. Results: Both treatments comparably augmented hepatic tissue blood flow, decreased liver enzyme release, and increased high-energy phosphate restoration during the reperfusion period, all of which contributed to rescuing all of the treated animals from the 2-hour total hepatic ischemia. In contrast, ischemia caused 70% mortality in the control group. Histologically, structural abnormality and neutrophil infiltration were markedly attenuated by the treatments. Systemic hypotension was observed in the animals treated with FK409, however. Conclusions: Our data demonstrate that NO enhancement alleviates the liver injury caused by ischemia and reperfusion. The supplementation of L-arginine, rather than FK409, is considered more applicable to clinical use because of the absence of systemic adverse effects.

A novel fully human anti-CD40 monoclonal antibody, 4D11, for kidney transplantation in cynomolgus monkeys.

Background. CD40-CD154 pathway blockade by anti-CD154 monoclonal antibodies (mAbs) significantly prolongs allograft survival in nonhuman primates. However, thromboembolic complications have prevented clinical application. Thus, blockade of the counter molecule by a novel fully human anti-CD40 mAb, 4D11, is an attractive alternative. Methods. Kidney transplantations were performed between outbred cynomolgus monkeys (stimulation index >3 in a mixed lymphocyte reaction). The animals were divided into five groups: nontreatment control (Group 1, n=3), 10-week treatment with either 10 mg/kg (Group 2, n=3), 20 mg/kg (Group 3, n=3), or 40 mg/kg (Group 4, n=1), and 4-week treatment (Group 5, n=1 each) with 10 mg/kg, 20 mg/kg, or 40 mg/kg followed by monthly administration. Graft survival, biochemistry, complete blood counts, lymphocyte phenotypes, blood drug levels, antidonor and antidrug antibodies, and renal histology were examined. Results. Survival (days) was as follows: Group 1 (5, 6, 7), Group 2 (150, 108, 108), Group 3 (84, 108, 379), Group 4 (147), and Group 5 (147, 102, 112). Two animals in Group 3 with normal graft function were killed upon development of hydronephrosis and cerebral infarction. B lymphocytes fell to one-third of the preoperative value at 4 weeks after transplantation in all animals. Antidonor antibodies developed in most of the animals after stopping drug treatment or at the time of death. No animals except for one formed anti-4D11 antibody. Conclusion. 4D11 appears to be a promising agent for antirejection treatment in clinical organ transplantation.

Control of Intraoperative Bleeding During Liver Resection: Analysis of a Questionnaire Sent to 231 Japanese Hospitals

Abstract To determine the safest and most efficient way of performing hepatectomy, the differences in methods employed by Japanese surgeons were examined. In November 1998, a questionnaire on bleeding control during hepatectomy was sent to 270 hospitals located throughout Japan. The answers from 231 hospitals (85.6%) were analyzed. Surgical apparatus such as an ultrasonic dissector (USD) was used in 203 hospitals. Pringles maneuver was performed routinely in 25%, for segmentectomy and subsegmentectomy in 25%, for lobectomy in 9%, depending on the situation in 34%, and never in 7%. In 135 hospitals (60%), hemostatic materials such as fibrin glue were always applied to the cut surface after hepatectomy. The USD was chosen and widely accepted by the hospitals studied. As Japanese patients with hepatoma often have liver cirrhosis, intermittent occlusion and the selective clamping of hepatic inflow were considered preferable to persistent inflow occlusion. The gentle exposure of hepatic venous branches, careful hemostasis during hepatectomy, and accurate location of the hepatic vein by intraoperative ultrasonography were all considered to be extremely important.

Three cases of acute or fulminant hepatitis E caused by ingestion of pork meat and entrails in Hokkaido, Japan: Zoonotic food-borne transmission of hepatitis E virus and public health concerns.

Aim:  In developed countries including Japan, the transmission route of indigenous hepatitis E virus (HEV) infection is obscure. Accordingly, public health implications of indigenous HEV infection have not been well addressed. The aim of this study was to clarify the route of transmission of a small outbreak of acute hepatitis E and assess the public health implications of indigenous zoonotic HEV transmission.

Percutaneous transluminal angioplasty for hepatic artery stenosis after living donor liver transplantation

The purpose of this study was to evaluate the efficacy of percutaneous transluminal angioplasty (PTA) for treatment of hepatic artery stenosis after living donor liver transplantation. Eighteen patients with hepatic artery stenosis after living donor liver transplantation were included in this study. The success rate and complications of PTA and recurrent stenosis of the hepatic artery were evaluated. Seventeen of 18 patients (94.4%) were successfully treated without complication by a first PTA procedure. Recurrence of hepatic artery stenosis occurred in 6 patients (33.3%). Repeated PTA was performed 12 times for the 6 patients. Two complications occurred as arterial dissection and perforation. As a consequence, the complication rate was 6.7%, involving 2 of 30 procedures in total. In conclusion, PTA is effective for treatment of hepatic artery stenosis after living donor liver transplantation without an increase in the complication rate. Liver Transpl 12:465–469, 2006.

Prolongation of canine liver allograft survival by a novel immunosuppressant, FTY720. Effect of monotherapy and combined treatment with conventional drugs

BACKGROUND The immunosuppressive effect and other properties of a novel immunosuppressant, FTY720, have been studied mostly in the experimental transplantation of various extrahepatic organs. In this experiment, we evaluated the antirejection potency and adverse effects of this agent on liver grafts using a canine liver transplantation model. METHODS Forty-eight orthotopic liver transplantations were performed by the standard technique under a veno-venous bypass. Liver recipients were divided into two studies: a single-dose study with FTY720 at various doses and a combined dose study with conventional immunosuppressants (cyclosporine or tacrolimus) alone and combined with FTY720. Survival, biochemical and hematological tests, blood levels of immunosuppressants, and postmortem histology were determined. RESULTS The median survival of untreated control animals was 9 days, whereas treatment with FTY720 at a dose of 0.1 mg/kg/day prolonged graft survival to 49.5 days. FTY720 at 1 mg/kg/day showed a slight but insignificant prolongation to 16 days, but when the dose was increased to 5 mg/kg/day, the graft was rejected at 10 days. The combination of FTY720, 0.1 mg/kg/day, with a subtherapeutic dose of cyclosporine, 5 mg/kg/ day, prolonged median animal survival from 40 days with cyclosporine alone to 74 days. A combination of FTY720 (0.1 mg/kg/day) with tacrolimus (0.5 mg/kg/ day) compromised animal survival, reducing survival from 83.5 days with tacrolimus alone to 30.5 days due to infectious complication and emaciation by overimmunosuppression. No evident drug-induced side effects were observed. CONCLUSIONS FTY720 has a potent immunosuppressive effect when used alone at 0.1 mg/kg/day in canine liver transplantation. FTY720 is a promising candidate for future clinical application in orthotopic liver transplantation.