Massive duodenal ulcer bleeding due to the ruptured hepatic artery pseudoaneurysm after living donor liver transplantation.

BACKGROUND: The rupture of a hepatic artery pseudoaneurysm (HAP) is a rare but lethal complication after living donor liver transplantation (LDLT) and often manifests as acute gastrointestinal bleeding. CASE PRESENTATION: This report describes three patients who experienced HAP after LDLT. These patients initially presented with active bleeding of a duodenal ulcer (DU) in the duodenal bulb, followed by diagnosis of the ruptured HAP by angiography. None of the patients had evidence of an active intra-abdominal infection or bile leakage preceding the rupture of HAP. All patients were initially treated by transcatheter arterial coil embolization (TAE). In all cases, TAE was successful for hemostasis but resulted in complete obstruction of the arterial inflow to the graft. Arterial revascularization by surgical reconstruction using the autologous arterial graft in one case and re-LDLT in another one was successfully performed. The other one succumbed to sepsis caused by later liver abscesses. CONCLUSION: This is the first detailed case series of massive DU bleeding as a warning signal of ruptured HAP after LDLT. HAP should be included in the differential diagnosis when an LDLT recipient presents with gastrointestinal bleeding.

Cancer therapy with major histocompatibility complex-deficient and interferon ß-producing myeloid cells derived from allogeneic embryonic stem cells.

We previously established a method to generate myeloid cells with a proliferative capability from pluripotent stem cells and designated them iPS-ML. Human iPS-ML cells share features with physiological macrophages including the capability to infiltrate into cancer tissues. We observed therapeutic effects of human iPS-ML cells expressing interferon ß (iPS-ML/interferon (IFN)-ß) in xenograft cancer models. However, assessment of host immune system-mediated therapeutic and adverse effects of this therapy is impossible by xenograft models. We currently evaluated the therapeutic effects of a mouse equivalent of human iPS-ML/IFN, a mouse embryonic stem (ES) cell-derived myeloid cell line producing IFN (ES-ML/IFN). The ES-MLs producing IFN-ß (ß-ML) and IFN-γ (γ-ML) and originating from E14 ES cells derived from the 129 mouse strain (H-2b ) were generated, and the MHC (H-2Kb , Db , and I-Ab ) genes of the ES-ML/IFN were disrupted using the clustered regularly interspaced short palindromic repeats (CRISPR)/CAS9 method. We used the ES-ML/IFN to treat allogeneic BALB/c mice (H-2d ) transplanted with Colon26 cancer cells. Treatment with ß-ML but not with γ-ML cells repressed the growth of colon cancer in the peritoneal cavity and liver. The transferred ES-ML/IFN infiltrated into cancer tissues and enhanced infiltration of T cells into cancer tissues. ES-ML/IFN therapy increased the number of immune cells in the lymphoid organs. Sensitization of both cancer antigen-specific CD8+ T cells and natural killer (NK) cells were enhanced by the therapy, and CD8+ T cells were essential for the therapeutic effect, implying that donor MHC-deficient ß-ML exhibited a therapeutic effect through the activation of host immune cells derived from allogeneic recipient mice. The results suggested the usefulness of HLA-deficient human iPS-ML/IFN-ß cells for therapy of HLA-mismatched allogeneic cancer patients.

Hydrogen-rich solution attenuates cold ischemia-reperfusion injury in rat liver transplantation.

BACKGROUND: Liver transplantation (LT) is considered the standard treatment for end-stage liver disease, but ideal donors remain in limited supply, resulting in an unavoidable increase in the need to use grafts from marginal donors. The attenuation of ischemia-reperfusion injury (IRI) in such marginal donors is therefore crucial for reducing the possibility of the primary non-function of grafts and graft loss. Some reports have found that molecular-hydrogen showed antioxidant and anti-inflammatory effects in preventing IRI in some non-hepatic transplant models. Therefore, we investigated whether or not molecular-hydrogen could attenuate IRI in LT model rats. METHODS: We used a hydrogen-rich water bath to dissolve hydrogen into solution and graft tissues and performed isogenic and orthotopic LT in Lewis rats with University of Wisconsin (UW) solution. Blood and tissue samples were collected 6 h after the reperfusion. Hepatic enzymes in serum were measured. Pathological findings including the expressions of cytokines and heme oxygenase (HO)-1 in liver tissues were evaluated. RESULTS: The concentration of hydrogen inside the graft tissues increased depending on the storage time, plateauing after 1 h. Serum liver enzyme levels were significantly lower and the histology score of liver damage markedly attenuated in the group given grafts preserved in hydrogen-rich UW solution than in the control group. The hydrogen-rich UW solution group also showed less oxidative damage and hepatocyte apoptosis than the control group, and the expression of proinflammatory cytokines tended to be lower while the protein levels of HO-1 were significantly increased (n = 3-12 per group, P < 0.05). CONCLUSIONS: Storage of liver grafts in hydrogen-rich UW solution resulted in superior functional and morphologic protection against IRI via the up-regulation of HO-1 expression.

Pretransplant trends in α-fetoprotein levels as a predictor of recurrence after living donor liver transplantation for unresectable hepatoblastoma: A single-institution experience.

LT is a practical therapeutic alternative for unresectable hepatoblastoma; however, deciding when to perform LT is difficult. The aim of this study was to optimize the timing of LT for hepatoblastoma using pretransplant trends in AFP levels. Trends in pretransplant AFP levels and their influence on post-transplant outcomes were retrospectively evaluated. All patients who underwent living donor LT for hepatoblastoma in our institution since 2002 were included. Variables analyzed included history of prior tumor resection, pretransplant AFP responses to chemotherapy, metastatic disease at diagnosis, and post-transplant chemotherapy. Eight patients (seven boys and one girl; median age, 35 months; range, 15 months-12 years) were transplanted. The overall post-transplant recurrence-free survival rate was 62.5% (5/8) with a mean follow-up of 77 months. Patients with post-transplant recurrence showed a 0.573 log increase in AFP levels after the last chemotherapy session before LT. This was significantly higher than the 0.279 log decrease observed in patients without post-transplant recurrence (P = .024). Because the AFP response cannot be accurately predicted before each cycle of chemotherapy, it may be appropriate to perform LT when AFP levels do not decrease after the last cycle and before they are found to be elevated again.

Long-term Outcomes of ABO-incompatible Pediatric Living Donor Liver Transplantation.

BACKGROUND: ABO-incompatible (ABOi) living donor liver transplantation (LDLT) has been performed to compensate for donor shortage. To date, few studies have reported detailed B-cell desensitization protocols and long-term outcomes of ABOi pediatric LDLT. METHODS: Twenty-nine pediatric ABOi LDLT recipients were retrospectively analyzed. We compared the clinical outcomes between ABOi (n = 29) and non-ABOi (n = 131) pediatric LDLT recipients. Furthermore, we evaluated the safety and efficacy of our rituximab-based regimen for ABOi pediatric LDLT (2 ≤ age < 18; n = 10). RESULTS: There were no significant differences in the incidence of infection, vascular complications, biliary complications, and acute cellular rejection between ABOi and non-ABOi groups. The cumulative graft survival rate at 1, 3, and 5 years for non-ABOi group were 92.1%, 87.0%, and 86.1%, and those for ABOi group were 82.8%, 82.8%, and 78.2%, respectively. Rituximab-based desensitization protocol could be performed safely, and reduced CD19+ lymphocyte counts effectively. Although rituximab-treated ABOi group showed comparable clinical outcomes and graft survival rate, 2 patients developed antibody-mediated rejection. CONCLUSIONS: ABOi LDLT is a feasible option for pediatric end-stage liver disease patients. However, it should be noted that current desensitization protocol does not completely prevent the onset of antibody-mediated rejection in several cases.

Intravital imaging of neutrophil recruitment in intestinal ischemia-reperfusion injury.

BACKGROUND: Neutrophils are known to be key players in innate immunity. Activated neutrophils induce local inflammation, which results in pathophysiologic changes during intestinal ischemia-reperfusion injury (IRI). However, most studies have been based on static assessments, and few have examined real-time intravital neutrophil recruitment. We herein report a method for imaging and evaluating dynamic changes in the neutrophil recruitment in intestinal IRI using two-photon laser scanning microscopy (TPLSM). METHODS: LysM-eGFP mice were subjected to 45 min of warm intestinal ischemia followed by reperfusion. Mice received an intravenous injection of tetramethylrhodamine isothiocyanate-labeled albumin to visualize the microvasculature. Using a time-lapse TPLSM technique, we directly observed the behavior of neutrophils in intestinal IRI. RESULTS: We were able to image all layers of the intestine without invasive surgical stress. At low-magnification, the number of neutrophils per field of view continued to increase for 4 h after reperfusion. High-magnification images revealed the presence or absence of blood circulation. At 0-2 h after reperfusion, rolling and adhesive neutrophils increased along the vasculature. At 2-4 h after reperfusion, the irregularity of crypt architecture and transmigration of neutrophils were observed in the lamina propria. Furthermore, TPLSM imaging revealed the villus height, the diameters of the crypt, and the number of infiltrating neutrophils in the crypt. In the IRI group, the villus height 4 h after reperfusion was significantly shorter than in the control group. CONCLUSIONS: TPLSM imaging revealed the real-time neutrophil recruitment in intestinal IRI. Z-stack imaging was useful for evaluating pathophysiological changes in the intestinal wall.

Therapy of primary and metastatic liver cancer by human iPS cell-derived myeloid cells producing interferon-ß.

BACKGROUND: iPS-ML are myeloid lineage cells with a proliferative capacity derived from induced pluripotent stem (iPS) cells. This study aimed to examine therapeutic effect of iPS-ML producing interferon-ß (iPS-ML/IFN-ß) towards primary and metastatic liver cancer and investigate the mechanism of that effect. METHODS: We established a xenograft model of liver metastasis by injecting the spleen of SCID mice with MKN-45 human gastric cancer cells and also a primary liver cancer model by injecting SK-HEP-1 human hepatocellular carcinoma cells into the liver. After cancer lesions were established, iPS-ML/IFN-ß was administered by intraperitoneal injection, and therapeutic effect was evaluated. RESULTS: The i.p. injection of iPS-ML/IFN-ß resulted in a significant retardation of cancer progression and prolonged mouse survival. The infiltration of i.p. administered iPS-ML into tumor lesions located below the liver capsule was observed, suggesting tumor-directed migration and penetration of the liver capsule by iPS-ML. The IFN-ß concentration in the liver was maintained at levels sufficient to exert an anti-cancer effect for at least 3 days post-injection, accounting for the potent therapeutic effect obtained by injection two to three times per week. CONCLUSIONS: This study demonstrates the therapeutic potential of the iPS-ML/IFN-ß in patients with liver cancer.