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A number of institutes have reported on the successful production of alpha-galactosyltransferase knockout (GalT-KO) pigs. After producing such pigs, hyperacute rejection appeared to no longer be a problem. However, acute vascular rejection (AVR)/acute humoral xenograft rejection (AHXR) is defined as a rejection that begins within 24 h after transplantation and gradually destroys the graft. The origin of AVR/AHXR continues to be a controversial topic, but is generally thought to be initiated by xeno-reactive antibodies, including non-Gal antibodies and subsequent activation of the graft endothelium, the complement and the coagulation systems. The complement is activated via the classical pathway by non-Gal antigens and ischemia-reperfusion injury, via the alternative pathway, especially on islets, and via the lectin pathway. Therefore the complement system is still an important recognition and effector mechanism of AVR/AHXR. In addition, quite recently, based on the relationship between complement and coagulation systems, a new pathway has been proposed. All complement regulatory proteins (CRPs) have the ability to regulate complement activation in different ways. Therefore, to effectively protect xenografts against AVR/AHXR, it appears reasonable to employ not only one but several CRPs including anti-complement drugs. Non-Gal antigens, such as the Hanganutziu-Deicher antigen, is still present on GalT-KO grafts. The further assessment of antigens continues to be an important issue in the area of clinical xenotransplantation. The above conclusions suggest that the expression of human CRPs on GalT-KO grafts is necessary. Moreover, multilateral inhibition of complement activation is required in conjunction with the regulation of the coagulation system.

PURPOSE We report here the outcomes and late effects of the Japanese Study Group for Pediatric Liver Tumors (JPLT)-2 protocol, on the basis of cisplatin-tetrahydropyranyl-adriamycin (CITA) with risk stratification according to the pretreatment extent of disease (PRETEXT) classification for hepatoblastoma (HB). PATIENTS AND METHODS From 1999 to 2012, 361 patients with untreated HB were enrolled. PRETEXT I/II patients were treated with up-front resection, followed by low-dose CITA (stratum 1) or received low-dose CITA, followed by surgery and postoperative chemotherapy (stratum 2). In the remaining patients, after 2 cycles of CITA, responders received the CITA regimen before resection (stratum 3), and nonresponders were switched to ifosfamide, pirarubicin, etoposide, and carboplatin (ITEC; stratum 4). Intensified chemotherapeutic regimens with autologous hematopoietic stem-cell transplantation (SCT) after resection were an optional treatment for patients with refractory/metastatic disease. RESULTS The 5-year event-free and overall survival rates of HB patients were 74.2% and 89.9%, respectively, for stratum 1, 84.8% and 90.8%%, respectively, for stratum 2, 71.6% and 85.9%%, respectively, for stratum 3, and 59.1% and 67.3%%, respectively, for stratum 4. The outcomes for CITA responders were significantly better than those for nonresponders, whose outcomes remained poor despite salvage therapy with a second-line ITEC regimen or SCT. The late effects, ototoxicity, cardiotoxicity, and delayed growth, occurred in 61, 18, and 47 patients, respectively. Thirteen secondary malignant neoplasms (SMNs), including 10 leukemia, occurred, correlating with higher exposure to pirarubicin and younger age at diagnosis. CONCLUSION The JPLT-2 protocol achieved up-front resectability in PRETEXT I/II patients with no annotation factors, and satisfactory survival in patients who were CITA responders in the remaining patients. However, outcomes for CITA nonresponders were unsatisfactory, despite therapy intensification with ITEC regimens and SCT. JPLT-2 had a relatively low incidence of cardiotoxicity but high rates of SMNs.

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Although an LDLT can successfully treat biliary atresia (BA), some patients develop liver fibrosis or inflammation. To study the incidence and risk factors associated with these complications, we performed serial protocol biopsies. Twenty-four patients with BA who received a pediatric LDLT underwent protocol biopsies. All patients received standard tacrolimus-based immunosuppression and steroids. The last available biopsies were assessed. The mean age at the time of transplant was 4.8yr and the follow-up period ranged from 1.2 to 12.3yr. The GRWR ranged from 0.8% to 4.5%. The mean time from transplantation to the latest biopsy was 4.7yr. No complications occurred with the biopsy protocol. The last available biopsies for 13 (54%) and 4 (17%) patients indicated grade 1 and grade 2 portal fibrosis, respectively, and 14 patients (54%) had inflammation. No ductopenia was detected. A younger age at LDLT was significantly correlated with graft fibrosis (p=0.036). These results indicate that biopsy-proven fibrosis can be detected in patients with BA after LDLT, even in the context of normal liver function blood tests. Therefore, a serial biopsy is a safe and effective follow-up procedure for pediatric LDLT.