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In the present study, we found that EZH1 depletion in MYCN‐amplified neuroblastoma cells resulted in significant cell death as well as xenograft inhibition. EZH1 depletion decreased the level of H3K27me1; the interaction and protein stabilization of MYCN and EZH1 appear to play roles in epigenetic transcriptional regulation. Transcriptome analysis of EZH1‐depleted cells resulted in downregulation of the cell cycle progression‐related pathway. In particular, Gene Set Enrichment Analysis revealed downregulation of reactome E2F‐mediated regulation of DNA replication along with key genes of this process, TYMS, POLA2, and CCNA1. TYMS and POLA2 were transcriptionally activated by MYCN and EZH1‐related epigenetic modification. Treatment with the EZH1/2 inhibitor UNC1999 also induced cell death, decreased H3K27 methylation, and reduced the levels of TYMS in neuroblastoma cells. Previous reports indicated neuroblastoma cells are resistant to 5‐fluorouracil (5‐FU) and TYMS (encoding thymidylate synthetase) has been considered the primary site of action for folate analogues. Intriguingly, UNC1999 treatment significantly sensitized MYCN‐amplified neuroblastoma cells to 5‐FU treatment, suggesting that EZH inhibition could be an effective strategy for development of a new epigenetic treatment for neuroblastoma. [ABSTRACT FROM AUTHOR]

Dendritic cells (DC) play a key role in the initiation of both antitumor immunity and immunological tolerance. It has been demonstrated that exposure to soluble factors produced by tumor cells modulates DC functions and induces tolerogenic DC differentiation. In this study, we investigated the effects of neuroblastoma cell line‐derived soluble factors on DC differentiation. Monocytes isolated from healthy volunteers were incubated with interleukin (IL)‐4 and granulocyte‐macrophage colony‐stimulating factor in the presence of culture supernatants from neuroblastoma cell lines. The culture supernatants from neuroblastoma cell lines, such as NLF and GOTO, partially blocked both downregulation of CD14 and upregulation of CD1a, and dramatically decreased IL‐12 and tumor necrosis factor (TNF)‐α production from mature DC, while no effect of SH‐SY5Y cell supernatant was noted. In addition, IL‐6 and IL‐10 production from monocytes was increased by the supernatants of NLF and GOTO cells at 24 hours after incubation. Furthermore, we evaluated DC functions through stimulation of invariant natural killer T (iNKT) cells. α‐Galactosylceramide‐pulsed DC co‐cultured with supernatants of NLF cells were unable to sufficiently stimulate iNKT cells. The decreased ability of iNKT cells to produce interferon (IFN)‐γ after stimulation with neuroblastoma cell line supernatant‐cultured DC was reversed by addition of IL‐12. CD40 expression and IL‐12 production in NLF‐sup‐treated DC were increased by addition of exogenous IFN‐γ. These results indicate that tolerogenic DC are induced in the neuroblastoma tumor microenvironment and attenuate the antitumor effects of iNKT cells. Interactions between iNKT cells and αGalCer‐pulsed DC have the potential to restore the immunosuppression of tolerogenic DC through IFN‐γ production. Treatment with NLF‐sup and GOTO‐sup induces the secretion of IL‐6 and IL‐10 by monocytes and generates tolerogenic DCs. Tolerogenic DCs secrete little IL‐12 and TNF‐α after maturation stimuli and have a decreased ability to activate iNKT cells. Furthermore, NLF‐sup‐treated DCs elevate CD40 expression and increase IL‐12 production by addition of IFN‐γ, and the interactions between iNKT cells and αGalCer‐pulsed DCs have the potential to recover the immunosuppression of tolerogenic DCs. [ABSTRACT FROM AUTHOR]

Abstract: HVOO can be a critical complication in pediatric LDLT. The aim of this study was to evaluate a modified triangular technique of hepatic vein reconstruction for preventing HVOO in pediatric LDLT. A total of 298 pediatric LDLTs were performed using a left lateral segment graft by 2 methods for reconstruction of the hepatic vein. In 177 recipients, slit‐shaped anastomosis was indicated with partial clamp of the IVC. A total of 121 recipients subjected to the modified triangular anastomosis with total clamp of the IVC. We compared the incidence of hepatic vein anastomotic complications between these 2 methods. Nine of the 177 cases (5.3%) treated with the conventional technique were diagnosed with outflow obstruction. All 9 cases underwent hepatic vein reconstruction with the slit‐shaped hepatic vein anastomosis. In contrast, there were no cases of outflow obstruction in the 121 cases treated with the modified triangular anastomosis. The modified triangular technique of hepatic vein reconstruction with total clamping of the IVC was useful for preventing HVOO in pediatric LDLT. [ABSTRACT FROM AUTHOR]

Anti-ganglioside GD2 antibodies mainly work through antibody-dependent cellular cytotoxicity (ADCC) and have demonstrated clinical benefit for children with neuroblastoma. However, high-risk neuroblastoma still has a high recurrence rate. For further improvement in patient outcomes, ways to maximize the cytotoxic effects of anti-GD2 therapies with minimal toxicity are required. Activated invariant natural killer T (iNKT) cells enhance both innate and type I acquired anti-tumor immunity by producing several kinds of cytokines. In this report, we investigated the feasibility of combination therapy using iNKT cells and an anti-GD2 antibody. Although some of the expanded iNKT cells expressed natural killer (NK) cell markers, including FcγR, iNKT cells were not directly associated with ADCC. When co-cultured with activated iNKT cells, granzyme A, granzyme B and interferon gamma (IFNγ) production from NK cells were upregulated, and the cytotoxicity of NK cells treated with anti-GD2 antibodies was increased. Not only cytokines produced by activated iNKT cells, but also NK-NKT cell contact or NK cell-dendritic cell contact contributed to the increase in NK cell cytotoxicity and further IFNγ production by iNKT cells and NK cells. In conclusion, iNKT cell-based immunotherapy could be an appropriate candidate for anti-GD2 antibody therapy for neuroblastoma. [ABSTRACT FROM AUTHOR]

Background Hepatoblastoma is a rare childhood malignant tumor that originates from immature hepatic cells. Aminopeptidase- N( CD13), an ectopeptidase that promotes tumor invasion and metastasis, is expressed in fetal stage hepatic progenitor cells, although its role in hepatoblastoma remains unclear. Methods The expression pattern of CD13 was investigated on immunohistochemistry in 30 tissue samples from 27 hepatoblastoma patients (16 with predominantly embryonal [ pE] histology and 14 with predominantly fetal [ pF] histology). Immunoreactive score ( IRS) was used to quantify staining data, and the relationship between CD13 expression, clinicopathological factors, and clinical outcome was investigated. The biological function of CD13 was also examined in the hepatoblastoma cell lines Huh6 and HepG2. Results All specimens stained positive for CD13, with higher CD13 expression in pE than in pF hepatoblastoma samples (median IRS, 4; range, 2-9 vs 2; range, 1-4). Strong CD13 expression was correlated with vascular invasion. Five year event-free survival and overall survival were better in patients with CD13low than in those with CD13high tumors (100% vs 51.0%, P = 0.026; and 100% vs 74.0%, P = 0.114, respectively). A CD13-neutralizing antibody and the potent CD13 inhibitor, Ubenimex, suppressed invasive activity in HepG2 cells in vitro. Conclusions CD13 expression is associated with hepatoblastoma invasiveness and could be a novel prognostic marker for hepatoblastoma. [ABSTRACT FROM AUTHOR]

Langerhans cell histiocytosis ( LCH) is a rare proliferative disease accompanied by the accumulation of pathological Langerhans cells, which often spreads into multi-site and multi-organ systems. We here describe a girl with a history of Kawasaki disease and cervical lymphadenopathy who presented with occipital LCH. Adrenal tumor was detected on staging evaluation of LCH and was diagnosed as neuroblastoma on resection using laparoscopic surgery. Neither tumor relapsed following chemotherapy for LCH and resection of neuroblastoma. Although LCH often spreads into multi-organ lesions, invasive biopsy may be needed for tumors with atypical localization for LCH in consideration of the synchronous occurrence of malignancies. [ABSTRACT FROM AUTHOR]