Wild-type AIRE cooperates with p63 in HLA class II expression of medullary thymic stromal cells.

During T cell development in the thymus, autoreactive T cells are deleted through a mechanism that is actively supported by medullary epithelial cells. These epithelial cells possess particular transcription factors including autoimmune regulator (AIRE), which is responsible for regulating expression of self-antigens, as well as p63, a p53-like molecule. Here we present evidence suggesting interaction of AIRE with p63 through a SAND domain and a transactivation domain, respectively. Interestingly an AIRE molecule with a mutated SAND domain of G228W, whose genetic alteration is inherited in an autosomal dominant manner, could not establish a complex with p63 as indicated by immunoprecipitation and molecular modeling analyses. Further in vitro study indicated that the G228W mutation led to downregulation of the transcription levels of CIITA and, accordingly, the cell surface expression of HLA class II molecules in thymic epithelial cells with p63. This indicates novel involvement of AIRE and p63 in the regulation of HLA class II, and suggests that defects in the AIRE-p63 interaction may lead to malfunction of HLA-based selection of self-reactive helper CD4(+) T cells in the thymus.

[Fulminating midbrain irradiation injury of pediatric brain tumor].

We report two children with post radiation midbrain damage causing severe neurological symptoms. A twelve-year-old boy with a four year history of hydrocephalus was diagnosed with tectal glioma, which endoscopic biopsy revealed to be low grade. He underwent gamma knife radiation surgery (central 24 Gy/peripheral 12 Gy). Two months later bilateral ptosis followed by total oculomotor palsy and drowsiness developed. Despite pulsed-steroid therapy the tumor size increased up to 4.6 times in volume. The tumor was totally removed and was diagnosed as an early delayed radiation reaction pathologically. His symptoms disappeared except for a slight upper gaze palsy. The second patient was a six-year-old girl with a medulloblastoma. Following total resection and a VP shunt she received conventional radiation therapy along with chemotherapy. After the final irradiation she became comatose (JCS II-2) and MRI revealed diffuse midbrain damage with acute aqueduct obstruction, which recovered in two weeks. Reports of irradiation injuries of the midbrain in childhood are rare but it should be considered as a possible cause of fulminant symptoms requiring emergency treatment. Because of midbrain anatomical complexity, midbrain radiation therapy requires great care, especially in children.

Sacrococcygeal yolk sac tumor developing after teratoma: a clinicopathological study of pediatric sacrococcygeal germ cell tumors and a proposal of the pathogenesis of sacrococcygeal yolk sac tumors.

PURPOSE: We evaluated the clinicopathological characteristics of pediatric sacrococcygeal germ cell tumors (SGCTs) and yolk sac tumors (YSTs) developing after sacrococcygeal teratoma (SCT) resection, and discussed the pathogenesis of sacrococcygeal YST. METHODS: We retrospectively analyzed pediatric SGCT patients attending 10 Japanese institutions. RESULTS: A total of 289 patients were eligible, of which 74.6% were girls. The mean age at surgery was 7.1months. There were 194 mature and 47 immature teratomas, and 48 YSTs. YST developed after SCT resection in 13 patients (5.4% of SCTs), and was detected between 5 and 30months after resection. At initial surgery, 9 of these 13 patients were neonates, 12 underwent gross complete resection with coccygectomy, and 9 had histologically mature teratoma without microscopic YST foci. Postoperative serum alpha-fetoprotein (AFP) levels were regularly examined in 11 patients. Intervals of AFP measurement≤4months helped to detect subclinical localized YSTs for resection. CONCLUSIONS: The characteristics of SGCT in Japanese children were similar with those reported in Europe or the United States. YST developed after SCT resection not only in patients with previously reported risk factors. We recommend that patients undergo serum AFP monitoring every 3months for≥3years after SCT resection.

Treatment of stage IV malignant rhabdoid tumor of the kidney (MRTK) with ICE and VDCy: a case report.

The prognosis of stage IV malignant rhabdoid tumor of the kidney (MRTK) has been extremely poor. However, a combination of ICE (ifosfamide, carboplatin, and etoposide) and VDCy (vincristine, doxorubicin, and cyclophosphamide) was recently reported to be effective for metastatic MRTK. We describe a 21-month-old girl with stage IV MRTK who was successfully treated with ICE, VDCy, and radiotherapy. She remained well, without recurrence, 24 months after diagnosis. Alternating therapy with ICE and VDCy might become a standard regimen for stage IV MRTK, although further study is required to confirm its effectiveness.

Expression profiles and functional implications of p53-like transcription factors in thymic epithelial cell subtypes.

In this study, we investigated the localization and functional significance of p53 tumor suppressor-like molecules, p63 and p73, in human thymic epithelial cells (TECs). Immunohistochemical studies showed particular distribution profiles of p63 and p73 in thymic epithelium, in which cortical TECs preferentially expressed p63 in their nuclei whereas subcapsular and medullary TECs expressed both p63 and p73 in their nuclei. The wide distribution of p63 in TECs was further suggested by studies using TECs of primary culture. In vitro studies using two human TEC lines demonstrated that p63 was capable of up-regulating intercellular adhesion molecule-1 (ICAM-1) and enhancing the production of IL-6 and IL-8. Moreover, in vitro studies also indicated that p73, but not p63, had the capacity to induce granulocyte macrophage colony stimulating factor (GM-CSF) and granulocyte colony stimulating factor (G-CSF) in the TEC lines. These findings suggest that p63 would regulate the cell adhesive property through ICAM-1/LFA-1 interaction and the production of IL-6 and IL-8, probably in all TEC subtypes. p73 in subcapslar and medullary TECs was suggested to play a role in the regulation of the production of GM-CSF and G-CSF, which might stimulate other stromal cells such as dendritic cells, macrophages and endothelial cells around these regions.