Mast cells, discovered and named by Ehrlich, are the progenies of hematopoietic stem cells. However, they leave from bone marrow as immature progenitors and accomplish their final development after reaching the peripheral tissues. Under the influence of the surrounding environment, mast cells show different phenotypes between mucosal type and connective-tissue type cells. Now stem cell factor (SCF) is identified as the mast cell-growth factor and an in vitro-derived mast cell culture system has been established, although there still remain many mysteries to be resolved. Especially in humans, mast cell proliferative diseases are quite rare, but they frequently affect children under 2 years old, and are spontaneously regressive. However, the mechanism still remains unknown. On the other hand, the role of mast cells in the innate immune system now attracts a great deal of attention.

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It is said that home care for dying children is difficult because family attitudes toward patients and care skills are different from the care for adults in the terminal stage. But the home care needs to be prepared when a patient and family want the patient to be back home and stay with their family. A team formation the same as in the treatment of cancer, makes home care for dying children possible. The team helps patients and their family get back to their local residence, and also reduces the burden of a caregiver and creates a better time for dying children and their family. The members of a team should include not only medical staff but others from every area of the patient's daily life, such as teachers, local emergency crews, public health nurses, social service division, persons of religion et al. It is important that a conference be held as often as possible, and then staff can perform their roles smoothly and give better care, resulting in quality time for patients and family. It is hoped that a total care system is established for family and other caregivers.

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We surveyed methods of total body irradiation (TBI) in conditioning regimens of stem cell transplantation (SCT) for children with acute lymphoblastic leukemia (ALL) at participating institutions of the Japan Association of Childhood Leukemia Study (JACLS) ALL-97 protocol. We obtained information about TBI from 25 institutions. Total dose of 12 Gy fractionated by four to six in two to three days for TBI was conducted in 22 of 25 institutions. High-risk patients, such as patients with Philadelphia positive ALL, received over 12 Gy in five institutions. Beam direction and patient's positioning were horizontal and lateral respectively in 15 institutions. Shielding of lung and/or eyes and boost irradiation to central nervous system and/or testis were done in 24 and 11 institutions respectively, but in various ways. We have to keep in mind that a great variety of TBI have been undergone in each institution when we intend to interpret multi-institutional trials of treatment including SCT for patients with ALL.

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Renal involvement of acute lymphoblastic leukemia (ALL) had been frequently reported in autopsy cases in the past. Current progress of the treatment decreased this problem. We report a 4-year-old boy presenting isolated renal masses at the time of second recurrence of ALL after receiving bone marrow transplantation (BMT). After 7 months of complete remission with conventional chemotherapy, he developed the first bone marrow relapse. An allogeneic BMT was performed from a HLA-identical donor of his brother in partial remission. However, 124 days after BMT, abdominal ultrasonography unexpectedly showed bilateral renal masses. Thorough medical examination showed isolated renal invasion of the leukemic cells. This suggested that the extramedullary masses were formed by surviving leukemic cells in peripheral organs due to an insufficient effect of graft-versus-leukemia (GVL) rather than that in the marrow. During the follow-up periods after BMT, regular ultrasonography of abdomen must be done to detect isolated extramedullary involvement. Urinary cytology should be useful if indicated.

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Conservative treatment reveals good response to muscle hemorrhage with hemophilia. We report here a 16-year-old boy with mild hemophilia who had surgical removal of iliopsoas hematoma. He was referred to the hospital with a chief complaint of inguinal pain. At presentation, his left lower extremity developed psoas position and desensitization was shown on anterior and lateral aspect of the left thigh. Hemorrhage located in the left pelvic cavity onCT accounted for his neurological symptoms. He was diagnosed with iliopsoas hematoma and impairment of both left femoral nerve and left lateral femoral cutaneous nerve. At first he was treated with conservative therapy, bed rest, analgesic and coagulation factor replacement; however, deterioration of neurological symptoms prompted us to surgically remove the hematoma on the sixth day from onset. Inguinal pain was decreased remarkably after the operation. He could walk on crutches and was discharge on the eighth postoperative day. About 2 months later, the neurological symptom was normalized completely. It is necessary to recognize the anatomical specificity especially with the iliopsoas hematoma among muscle hemorrhage of the hemophilic patient because neurological damage tends to occur. It is reported that iliopsoas hematoma is occasionally seen in the mild hemophilia patient. In conclusion, it is important to take prompt surgical intervention to evade irreversible neurodegeneration in cases with poor response to conservative treatment.

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We report a 7-month-old girl at onset of juvenile myelomonocytic leukemia (JMML) demonstrating huge splenomegaly. The patient was treated by related bone marrow transplantation (r-BMT). According to MDS99, the conditioning regimen consisted of BU, Ara-C and CY, and only MTX was given for graft-versus-host disease (GVHD) prophylaxis. The post-transplant course was uneventful. She never developed severe infection and there was no evidence of clinically obvious symptoms of acute or chronic GVHD such as exanthema, diarrhea or liver dysfunction. However thrombocytopenia persisted and immature myeloid cells were seen in the peripheral blood. Following discontinuation of MTX on day 60 after r-BMT according to MDS99, huge splenomegaly started to reduce and platelet count increased gradually. We think graft-versus-leukemia (GVL) effect was induced only by discontinuation of the immunosuppressive agent. Immunosuppressive agents for post-transplant GVHD should be reduced in cases at low risk of GVHD such as related HLA-full matched BMT.

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Shp-2, a membrane-unbound tyrosine phosphatase coded by PTPN l l gene, regulates the cellular proliferation signaling in response to stimuli including cytokines. Moreover, the germline mutation of Shp-2 causes Noonan syndrome, an inherited disorder with autosomal dominant trait. Recently, it has been revealed that the somatic mutation of PTPN11 gene is involved in juvenile myelomonocytic leukemia (JMML) and other leukemias in children.These mutations are exclusively located in the N-SH2 and PTP domains of Shp-2 protein and the mutant Shp-2 gains an increased phosphatase activity as compared with the wild type Shp-2. Shp-2 physiologically suppresses the activity of GTPase-activating protein (GAP), a protein coded by NF-1 gene which inhibits Ras activity, and the mutant Shp-2, therefore, increases the Ras-signaling activity through the excessive inhibition of GAP. For patients with JMML, mutations of PTPN11 (approximately 30%), Ras (20%) or inactivation of NF-1 (15%) were mutually exclusive, and this finding suggests that these mutations may play central roles in the activation of Ras signaling which leads to an increased sensitivity to GM-CSF stimulation. In this symposium, we present our investigation of Shp-2 (PTPN11) mutation in 41 patients with NS and 29 with childhood leukemia and we also review the role of mutant Shp-2 in childhood leukemia.

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Point mutations of D835/I836 in the activation loop of the second tyrosine kinase (TK) domain of the FLT3 gene have been reported in adult acute myeloid leukemia (AML), but not in pediatric AML or acute lymphoblastic leukemia (ALL). To determine the frequency and clinical significance of mutations of the FLT3 TK, c-KIT, and PDGFRA genes in pediatric leukemias, we examined 17 cell lines and 150 fresh pediatric leukemias of AML, and 47 cell lines and 167 fresh pediatric leukemias of ALL. We found the mutations in 6 (4.7%) of 127 pediatric ALL patients more than one year old, and 8 (20%) of 40 infant ALL patients. All the mutations were heterozygous mutations. Remarkably, FLT3 TK-mutations were frequently found in 4 (21.5%) of 19 hyperdiploid ALL patients. The infant ALL patients with mutations tended to have a poorer prognosis than those without the mutations, while pediatric ALL patients more than one year with mutations had a good prognosis. We also found TK-mutations in 2 of 11 leukemic cell lines with MLL rearrangements. c-KIT mutations were found in only one patient with t (8;21) out of 150 AML patients. Mutations of PDGFRA gene were found in 2 patients of 150 AML patients. These results suggested that mutations of the FLT3, c-KIT and PDGFRA genes may be one of the second hit mutations involved in the development of pediatric ALL and AML.

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In Philadelphia chromosome (Ph1) -positive acute lymphoblastic leukemia (ALL), Imatinib induces cell-cycle arrest and apoptosis through inactivation of signaling molecules constitutively activated with BCR-ABL, but they are canceled by the addition of exogenous growth factors via reactivation of the signaling molecules. Ph 1-positive ALL is frequently sensitive to the anti-leukemic activity of TRAIL, which is expressed in cytotoxic T and natural killer cells and plays an important role in graft-versus-leukemia effect after allogeneic stem cell transplantation (allo-SCT), suggesting that recombinant soluble TRAIL will be an attractive therapeutic tool in the near future. In ALL with t(17;19), E2A-HLF promotes cell survival and might link to extremely poor prognosis. ALL cell lines with t (17;19) are highly sensitive to the anti-leukemic activity of TRAIL, suggesting the effectiveness of allo-SCT in the first complete remission. In contrast, ALL with 11q23 translocation is highly resistant to the anti-leukemic activity of TRAIL. MLL-fusions have been reported to activate histone deacetylase (HDAC) and mutations of the FLT-3 gene have been frequently identified in ALL with 11q23 translocation. Both the inhibitors against HDAC and FLT-3 have induced cell-cycle arrest and apoptosis in most cell lines with 11q23 translocation, suggesting their effectiveness in molecularly targeted therapy.

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Many researchers have been actively investigating the issue of stem cell plasticity with conflicting results. With regard to human stem cells, experiments are impeded by the lack of an appropriate assay system and limited information is available at the moment. We utilized our NOD/SCID/γ_c^null mice model, a highly efficient recipient of human hematopoietic stem cells, to approach this issue. We observed a high percentage of human type hepatocytes developing in the liver-damaged recipient mice after human hematopoietic stem cell transplantation. We are now analyzing the pathway involved in this phenomenon. The NOD/SCID/γ_c^null mice model provides an excellent tool to explore the human stem cell system in vivo.

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Embryonic stem (ES) cells are pluripotent cells derived from preimplantation embryos. Since ES cells have the ability to be maintained in culture indefinitely as undifferentiated cells, yet they are capable of forming more differentiated cell types, human ES cells recently established are expected as a novel source of human transplantable cells. We planned to produce hematopoietic stem cells (HSC) for transplantation and functional blood cells for transfusion from human ES cells. To reconstitute the hematopoietic circumstances of embryos in vitro, we established stromal cells from embryonic hematopoietic tissues. As expected, blood cells were generated from human ES cells in the coculture with the mouse embryo-derived stromal cells. We are now evaluating the function of the blood cells differentiated from human ES cells, and searching for the molecules contributing to the capability of the stromal cells to induce the differentiation of human ES cells to blood cells.

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