The identification of the receptor activator of NF-kappaB ligand (RANKL) /RANK/OPG (osteoprotegerin) system and bisphosphonates (BPs) represents a major advance in bone biology. BPs have also recently become important in the management of tumor-induced osteoclastgenesis, and they now have a widely recognized role for adult patients with malignancy. However, in pediatric hemato-oncological settings, clinical use of BPs is limited except for tumor-induced hypercalcemia. First, in this present review we summarize BP therapy for tumor-induced hypercalcemia and bony morbidity as a complication of treating acute lymphoblastic leukemia. Secondary, we summarize the role of the RANKL /RANK / OPG system in osteolytic lesion and the efficacy of nitrogen-containing BPs due to direct antitumor effect via the inactivation of Ras proteins as a result of these biochemical effects on the mevalonate pathway (leading to caspase-dependent apoptosis, inhibiting matrix metalloproteinases and angiogenesis, and downregulating integrins) and due to indirect anti-tumor effect by expanding γδT cells. Finally, we present our preclinical and clinical study of BP therapy for Langerhans cell histiocytosis (LCH) with refractory osteolytic lesions and discuss the role of RANKL + T cell and abnormal differentiation of myeloid-derived dendritic cells in LCH. Furthermore we highlight now ongoing preclinical BP therapy studies on advanced neuroblastoma with bone metastases, Ph+ leukemia, γδT cell immunotherapy and cancer-induced bone pain. Further preclinical studies are ongoing to fully elucidate these biochemical mechanisms, and well-designed clinical trials are necessary to investigate whether the anti-tumor potential of BPs can be realized in the clinical setting.

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Although most pediatric oncologists are aware that Li-Fraumeni syndrome (LFS) is characterized by germline p53 mutations, few appreciate that the discovery of this syndrome in 1969 ultimately finds its origins in the detailed epidemiological investigations of cancer in the victims of the atomic bomb at Hiroshima. Both Dr. Robert W. Miller, a pediatrician who became Director of the U.S. National Cancer Institute, and many Japanese pediatricians and paramedical staff from the Atomic Bomb Casualty Commission (ABCC) Pediatrics Study expended enormous efforts to clarify this relationship. The importance of the study of cancer clusters to better understand cancer etiology is derived from their work. We now understand LFS to be a rare autosomal dominantly inherited familial cancer predisposition syndrome characterized by malignancies of both epithelial and mesenchymal origin including soft tissue sarcomas, breast cancer, osteosarcoma, leukemia, brain tumors and adrenocortical carcinoma. In 1990, constitutional mutations of the p53 tumor suppressor gene were shown to be responsible for LFS, a discovery that defined cancer as a genetic disease. Since then, LFS has been the subject of intense clinical and fundamental biological investigation. Recent studies suggest that the types of tumors that develop may in part be determined by the specific p53 mutation, and that murine models of p53 dysfunction accurately reflect the LFS phenotype, providing in vivo models with which to study p53-mediated mechanisms of carcinogenesis. Whereas approximately 70% of LFS is associated with p53 mutations, the cause of the remaining 30% are generally unknown. This unpredictability of genetic penetrance raises numerous ethical issues related to genetic testing and clinical surveillance. This year, 2005, is the 60th anniversary of the bombing of Hiroshima, an appropriate time to review what is known about LFS, the paradigm cancer predisposition syndrome.

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To elucidate the influence of various storage conditions on cell viability and flow cytometric (FCM) detection of cell surface antigens, bone marrow aspirates obtained from 8 patients with acute lymphoblastic leukemia were divided into aliquots with or without culture medium, and stored at 4°C or 20°C for 12, 24, and 48 h. Mononuclear cells were isolated from aliquots either immediately after bone marrow collection or after storage under various conditions. There were no significant differences between fresh and stored cells in cell viability assessed with trypan blue stain, or in FCM detection of cell surface antigens including CD10, CD19, CD20, CD34, CD38, CD45 and CD58. However, CD22 levels that were positive in 2 patients became negative under all storage conditions. These results indicate that FCM with CD22 antibody may affect an evaluation of neoplastic B cell differentiation when samples are not processed immediately after collection.

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We mailed a questionnaire to pediatric hematologists in 22 hospitals participating in the Children's Cancer and Leukemia Study Group on pain care, anesthesia and informed assent for painful procedures (spinal puncture and bone marrow aspiration). When performing spinal puncture, 15 hospitals (68.2%) provide general anesthesia to 3-year-old patients and two hospitals (9.1%) do not. Of the 22 hospitals surveyed, nine (40.9%) provide local anesthesia and seven (31.8%) do not provide anesthesia to 14-year-old patients during spinal puncture. When performing bone marrow aspiration, 16 hospitals provide general anesthesia to 3-year-old patients but 15 hospitals only provide local anesthesia to 14-year-old patients. Monitoring and management of patients during and after sedation also differed between hospitals. Of 22 hospitals, 11 hospitals ask family members to check the patient's state after sedation. Before these procedures, all hospitals explain the procedures to 14-year-old patients. Eight hospitals do not explain the procedure to 5-year-old patients. These results indicate that the guidelines on pain care for painful procedures must be considered for children with leukemia.

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We encountered a 3-year-old boy with isolated left testicular relapse of acute myelogenous leukemia (AML : FAB classification M5a) that occurred 11 months after the completion of chemotherapy. The bone marrow specimen revealed a massive infiltration of monoblasts with chromosomes involving t (9; 11) (p22; q23) at the initial diagnosis. At the time of recurrence, histopathological findings on biopsied testis mimicked those of non-Hodgkin's lymphoma (NHL); however, MLL/AF9 chimera mRNA was detected from blasts of testis by reverse transcription-polymerase chain reaction (RT-PCR). On the basis of this finding, he was diagnosed as having testicular relapse of acute myelogenous leukemia. Although a bone marrow specimen revealed infiltration of leukemic cells and monoblasts were detected in cerebrospinal fluid, he has again been in remission with AML-99 protocol. As testicular relapse in AML is extremely rare, it was difficult for us to diagnose this case. It is suggested that RT-PCR is useful to diagnose overt testicular relapse of AML, even though histopathological findings mimic those of NHL.

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We report a case of macrophage activation syndrome (MAS) that was treated successfully with a liposteroid, dexamethasone palmitate. The patient was a 5-year-old girl who had developed systemic-onset juvenile idiopathic arthritis at the age of 3 years and 8 months, and suffered a second episode of MAS with high fever, vomiting, diarrhea and consciousness disturbance. Although her condition was complicated by disseminated intravascular coagulation, cardiac failure and renal insufficiency, administration of dexamethasone palmitate (10 mg/m²/day) promptly relieved her symptoms. Because rapidly fatal cases of MAS have been reported, prompt first-line treatment for MAS is important. In some cases of MAS with renal insufficiency where use of cyclosporine A is difficult, dexamethasone palmitate might be added as a first-line treatment of MAS.

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We report a case of double cancer of acute lymphoblastic leukemia (ALL) and renal cell carcinoma. A 6-year-old boy was referred to the hospital to make a correct diagnosis for a suprarenal mass detected by CT and ultrasound. He underwent needle biopsy and pathological finding was consistent with renal cell carcinoma. In the consolidation phase, he underwent left nephrectomy. The mass was completely removed with a negative margin and the pathological stage was pT2NOMO. Six months after the surgery, he underwent bone marrow transplant from an unrelated donor for his ALL.

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There have been few reported cases of autoimmune neutropenia combined with thrombocytopenic purpura with clearly identifiable autoantibodies against specific antigens. We here describe the case of 6-month-female with autoimmune neutropenia and thrombocytopenic purpura in whom we were able to identify autoantibodies against NA1 antigen of neutrophils, and GPIIb/IIIa and GPIb/IX antigens of platelets at her acute stage. Virologic studies including parvovirus B19, cytomegalovirus, and Epstein-Barr virus were all negative. Following treatment with 1 g/kg γ-globulin, platelet counts increased gradually and reached the normal level at 3 months. Neutrophil counts were refractory to the γ-globulin treatment, but they exceeded 500 /μl at 5 months, and the patient did not suffer from any serious infection by prophylactic administration of sulfamethoxazole and trimethoprim. A review of the Japanese literature revealed that the occurrence of autoimmune cytopenia has two age peaks, one at around 1 year and one after 10 years, and the latter cases tend to have certain underlying disorders.

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We report a 3-year-old girl with precursor B-cell acute lymphoblastic leukemia (ALL). Cytogenetic analysis at diagnosis showed 46, XX, t (3;12) (q12;p12), -18, +mar/47, idem, +8; however, cDNA panhandle polymerase chain reaction revealed the TEL-AML1 fusion transcript created by t (12, 21) (p13;q22). The counterpart gene of TEL was not located to the gene on 3q12 predicted by cytogenetic analysis but to AML1 gene on 21q22. She has so far survived to the age of five and half years. TEL-AML1 fusion gene is the most common molecular genetic abnormality in childhood ALL. However, the t (12, 21) (p13;q22) is usually difficult to detect by chromosome analysis because of reciprocal translocation in the refined region of the chromosomal tail end. Molecular analysis would be needed to detect TEL-AML1 fusion gene in normal karyotype and the other chromosomal abnormality involving chromosome 12 at band p12-13.

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We report a 6-year-old boy with atypical Burkitt lymphoma who presented with paraplegia. Bone marrow smear showed that the majority of nuclear cells were leukemic blasts with L3 morphology. Flow cytometry revealed neoplastic clone consistent with B-precursor immunophenotype (CD 10⁺, CD 19⁺, HLA-DR⁺), on the basis of a lack of cytoplasmic immunoglobulins, surface immunoglobulins and light chain immunoglobulins. Accordingly he initially received chemotherapy for B-precursor lymphoblastic lymphoma and then switched to B-NHL treatment protocol after cytogenetic study revealed t (8;14) (q24;q32), which is the characteristic translocation for Burkitt lymphoma. He achieved complete remission after the first induction course and maintained the remission state for the 6 months of chemotherapy. However he relapsed 1 month after off going therapy. The blast cells in the bone marrow expressed the same cell markers. The second remission state was achieved only after unrelated cord blood transplant but unfortunately the blast cells were detected in his peripheral blood on day 42 post-transplant. He died of progressive disease 12 months after initial presentation.

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Because of improvements in the treatment of aplastic anemia (AA), such as allogenic bone marrow transplantation (BMT) and immunosuppressive therapy (IST) in the past several decades, the survival rate of patients is between 80 and 90%. The number of long-term survivors after treatment of AA has been increasing, and quality of life (QOL) has become an important end-point. A retrospective comparative study under The Japanese Society of Pediatric Hematology Aplastic Anemia Committee was designed to assess the QOL in the group of children with acquired AA treated with BMT or IST. Children with AA undergoing an IST or an allogenic BMT from 1992 to 1997 were eligible for this study. The IST group were treated by the protocol of the Japan Childhood Aplastic Anemia Study Group. Questionnaires for QOL assessment have been completed by their parents. Comparative QOL studies are now under review to obtain data for use in medical decision making.

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A total of 580 aplastic anemia (AA) related cases who received the first hematopoietic stem cell transplantation (SCT) between 1980 and 2002 were analyzed. Survival curves were calculated by overall survival (OS) and event free survival (EFS). They consisted of 494 AA, 53 Fanconi anemia, 30 pure red cell anemia (PRCA) and 3 other cases. They were 316 boys and 264 girls whose age at SCT ranged from 5 months (5 m) to 31 years 2 months (31y2m) (median 10y4m). The observation period ranged from 0 m to 250 m (median 69 m). OS/EFS of AA from HLA matched siblings, AA from other than HLA matched siblings, Fanconi anemia and PRCA were 85.0 ± 4.4%/76.5 ± 4.5%, 73.9±3.6%/68.9±3.8%, 48.0± 15.9%/48.0± 15.9% and 83.2±6.9%/73.2±8.1%, respectively.

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Multicenter studies show that intensive immunosuppression with antithymocyte globulin and cyclosporine restore the hematopoiesis in 60 to 70% of children with acquired aplastic anemia. The remaining 30 to 40% of children do not respond to the current drug regimens. Unresponsive children might suffer from a nonimmunologic disease. It is quite useful to develop a method which will predict responsiveness to immunosuppressive therapy.

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