[in Japanese]

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[in Japanese]

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[in Japanese]

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[in Japanese]

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[in Japanese]

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Hereditary spherocytosis (HS) is a common syndrome characterized by abnormal quantities of red cell membrane proteins. In this study, we attempted to establish a simple diagnostic technique that can discriminate between HS and other conditions, such as congenital hemolytic anemia, β thalassemia (β thal), hemoglobinopathy (HP), autoimmune hemolytic anemia (AIHA), erythroenzymopathy, and iron deficiency anemia. We studied peripheral blood red cells stained with standard Wright–Giemsa and eosin-5′-maleimide (EMA), and evaluated red cell hemoglobin peak patterns by high-performance liquid chromatography (HPLC). Furthermore, the remainder of the blood sample was biochemically analyzed for quantities of red cell membrane proteins by SDS-polyacrylamide gel electrophoresis (PAGE). Red blood cells from pre-splenectomized HS (pre-HS) patients were faintly stained with EMA, whereas those from other patients and controls were brilliantly stained. Pre-HS patients exhibited lower quantities of the band 3 protein than patients with other anemias. The hemoglobin peak patterns showed abnormal and characteristic waves for patients with HP, β thal, and AIHA, but not in pre-HS or post-splenectomized HS (post-HS) patients, IDD, and controls. Pre-HS patients with low quantities of the band 3 protein showed red blood cells faintly stained with EMA, which correlated with HS and other hemolytic anemias. Red blood cells from post-HS patients were stained similarly to those from controls but were stained more brilliantly than those from pre-HS patients. Thus, these two simple techniques, EMA staining and HPLC, along with SDS-PAGE, enable the discrimination between the initial stages of HS and other anemias. However, DNA analyses may be necessary for cases where these methods cannot adequately distinguish between the conditions.

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Relapse after allogeneic hematopoietic stem cell transplantation (HSCT) shows an extremely poor prognosis. Here, we retrospectively examined both the clinical outcome and the usefulness of minimal residual disease monitoring of nineteen patients who experienced relapse after the first HSCT with the aim of identifying significant prognostic factors. The median observation period from relapse after the first HSCT was 804 days. The three-year overall survival and disease-free survival rates were 25.2±9.9% and 18.5±10.3%, respectively. Fifteen of 19 patients developed bone marrow (BM) relapse and four experienced isolated extramedullary relapse. Fourteen (12 with BM and two with extramedullary relapse) underwent a second HSCT. Eleven of twelve patients with hematological relapse in BM failed to regain complete remission and succumbed. By contrast, two patients with molecular relapse regained molecular remission after post-transplant chemotherapy and remained disease-free after the second HSCT. The time of the second HSCT was the only factor significantly associated with improved outcome. Molecular relapse was detected in four of five patients in whom MRD levels were serially measured by WT1 mRNA PCR assay. Thus, early detection of post-transplant relapse by aggressive MRD monitoring and chemotherapeutic intervention at the time of molecular relapse are mandatory to improve the clinical outcome of patients who relapsed after allogeneic HSCT.

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The HiMEC conditioning regimen, consisting of melphalan (Mel), etoposide (VP16), and carboplatin (CBDCA), has been widely employed for high-dose chemotherapy against various pediatric solid tumors: however, fatal adverse effects, especially severe renal toxicity or infection, were sometimes observed after this regimen. In this study, we retrospectively analyzed the clinical outcome of 17 patients who underwent autologous transplantation using the HiMEC regimen. The incidence and severity of regimen-related adverse effects were compared between 9 patients treated with Mel after VP16 and CBDCA treatment (post-Mel group) and 8 patients before VP16 and CBDCA treatment (pre-Mel group). Compared with the pre-Mel group, the incidence of severe hypertension was significantly higher (0% vs 66.7%, p=0.009) and the incidence of severe renal toxicity tended to be higher, although not significantly, in the post-Mel group. By contrast, the duration of severe neutropenia was significantly longer [13 days (median, range 10–18) vs 10 days (median, range 8–14), p=0.028] and the incidence of severe mucositis was significantly higher (87.5% vs 33.3%, p=0.049) in the pre-Mel group. These results suggest that the preceding administration of Mel was recommended in most patients in consideration of the higher risk of renal toxicity and angiopathy caused by the subsequent administration of Mel. However, safer administration schedules of this regimen will be required to reduce the risk of infection and mucositis caused by the preceding administration of Mel.

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There is limited information on the pharmacokinetics of micafungin (MCFG) in pediatric patients with febrile neutropenia (FN). Therefore, the pharmacokinetics and safety of MCFG were investigated in pediatric patients with FN. Plasma samples were obtained 1, 1.5, 4, 6, and 24 h after the first administration of MCFG and immediately before and 1 h after the fourth to seventh doses. Plasma MCFG concentration was measured by high-performance liquid chromatography. Plasma concentrations after intravenous infusion of MCFG at 3.8–10 mg/kg/day over 1 h were determined in 7 patients aged 3–9 years old.
The mean total clearance (CL) and distribution volume at steady state after the initial administration of MCFG were 0.351 mL/min/kg and 0.354 L/kg, respectively. Plasma MCFG concentrations decreased with a half-life of 13.4 h. These pharmacokinetic parameters were comparable to reported values in healthy adult volunteers, although CL in pediatric patients was slightly higher. The laboratory parameters of hepatic and renal functions remained unchanged from the baseline to the end of MCFG therapy. No adverse events related to MCFG were observed. The pharmacokinetics of MCFG in pediatric patients with FN is similar to that in adults. MCFG can be safely administered to pediatric patients with FN.

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Patient 1 was diagnosed as having stage 3 rhabdomyosarcoma (RMS) at age three. She achieved complete remission with chemotherapy, radiotherapy and surgery. Six months after the completion of treatment, she developed acute myeloid leukemia (AML) and received chemotherapy with allogenic peripheral blood stem cell transplantation (SCT) from her mother. She has been in remission for the past 13 years. Patient 2 with stage 3 RMS also achieved complete remission with chemotherapy, radiotherapy and surgery at age three. RMS relapsed at age five, but the patient again achieved complete remission with chemotherapy, surgery and proton radiotherapy. Six months after the completion of treatment, he developed AML and received chemotherapy with allogenic SCT from his father. He has been in remission for the past three years. Secondary AML is difficult to treat, but performing hematopoietic SCT directly after obtaining early remission with chemotherapy may improve prognosis.

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Pulmonary mucormycosis is an invasive fungal disease with a progressive clinical course and poor prognosis in patients with hematologic malignancies. Here, we report the case of a 15-year-old male with pulmonary mucormycosis during imatinib-containing induction chemotherapy for Philadelphia-chromosome-positive acute lymphoblastic leukemia. The biopsy of the lung lesion was compatible with mucormycosis. Liposomal amphotericin B (L-AMB) was administered for a prolonged period, and residual lung lesions were surgically resected. The patient underwent unrelated bone marrow transplantation, but he developed severe graft-versus-host disease and died on day 93. The patient’s mucormycosis did not relapse during the course, although no autopsy was performed for confirmation. Thus, the prolonged course of L-AMB and the surgical resection of lung lesions were effective for controlling pulmonary mucormycosis.

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Malignant lymphoma sometimes infiltrates kidneys. We report the case of an 11-year-old boy with fever and unbearable lumbar backache 5 days before admission. He was diagnosed as having multiple nodular renal and multiple spinal involvements on the basis of enhanced CT and MRI findings. His renal function was spared and blood test showed no anemia, thrombocytopenia, or blasts in contrast to high urine acid and LDH levels. We performed bone marrow examination, and he was diagnosed as having precursor B-cell lymphoblastic lymphoma (stage IV) on the basis of the findings of cell surface markers and 10.8% blasts of all nucleated cells. He was treated following the ALB-NHL03 protocols of the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG), and he attained and maintained remission. There are many differential diagnoses of renal hypovascular lesions. Renal infiltration of malignant lymphoma is one of the differential diagnoses that we should be concerned of.

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We experienced treating a 12-year-old boy who developed severe myelosuppression caused by 6-mercaptopurine (6-MP) during maintenance therapy of T-cell acute lymphoblastic leukemia. We were able to continue his chemotherapy by reducing the 6-MP dose. We suspected a relationship between his severe myelosuppression and the enzymes involved in 6-mercaptopurine metabolism, but his gene alleles that have been reported to be related to 6-MP metabolism, such as TPMT, ITPA, MTHFR, and ABCC4, were of the wild type. However, we detected a heterozygous variant in NUDT15, which was reported to be associated with 6-MP intolerance.

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A 2-year-old boy was diagnosed as having stage IV hepatoblastoma in the right hepatic lobe, liver S2 tumor, and bilateral multiple lung metastases with high α-fetoprotein levels. After chemotherapy, the right hepatic lobe and metastatic lesions in S2 were resected. Some metastatic lesions in bilateral lungs were resected thereafter. After additional chemotherapy including autologous bone marrow transplantation, the remaining metastatic lesions in the right lung and left lower lobe were resected completely 41 months after onset. Although he developed brain metastasis at 44 months, this was resected completely followed by whole-brain irradiation. Since then, he has been in remission for 19 years. Complete resection is the most important prognostic factor and a principle of hepatoblastoma treatment. This case indicates that it is indispensable for achieving cure to resect lesions completely in multimodal treatments for metastatic hepatoblastoma.

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Kaposiform hemangioendothelioma (KHE), a rare vascular neoplasm that mainly occurs during infancy, is often associated with the Kasabach-Merritt phenomenon (KMP) characterized by consumptive coagulopathy and thrombocytopenia. Although the systemic administration of corticosteroids is often used as a first-line therapy, there exist refractory cases that require alternative treatment. Here, we report the case of an infant with KHE spreading from the oral cavity to the anterior chest wall, who developed KMP and respiratory failure due to airway obstruction. The tumor was refractory to various treatments, but responded to treatment with interferon-alpha (IFNα). Despite a concern regarding its side effects in infants, IFNα can be included as a treatment option for refractory KHE.

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A 7-year-old boy, who developed diffuse papules on his trunk and extremities 1 year ago, was admitted to our hospital owing to polydipsia and polyuria. Cranial magnetic resonance imaging revealed a swelling of the pituitary gland and multiple macular lesions in the cerebellar hemisphere. Histopathological examination of a papule resected from the waist revealed the accumulation of skin dendrocyte-derived histiocytes. Multiple lesions were also detected in the skin and central nervous system; therefore, the patient was diagnosed as having disseminated juvenile xanthogranuloma (JXG). After 6 weeks of multiple-drug chemotherapy, the lesions in the pituitary gland and papules decreased in size. Maintenance therapy was provided for 1 year. Six months after the cessation of maintenance therapy, the patient is alive and shows no signs of disease progression. Because JXG affects the central nervous system, histological analysis of intracranial lesions or lesions elsewhere is mandatory for the proper selection of treatment.

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