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We investigated whether multiple food allergies could be safely prevented by simultaneously administering very small amounts of multiple foods.Infants 3-4 months old with atopic dermatitis from 14 primary care pediatric clinics in Japan were enrolled in this randomized, placebo-controlled trial. The infants were administered either mixed allergenic food powder (MP) containing egg, milk, wheat, soybean, buckwheat, and peanuts, or placebo powder (PP). The amount of powder was increased in a stepwise manner on weeks 2 and 4, and continued until week 12. The occurrence of food allergy episodes after powder intervention was assessed at 18 months old. This trial was registered with the University Hospital Medical Information Network Clinical Trials Registry (number UMIN000027837).A total of 163 participants were randomly allocated to either the MP group (n = 83) or the PP group (n = 80). The incidence of food allergy episodes by 18 months was significantly different between the MP and PP groups (7/83 vs. 19/80, respectively; risk ratio 0.301 [95% CI 0.116-0.784]; P = 0.0066). Egg allergies were reduced in the MP group. In addition, food allergy episodes from any of the other five foods were significantly reduced, although the reductions in those due to individual foods were not significant.Gradually increasing the intake of very small amounts of multiple foods in early infancy can safely reduce the incidence of egg allergies. Other foods may also suppress food allergies, but no definitive conclusions could be reached.

Background: There is controversy regarding the efficacy and side effects of proactive administration of allergenic foods in early infancy to prevent food allergies. This is the first trial involving the gradual introduction of trace amounts of multiple foods to infants. Methods: Infants under 4 months old with atopic dermatitis from 14 primary care pediatric clinics in Japan were enrolled in this randomized, double-blind, placebo-controlled trial. The infants were administered either mixed allergenic food powder (MP) containing eggs, milk, wheat, soybeans, buckwheat, and peanuts, or placebo powder (PP). The amount of powder was increased in a stepwise manner on weeks 2 and 4 and continued until week 12. Weaning food was started subsequently according to the Japanese guidelines for nursing/bottle feeding, and for baby food. The occurrence of food allergy episodes after powder intervention was assessed at 18 months old by the physician responsible for each participant. Findings: A total of 163 participants were randomly allocated to either the MP group (n = 83, 50.9%) or the PP group (n = 80, 49.1%). There was a significant difference in the incidence of food allergy episodes by 18 months between the MP and PP groups (7/83 vs. 19/80, respectively; risk ratio 0.301 [95% CI 0.116 – 0.784]; P = 0.008). No serious adverse events attributable to MP were observed. Interpretation: Gradually increasing the intake of trace amounts of multiple foods in early infancy can safely reduce the incidence of food allergies. Clinical Trial Registration Details: UMIN000027837. The protocol for this study and the subsequent changes are available on the UMIN-CTR Trial website. Funding Information: This study was self-funded and did not receive any other support. Declaration of Interests: The authors declare that no conflicts of interest exist. Ethics Approval Statement: Written informed consent was obtained from the parents of the participants at the time of enrollment. The study was approved by the institutional review board of Umezu Clinic.

Treating patients with severe aplastic anemia (SAA) who fail to respond to immunosuppressive therapy (IST) and do not have an HLA-matched donor is challenging. We report favorable outcomes in 11 patients who underwent bone marrow transplantation (BMT) from an HLA-mismatched unrelated donor. The median age was 11 years (range, 3-20 years). The conditioning regimen consisted of cyclophosphamide (200 mg/kg), antithymocyte globulin (10 mg/kg), and total body irradiation (5 Gy). Patients received tacrolimus and methotrexate for prophylaxis against graft-versus-host disease (GVHD). Donorrecipient pairs were mismatched for the HLA-DR antigen in 8 patients by serologic typing. HLA-A and HLA-B antigens were mismatched in 1 and 2 patients, respectively. Ten patients achieved engraftment. One patient who failed to engraft was rescued by a second transplantation from her mother, who was mismatched at 2 HLA antigens. Acute GVHD of grades II to IV occurred in 2 patients. Three patients developed limited chronic GVHD, and 1 patient developed extensive chronic GVHD of the lung. All patients are alive at 9 to 56 months after transplantation (median, 33 months). Considering our encouraging results, HLA-mismatched unrelated-donor BMT for SAA is feasible as a salvage therapy for nonresponders to IST.

To characterize childhood acute megakaryoblastic leukaemia (AMKL), we reviewed 45 children with AMKL diagnosed between 1986 and 2005 at Nagoya University Hospital and Japanese Red Cross Nagoya First Hospital. Twenty-four patients (53%) had AMKL associated with Down syndrome (DS-AMKL) and 21 (47%) had non-DS-AMKL. The median age of the DS-AMKL patients was 21 months (range, 8-38 months) and that of non-DS-AMKL patients was 15 months (range, 2-185 months). The morphology of blast cells was categorized into three groups according to the stage of megakaryocyte maturation. The blast cells were more immature in DS-AMKL than in non-DS-AMKL in terms of morphology and immunophenotyping. Cytogenetic abnormalities of leukaemic cells were classified into seven categories: normal karyotype including constitutional trisomy 21 in DS-AMKL; numerical abnormalities only; t(1;22)(p13;q13); 3q21q26 abnormalities; t(16;21)(p11;q22); -5/del(5q) and/or -7/del(7q); and other structural changes. The outcome of children with either DS-AMKL or non-DS-AMKL is excellent. The 10-year overall survival estimate was 79% [95% confidence interval (CI): 54-90] for DS-AMKL and 76% (95% CI: 58-91) for non-DS-AMKL (P = 0.81) with a median follow-up of 78 months (range, 20-243 months). Our study shows the diverse heterogeneity of childhood AMKL and the need for subclassification according to cytogenetic and morphological features.

Recent molecular studies have revealed that the GM-CSF/RAS signaling pathway plays a central role in the pathogenesis of juvenile myelomonocytic leukemia (JMML). CFU-GM colony assay is an important test for GM-CSF hypersensitivity in patients with JMML, but requires specific skills. We established a simple and easy quantification method to test GM-CSF hypersensitivity, using a (3)H-thymidine assay. With this quantification method, JMML patients with RAS mutations showed significantly higher GM-CSF sensitivity than JMML patients with PTPN11 mutations. This method will be useful not only in the diagnosis of JMML, but also to evaluate the difference of GM-CSF sensitivity among patients.

Midkine (MK) is a heparin-binding growth factor and overexpressed in a number of solid tumors, contributing to their growth. Its expression in acute leukemia, however, has not been clarified. We examined relative levels of MK gene expression defined in K562 cells as 1.00 using real-time quantitative polymerase chain reaction (PCR) in 94 children with acute leukemia and compared with those in normal bone marrow (BM; n=18) and peripheral blood (PB; n=10). Median age was 6 years (range, 0–15 years). Diagnosis included B-precursor ALL (n=41), T-ALL (n=14), B-ALL (n=4), Ph1-ALL (n=6), infant ALL (n=5) and AML (n=24). 8 normal BM samples were separated into CD34+ and CD34− fractions. MK gene expression was detected in normal control samples. Median MK gene expression level was significantly lower in normal PB (2.9×10e-3) than in normal BM (8.0×10e-3) (p DR+,CD19+,CD10+,CD20−,slg−, DR+,CD19+,CD10+,CD20+,slg−, DR+,CD19+,CD20+,slg+. MK gene expression decreased with B-cell lineage differentiation of leulkemic blast. It was also overexpressed in more than half of the patients with FAB M1 and M2 types of AML. In contrast, overexpression of MK gene was observed only in one of the 13 patients with T-ALL and none of the 6 patients with AML-M5. Supporting the possible involvement of MK in carcinogenesis, overexpression of MK may be not only merely assoziated with total development but also related to leukemic transformation of hematopoietic progenitors. Quantification of MK gene by real-time PCR is relatively simple and widely applicable in patients with acute leukemia. This technique offers particular promise as a prognostic marker and a marker for minimal residual disease in children with B-precursor ALL.

Rabbit antithymocyte globulin (ATG) has been used in allogeneic stem cell transplantation to facilitate engraftment as well as prevent graft-versus-host disease (GVHD). ATG can reduce the incidence of acute and chronic GVHD, but it prolongs the period of immunodeficiency and increases the incidence of infectious complications such as Epstein-Barr virus-related lymphoproliferative disorders (EBV-LPD). To evaluate the advantages and disadvantages of incorporating ATG into the preconditioning regimen, we reviewed records of 70 children with malignant (n=16) or non-malignant disease (n=54) who received unmanipulated bone marrow transplant (BMT) from alternative donors at our hospitals. Eleven patients (15.7%) received BMT from an HLA-mismatched related donor and 59 (84.3%) received BMT from an unrelated voluntary donor. The median age was 9 years (range, 0–21 years). The ratio of boys to girls was 2:1. The serological compatibility of HLA was as follows: 6/6 matched (n=43), 5/6 matched (n=21), 4/6 matched (n=5), and 3/6 matched (n=1). Fifty-one patients (72.9%) received a preconditioning regimen including total body irradiation, 15 (21.4%) received busulfan-based regimens, and 4 (5.7%) received other regimens. ATG (2.5mg/kg/day) was administered for 4 days (day -5, -4, -3, and -2) in all patients. For prophylaxis against GVHD, cyclosporine + methotrexate (MTX) was administered to 34 (48.6%) patients and tacrolimus + MTX to 36 (51.4%). Stable engraftment was not achieved in 2 of 70 (2.9%) patients. Both patients were rescued by second transplants from another donor. Acute GVHD (grade 2–4) developed in 13 of 68 (19.1%) evaluable patients and chronic GVHD in 16 of 62 (25.8%) evaluable patients (limited type, 4; extensive type, 12). Six patients (8.8%) suffered from interstitial pneumonitis and 5 patients (7.4%) developed EBV-LPD. Ten patients died of regimen-related toxicities and 3 died due to relapse of malignant disease. The estimate for 5-year survival from BMT was 88.5% for patients with non-malignant disease and 51.1% for patients with malignant disease. Our dose schedule of ATG appeared to be well tolerated and effective at reducing the incidence of acute and chronic GVHD in high-risk recipients.

Juvenile myelomonocytic leukemia (JMML) is a rare clonal myeloproliferative disorder that affects young children. It is characterized by specific hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) in vitro. Mutations in RAS, NF1, or PTPN11 positioned in the GM-CSF signal transduction pathway, which contribute to myeloid proliferation, have been recognized in the pathogenesis of JMML. Recently a multi-step model for leukemogenesis has been proposed. In this model, the pathogenesis of leukemia requires at least two classes of mutations:primary mutations of genes implicated in cell differentiation such as AML1 and PU.1 andadditional mutations of genes contributing to myeloid proliferation such as FLT3, RAS, and PTPN11. We hypothesized that in patients with JMML, in addition to known mutations of genes in the GM-CSF pathway involved in myeloid proliferation, potential causative mutations of other classes might be acquired. AML1 encodes a transcription factor that is essential for definitive hematopoiesis, and its mutations have recently been found in adults with acute myeloid leukemia and myelodysplastic syndrome. However, no information is available on the profiles of mutations in these genes and the relationship between these mutations and clinical features of JMML in children. We analyzed mutations of N-RAS, K-RAS, and PTPN11 in 50, and of AML1 in 30 Japanese children with JMML by direct sequencing. Correlation between the mutational status and clinical and laboratory findings, including age at diagnosis, sex, fetal hemoglobin (HbF), platelets count, cytogenetic abnormalities, and hepatomegaly, all which are suggested prognostic factors for JMML, were also assessed. Of the 50 patients with JMML, cytogenetic abnormalities were detected in 14, including 8 with monosomy 7. PTPN11 and N-/K-RAS mutations were found in 24 (48%) and 7 (14%) patients, respectively, and a novel mutation in AML1 was identified in one patient. No simultaneous mutations in these genes were found. Age at diagnosis was older (median 36 vs 11 months, p=0.0005) and HbF level was higher (31.0% vs 5.1%, p=0.033) in patients with the PTPN11 mutation than those with the RAS mutation. No difference was observed between patients with PTPN11 and RAS mutations in sex ratio, white blood cell count, platelets count, and the incidence of cytogenetic abnormalities and hepatomegaly. Our results suggest that the clinical outcome of patients with PTPN11 might differ from those with RAS mutations because a higher level of HbF and older age have been reported to be poor prognostic factors. In one patient with JMML, we identified a novel mutation in the AML1 gene that belongs to the class of genes contributing to cell differentiation instead of the class of genes in the GM-CSF pathway involved in myeloid proliferation.