Naoki Sakata

Isolation of human herpesvirus 7 from a child with symptoms mimicking chronic Epstein‐Barr virus infection

Summary. Human herpesvirus‐7 (HHV‐7), which is a newly identified human herpesvirus with an unknown pathologic role, was isolated from a 5‐year‐old boy suffering from fever, hepatosplenomegaly and pancytopenia. Although the clinical course was similar to that of chronic active Epstein‐Barr virus infection, no viruses other than HHV‐7 were isolated. This finding raises the possibility that HHV‐7 played a pathogenic role in the present patient.

Development of Langerhans cell histiocytosis associated with chronic active Epstein–Barr virus infection

Chronic active Epstein–Barr virus (CAEBV) infection is characterized by a status of lymphoproliferative disease of EBV‐infected cells, resulting in chronic or recurrent infectious mononucleosis‐like symptoms. CAEBV is always accompanied by life‐threatening complications. We report the case of a 2‐year‐old female patient with CAEBV who subsequently developed Langerhans cell histiocytosis (LCH) presenting with bilateral exophthalmos, bone, and skin involvement. In situ hybridization for EBER revealed EBV‐infected B‐cells present in lesional tissue implying that interactions between EBV‐infected B‐cells and lesional Langerhans cells may be associated with the development of LCH. Pediatr Blood Cancer 2008;50:924–927.

Features and outcome of neonatal leukemia in Japan: Experience of the Japan Infant Leukemia Study Group

Neonatal leukemia characterized by early stem cell origin and extramedullary infiltration in the first 4 weeks of life is rare. We analyzed the features and outcome of neonatal leukemia in Japan to establish an appropriate treatment strategy for this rare disorder.

Autologous Hematopoietic Stem Cell Transplantation for 3 Patients with Severe Juvenile Rheumatoid Arthritis

We performed autologous CD34+ stem cell transplantation in 3 patients with juvenile rheumatoid arthritis (JRA) refractory to conventional treatment. All patients had systemic type JRA. In case 1 (a 3-year-old boy), purified CD34+ cells from bone marrow were transplanted after a preconditioning regimen consisting of cyclophosphamide (200 mg/kg) and antithymocyte globulin (ATG) (40 mg/kg). However, the disease flared soon after transplantation. In case 2 (a 13-year-old girl) and case 3 (a 21-year-old woman), a preconditioning regimen consisting of etoposide (VP16) (2 g/m2), thiotepa (300 mg/m2), and ATG (40 mg/kg) was followed by transplantation of purified CD34+ stem cells harvested from peripheral blood mononuclear cells. The patients in cases 2 and 3 attained complete remission without any medication. Thus for patients with refractory JRA, autologous CD34+ cell transplantation appears to be a safe and feasible choice of treatment in terms of good quality of life. However, a greater number of patients and a longer observation period are needed before definitive conclusions can be drawn.

Clinical significance of minimal residual disease in childhood acute myeloid leukemia

Many studies have assessed the clinical significance of the detection of minimal residual disease (MRD) in acute leukemia.Thus far, many studies have suggested that MRD detection to evaluate the response to chemotherapy is useful for predicting the prognosis of childhood acute lymphoblastic leukemia (ALL). However, few studies have reported on the significance of MRD in childhood acute myeloid leukemia (AML), because of small numbers of patients and limited availability of MRD markers.Therefore, we monitored MRD using currently available markers at several points during the treatment for childhood AML and tried to intensify the treatment based on the results of MRD.Thirty-one patients (26 de novo cases and 5 other cases) were examined for MRD between February 1999 and May 2002.After the first consolidation therapy (consolidation 1), the expression of Wilms tumor gene (WT1) and/or leukemia-specific fusion genes such as AML1/MTG8,PML/RAR_, and MYH11/CBF_were analyzed. Patients with positive MRD but in hematological remission at that point were recommended to undergo stem cell transplantation (SCT). Positive WT1 expression (more than 103 copies/_g RNA) was detected in 18 of 31 patients (58.1%) at onset. After consolidation 1 therapy, the WT1 expression became negative in 14 of 18 patients. The AML1/MTG8 fusion gene was expressed in 8 patients,PML/ RAR_was expressed in 3 patients, and MYH11/CBF_ was expressed in 1 patient.Four of the 8 patients withAML1/MTG8 expression and all 3 with PML/RAR_expression also demonstrated positive WT1 expression at onset. Eight (5 de novo cases and 3 other cases) of the 31 patients had no available MRD markers. Four patients who showed persistently high expression of WT1 after consolidation 1 therapy underwent SCT, and only 1 patient remained in complete remission (CR). Among 14 patients who became negative for WT1 expression, 6 patients received SCT for various reasons. Among 8 patients with the AML1/MTG8 fusion gene, 2 became MRD negative and 6 continued to be positive. Four of these 6 patients underwent SCT, and all but one who underwent syngeneic SCT became MRD negative. On the other hand, 1 of the 2 patients who continued on chemotherapy continued to be MRD positive, suggesting a graft-versus-leukemia effect in allogeneic SCT. All patients with the PML/RAR_and MYH11/CBF_ fusion gene continued to be in CR. The 3-year event-free survival in de novo AML was 69.4% _ 9.8% (n = 26), a result that is encouraging and superior to other reported outcomes.Thus, an MRD-based treatment strategy together with conventional risk factors appears to be required for further improving the outcomes of AML.

Rabbit antithymocyte globulin and cyclosporine as first-line therapy for children with acquired aplastic anemia

To the editor: Horse antithymocyte globulin (hATG) and cyclosporine have been used as standard therapy for children with acquired aplastic anemia (AA) for whom an HLA-matched family donor is unavailable. However, in 2009, hATG (lymphoglobulin; Genzyme) was withdrawn and replaced by rabbit ATG (rATG

Rapid disappearance of AMLI/ETO fusion transcripts in patients with t(8;21) acute myeloid leukemia following bone marrow transplantation and chemotherapy

To assess the clinical significance of monitoring minimal residual disease in t(8;21)(q22;q22) AML, RT-PCR assay was conducted during the clinical course of 12 patients who had undergone BMT or conventional chemotherapy. Two cases relapsed after BMT and chimeric RNA was detected soon after BMT in their bone marrow cells. The other three cases, in whom chimeric RNA was not detected after BMT, are in CR at 21 to 33 months following BMT. Similarly, four out of 7 cases who showed negative chimeric RNA after completion of chemotherapy have been in CR at 11 to 34 months following completion of chemotherapy. The present findings appear different from other studies which reported the detection of AML1-ETO chimeric RNA in long-term CR patients.

Unrelated donor marrow transplantation for congenital immunodeficiency and metabolic disease: An update of the experience of the Japan Marrow Donor Program

We retrospectively analyzed the clinical results of 81 patients with congenital genetic diseases who were treated with bone marrow transplantation (BMT) from unrelated donors identified through the Japan Marrow Donor Program.The patients were aged between 1 and 38 years (median, 4 years).Thirty-five patients underwent transplantation for metabolic disease (MD), ie, mucopolysaccharidosis (n = 25), adrenoleukodystrophy (n = 7), and others (n = 3). The remaining 46 patients had Wiskott-Aldrich syndrome (n = 16), hemophagocytic syndrome including the inherited type (n = 9), severe combined immunodeficiency (n = 6), hyper-IgM syndrome (n = 4), Chédiak-Higashi syndrome (n = 3),Kostmann syndrome (n = 3), and others (n = 5). Fiftytwo donor-patient pairs were fully matched at HLA-A, HLA-B, and HLA-DRB1 alleles. The remaining 24 patients received allele-mismatched grafts (20 matched at 5 of 6 loci and 4 matched at 4 of 6 loci). Engraftment occurred in 82.4% of the MD group and 90.7% of the other genetic disease (OGD) group; however, 14 patients (18.2%) experienced either early or late graft failure.The cumulative incidence of grade II to IV acute graft-versus-host disease (GVHD) was 35.5% _ 9.8% in the MD group and 47.3% _ 9.5% in the OGD group, and the rate of chronic GVHD was 20% in both groups. Forty-nine patients have survived for 3 to 96 months (median, 20 months).The probabilities of 5-year overall survival and event-free survival were 72.6% _ 11.5% and 65.3% _ 8.6%, respectively, for MD (n = 35) and 72.5% _ 7.3% and 63.6% _ 7.3% for OGD (n = 46). Although patient status before BMT and the occurrence of grade III to IV acute GVHD significantly affected outcome, unrelated BMT is a curative therapeutic option for children with congenital genetic diseases who have no HLA-matched family donors.

Effects of the Cessation of Mass Screening for Neuroblastoma at 6 Months of Age: A Population-Based Study in Osaka, Japan

Background In 2004, the Japanese government halted the 6-month mass screening program for neuroblastoma. We investigated whether its cessation had led to an increase not only in mortality due to this disease but also in the incidence of advanced-stage disease among older children. Methods Study subjects were neuroblastoma patients retrieved from the population-based Osaka Cancer Registry. Trends of incidence and mortality from neuroblastoma were analyzed by calendar year and birth cohort. Prognostic factors, including stage and v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) oncogene status, were compared before and after the cessation of mass screening. Results Age-standardized incidence rates in 2005–2009 (the cessation period of mass screening; 11.1 per million) were similar to those in 1975–1979 (the pre-screening period; 8.6 per million). Age-standardized mortality rates tended to decrease from 1975–1979 (4.0 per million) to 2005–2009 (2.7 per million) in parallel with the improvement in survival. Analysis by birth cohort indicated that the mortality rates in 2004–2005 (after cessation) for children 0–4 years of age were lower than those in 1975–1979 (O:E ratio 0.25; 95% confidence interval, 0.03–0.90). For children 1–9 years of age, there was a not significant difference in the distribution of stage, MYCN oncogene status, and DNA ploidy between 1991–2003 (the mass screening period) and 2004–2008 (after cessation). Conclusions The cessation of mass screening for neuroblastoma does not appear to have increased mortality due to this disease or incidence of advanced-stage disease among older children.

Comparison of continuous and twice‐daily infusions of cyclosporine A for graft‐versus‐host‐disease prophylaxis in pediatric hematopoietic stem cell transplantation

Cyclosporine A (CsA) is used widely for graft‐versus‐host disease (GVHD) prophylaxis in hematopoietic stem cell transplantation (HSCT); however, the optimal schedule of its administration has not been established. Although comparative studies of adult patients undergoing HSCT have demonstrated enhanced efficacy and safety of twice‐daily infusion (TD) compared with continuous infusion (CIF) of CsA, to our knowledge, similar studies have not yet been performed in pediatric groups.