Pediatric acute lymphoblastic leukemia (ALL) is a malignant disease resulting from accumulation of genetic alterations, and various genomic abnormalities are reported. Although these genetic lesions are important in leukemia initiation, they are insufficient to elucidate an entire etiology. Recently, we have developed a novel algorithm, CNAG/AsCNAR, to detect copy number alteration and allelic composition using SNP-genotyping microarrays, without dependence on the availability of self germ-line DNA. This robust algorithm also enabled sensitive detection of loss of heterozygosity (LOH) even in the primary samples contaminated by 70-80% of normal cells by finding subtle distortions in allele-specific signals (Molecular allelo-karyotyping). We examined 399 pediatric ALL samples using an SNP-chip platform, and discovered a detailed profile of genomic abnormalities. Molecular allelo-karyotyping also showed that alterations of genes related to B-cell development and differentiation, including PAX5, contributed to leukemogenesis.

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Morphological observation of blood and bone marrow films with light microscope is a fundamental and essential part of hematology. Light microscopy is observing the light coming through the specimen. Therefore, satisfactory observation requires well-prepared specimens of good quality and appropriate illumination. The bone marrow specimen of good quality must contain bone marrow spicules. The preparation of good quality must be made according to the method traditional and familiar to many hematologists and have a large observable area where red blood cells are evenly spread without overlapping and have discoid shape with central pallor. The light of good quality can be obtained with the Köhler illumination method. In order to obtain a bright picture with good contrast, the diameters of the field iris diaphragm, the aperture iris diaphragm and location of the condenser must be appropriately adjusted.

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To ascertain the current state of vaccination for pediatric patients after allogeneic hematopoietic stem cell transplantation, a questionnaire was distributed to all 99 participating hospitals of the Japan Association of Childhood Leukemia Study (JACLS). Sixty-six of the 99 hospitals (66.7%) surveyed responded. Fifteen of 44 hospitals (34.1%) reported having established vaccination guidelines including Centers for Disease Control and Prevention (CDC) and European Group for Blood and Marrow Transplantation (EBMT) guidelines. Rates of vaccine coverage in patients without receiving immunosuppressants was 86.8% for inactive and toxoid vaccines and 86.8% for live vaccines, while those in patients receiving a low dose of immunosuppressants is 30.2% for inactive and toxoid vaccinesand 11.3% for live vaccines, respectively. More than half of the hospitals applied some assays of immunological reconstitution for the start of vaccination. In some hospitals, varicella and polio vaccinations were performed even for patients receiving a low dose of immunosuppressants. Furthermore, live vaccines were given 6 or 12 months after transplantation in most of the hospitals without any adverse effects. Prospective studies are required to evaluate the utilityof immunologic reconstitution assays for assessing the safety and efficacy of vaccination at an early stage after transplantation.

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We have employed continuous chemotherapy consisting of etoposide 30 mg/m²/day and cytarabine20 mg/m²/day (low dose VP + CA) for the treatment of pediatric patients since March, 2002. The aims were cytoreduction to prevent tumor lysis syndrome or for refractory leukemia against standard chemotherapy, reduction of leukemic cell burden for refractory leukemia as a part of conditioning regimen for stem cell transplantation (SCT), and ensuring engraftment in SCT for non-malignant diseases. We evaluated 35 patients (a total of 52 courses of this therapy). 27 patients had refractory leukemia, including 17 with acute myeloid leukemia (AML) and 10 with acute lymphoblastic leukemia (ALL). Eight patients had other conditions. Disappearance of leukemic cells from peripheral blood was observed in 32 out of 46 courses for the first aim and in 13 out of 16 courses for the second aim. The reduction rate of white blood cells was 88.3% in a total of six courses for the third aim. Mild adverse events such as stomatitis were observed in eight courses (15.3%). We concluded that low dose VP + CA is useful in making time and slow cytoreduction before intensified chemotherapy or SCT.

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Aim : To evaluate the clinical course and outcome of Langerhans cell histiocytosis (LCH) in children. Methods : We evaluated 50 patients with confirmed LCH who were diagnosed and treated at our unit between 1970 and 2007. Results : Median age at diagnosis was 3.6 years. Median follow-up time was 8 years (range 8 months to 20 years). Fifty patients were stratified into three groups (SS : Single-system Single-site [n =29]; SM : Single-system Multi-site [n=10]; MM : Multi-system Multi-site [n=11]). Four out of 50 children died. They had multi-system multi-site disease at less than 2 years of age at diagnosis before 1988. Survival of the 11 children with multi-system disease was significantly poor compared with the 39 children with single-system disease (p= 0.00008).Disease reactivations occurred in 21%, 40% and 71% of patients with SS, SM and MM type LCH, respectively. Late sequelae had developed in 12 out of 46 patients (26%), including diabetes insipidus (4 out of 46 ; 8.8%), orthopedic abnormali-ties (4 out of 46; 8.8%) and hypothyroidism (3 out of 46; 6.5%). Six out of 10 patients (60%) with SMtype and 5 out of 7 patients (71%) with MM type were alive with sequelae at follow-up, as compared to 1 out of 29 patients (8%) with SS type. Conclusion : MM type LCH is associated not only with increased mortality but also pronounced propensity for severe late sequelae such as diabetes insipidus and sex hormone deficiency. SM type LCH is accompanied with sequelae such as orthopedic abnormalities and diabetes insipidus. Secondary malignancies did not occur in our center.

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We report three children who developed Pneumocystis pneumonia (PCP) during maintenance chemotherapy for acute lymphoblastic leukemia. We could not identify Pneumocystis jiroveci in biological specimens, but PCP was diagnosed on the basis of rapidly progressive hypoxemia, chest radiographic findings, elevated serum levels of (1→ 3) β-D-glucan, differential diagnosis from other infectious diseases, and the patients' clinical courses. Elevated levels of serum ferritin, soluble interleukin-2 receptor, and urinary β₂ microglobulin were revealed, and apparent hemophagocytosis was seen in bone marrow smears from one patient who underwent bone marrow aspiration. Adjunctive corticosteroids with TMP-SMX were effective, and the delay in starting corticosteroid treatment led to worsening of the respiratory conditions as well as laboratory and radiographic findings. Adjunctive corticosteroids were considered to be effective for the host inflammatory response to Pneumocystis jiroveci which affected the clinical condition of these patients. These laboratory findings, suggesting the presence of hypercytokinemia, might be useful markers for deciding the use of adjunctive corticosteroids for PCP.

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A 7-year-old boy with severe hemophilia A and poor response to immune tolerance induction (ITT) treat-ment for 33 months was treated with factor VIII/von Willebrand factor (FVIII/VWF) concentrate used as rescue ITI and followed by plasma derived factor VIII (pd.FVIII) concentrate. 1, 500 units (55 units/kg) of FVIII/VWF concen-trate were administered 3 times per week. After the initiation of rescue ITI, the titer of inhibitor decreased rapidly. Furthermore, the titer of inhibitor decreased to less than 5 BU/ml within eights months. We have judged that partial success was achieved in this case after rescue ITI because the titer of inhibitor remained under 3 BU/ml for more than five months (Current inhibitor titer is 0.6 BU/ml). The joints and muscular bleeding episodes decreased as well, and there was marked improvement in quality of life (QOL) for this patient. The results suggest that the rescue ITI with FVIII/VWF is effective. Notwithstanding, further study is necessary to identify clearly the factors that influence the results of rescue ITI.

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We report the death for liver cirrhosis of a boy who contracted Langerhans cell histiocytosis at the age of three. On admission, laboratory data revealed cholestasis. Despite chemotherapy, abnormal liver function tests persisted. Two months after admission, needle liver biopsy showed relatively massive fibrosis and proliferation of bile ductules with lymphocyte infiltration in the portal areas. Five years after onset of disease, recurrent bleeding from esophagogastric varices occurred, and endoscopic sclerotherapy was done a total of 10 times. Although living related liver transplantation was considered, it could not be done because of several factors. Thirteen years after onset of disease, ascites and coagulation abnormality developed. Two years later, he suddenly died with acute respiratory distress. Autopsy revealed pulmonary bleeding and liver cirrhosis.

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We report a 12-year-old boy at onset of acute myeloid leukemia (AML) with t (6;9) (p23;q34). The patient achieved the first complete hematological remission (CR) after induction chemotherapy, but the DEK/CAN fusion gene continued to be detected by quantitative reverse transcription polymerase chain reaction (RT-PCR) during the long course of consolidation chemotherapy. He received allogeneic bone marrow transplantation from an unrelated donor (u-BMT). The post-transplant course was uneventful and engraftment was rapid. After u-BMT, CR with negative RT-PCR for the DEK/CAN fusion gene has been maintained. Because of the low frequency, t (6;9) (p23;q34) is not accepted as an independent prognostic factor. Further large-scale studies on patients with AML involving such rare chromosomal abnormality showing a poor prognosis are indicated in order to evaluate the indications for BMT and the optimal conditioning regimen.

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In order to clarify the clinical pictures, outcome for childhood idiopathic thrombocytopenic purpura (ITP) and the trends of the choice of management, questionnaires were sent to all the councilors of the Japanese Society of Pediatric Hematology every year since 2000. In 2007 we conducted the same survey on ITP patients newly diagnosed between January 2006 and December 2006 and on the follow-up cases. Of 167 patients, 94 were boys and 73 were girls. The male-to-female ratio was 1.29 : 1. The mean age at diagnosis was 3.93 ± 3.63. The occurrence of ITP peaked in children under or less than 1 year of age, and the number of cases gradually decreased with age. The platelet counts at diagnosis were under 10, 000/ μl in more than half of the patients. In the initial treatment, morethan 80% of the patients with platelet counts < 10, 000/ μl were treated with IVIgG, whereas in the patients with platelet counts > =20, 000/ μl more than half of the patients were observed without any treatment. 26.4% of the cases were diagnosed as chronic ITP. The frequency of chronic ITP was increased according to the increase of age and wasextremely low in the patients with antecedent vaccination. In 199 follow-up cases, 48 cases received no medication and 28 cases underwent a splenectomy.

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Among the survey of newly diagnosed idiopathic thrombocytopenic purpura (ITP) patients which were collected by the ITP committee, The Japanese Society of Pediatric Hematology, ITP patients following vaccination were analyzed. During 2000 to 2005, 8 patients were registered with ITP following vaccination. Their ages ranged from 0-6 years old, 7 patients were boys, 5 patients were followed by rubella vaccination, 6 patients had only dry purpura, and 2 patients were of the chronic type. In 2006, 18 patients were registered with ITP following vaccination. Their ages ranged from 0-9 years old, 8 patients were boys, 13 patients had only dry purpura, and 1 patient was of the chronic type. Further survey is needed to clarify the kinds of vaccine which cause ITP. Information collection for not only ITP, but also other side effects following vaccinations in a larger scale and by a more systematic method is needed.

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Criteria for hospitalization and management of daily activities including exercise by children with idio-pathic thrombocytopenic purpura (ITP) differ significantly among institutions and physicians, causing confusion among patients and their families. The ITP Committee of the Japanese Society of Pediatric Hematology recently prepared draft ITP management guidelines on the basis of the results of a quality of life (QOL) survey in ITP children in institutions in which members of the Japan Pediatric ITP Study Group practice. Although the ITP guidelines may not be applicable to all children with ITP, who may differ significantly in age, sex, family environment, healthcare services available in the institutions they visit, and other social factors, we hope the guidelines will provide a rough outline for use by medical instructions to ensure the quality of life of children with ITP.

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