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We identified unusually large von Willebrand factor (vWF) multimers caused by deficient activity of vWF-cleaving protease in 2 patients with Upshaw-Schulman syndrome. The autoantibodies that inhibited the protease activity were not detected in the plasma of either patient. Periodic fresh-frozen plasma transfusion was effective for management of the hemolysis and thrombocytopenia. We detected enriched enzyme activity in a particular plasma fraction, although molecular cloning of this specific protease is needed to determine a more detailed pathogenesis and to develop new therapeutic approaches. [ABSTRACT FROM AUTHOR]

The heights of children with acute lymphocytic leukaemia were compared with controls matched for age, sex, and period. In contrast to a previous report the subject patients were not taller than their matched controls. [ABSTRACT FROM AUTHOR]

Parental age at birth has been investigated in patients diagnosed with pediatric cancer. The Japan Children's Cancer Registry1985-2007 recruited 5,510 patients with leukemia and 8,782 with other cancers. The proportion of patients born to mother and father aged >40 years showed a higher trend in leukemia than that in other cancers (odds ratio [OR] 1.41, p=0.057), especially in <12-month-old infants born to mother aged >40 years (OR 2.55, p=0.031). We then divided 27,335 patients diagnosed in 1969-2006 into every 8-year birth cohorts to compare proportions of mothers with prenatal medical irradiation. The OR of leukemia was higher than that of other cancers in 1969-1976 (1.25) or 1977-1984 (1.39), which reached statistical significance. We have also studied caregiver's exposure to anticancer drugs. In 15 pediatric patients with cancer who received cyclophosphamide (CPM), the concentration was measured using mothers and medical staff's urine. Five of 7 infants' and 2 of 8 adolescent's mothers showed increased urine CPM levels. CPM was not detected in any medical staff's samples. Maternal exposure to anticancer drugs should also be considered. Efforts of reducing the genotoxicity in both infants and mothers are crucial for pediatric cancer prevention.

Germline pathogenic ETV6 variants have been discovered in families with inherited thrombocytopenia and predisposition to hematological and solid malignancies. We present a patient with short stature who was initially diagnosed with chronic immune thrombocytopenia. Subsequently, the patient developed acute lymphoblastic leukemia, followed by mammary analog secretory carcinoma. Sequencing analysis identified an ETV6 c.641C > T (p.Pro214Leu) germline variant. The variant protein exhibited attenuated nuclear localization, increased protein degradation, and reduced transcription repression function. Our findings suggest that the ETV6 gene should be sequenced in patients with inherited thrombocytopenia and malignancy, and emphasize the importance of careful follow-up to identify secondary cancer in patients with pathogenic ETV6 variants.

The JLSG-96 study reported very low mortality rates for children newly diagnosed with multifocal Langerhans cell histiocytosis (LCH). The JLSG-02 study was performed to further improve the prognosis from 2002 to 2009. The present study compared the therapeutic results of these two studies in terms of multisystem disease. All patients were treated with 6 weeks of the Induction A regimen, comprising cytarabine, vincristine and prednisolone, followed by maintenance therapy. Poor responders to Induction A were switched to Induction B. JLSG-02 has been revised from JLSG-96 in the following respects: prednisolone dosage during Induction A increased; duration of maintenance therapy extended from 24 to 48 weeks; cyclosporine introduced to Induction B for progressive disease. One hundred forty-seven children with multisystem LCH were evaluated. Of these, 84 were positive for risk of organ involvement (RO) and 63 were RO-negative. At the 6-week point, 76.2 % of RO+ and 93.7 % of RO- patients responded to Induction A. Five-year event-free survival (EFS) was 46.2 % [95 % confidence (CI), 35.5-56.9] for RO+ and 69.7 % (58.4-81.1) for RO-, which was significantly superior to that in JLSG-96 [26.8 % (13.3-40.4) and 38.9 % (16.4-61.4), respectively]. The intensified induction and prolonged maintenance regimens in JLSG-02 improved EFS in patients with multisystem LCH.

We report a 4-year old boy with a large arteriovenous malformation (AVM) exhibiting attention-deficit hyperactivity disorder (AD/HD). He presented with hyperkinesis at the age of 3 years and jacksonian seizure at 3 years 11 months, when he was diagnosed as AVM by cranial computed tomography. Magnetic resonance imaging revealed an AVM of 6 cm in diameter in the left frontal lobe. After 1 year, the AVM developed a varix, and both were surgically removed. We speculate that the prefrontal area was affected by direct compression from AVM and chronic ischemia due to steal phenomenon. Although AD/HD is rarely caused by parenchymal lesions, such as AVM, physicians should carefully investigate causative lesions.

Data on long-term outcomes of children with refractory immune thrombocytopenia (ITP) treated with rituximab are limited. We retrospectively analyzed the long-term effect of rituximab on 22 pediatric ITP patients (11 boys and 11 girls). Compete response (CR) (platelet count ≥100 × 10(9)/L) and partial response (PR) (platelet count 30-99 × 10(9)/L) were achieved in nine (41 %) and two (9 %) patients, respectively. Of the 11 responders, eight subsequently relapsed 2-26 months after initial rituximab treatment. The 5-year relapse-free rate was 14 % (3/22, 95 % confidence interval: 0-27 %) with a median follow-up period of 6.4 years. Five initial responders with subsequent relapse and one non-responder received multiple rituximab treatments of nine courses; all patients responded to the second rituximab therapy without any significant toxicity. All eight patients who relapsed after an initial response and six of 11 non-responders achieved CR or PR with subsequent treatment, including repeated courses of rituximab, splenectomy, steroids, and other immunomodulating agents. Our findings indicated that the sustained effect of rituximab on children with refractory ITP is low, but that the long-term outcome of ITP itself is not poor. Furthermore, repeated rituximab administration may be a promising therapy for those who relapse after an initial response.

Lymphoblasts of acute lymphoblastic leukemia origin reappeared in a male patient 34 years after the initial diagnosis. Comparison of DNA profiles of the initial and reappeared lymphoblasts revealed a partially identical sequence, indicating the possibility that these lymphoblasts may have been present as preleukemic stem cells at the time of diagnosis and remained dormant for a long period until additional events conferred proliferative activity to these dormant preleukemic stem cells. Thus, in some cases of very late relapse, the reappearance of lymphoblasts may not be due to the relapse of the original leukemic clone, but to a clonal progression of a pre-existing subclone derived from preleukemic stem cells.

Adolescents are unique for tobacco control. They are easy to become tobacco-addicted and more than 70 % of adult smokers start to smoke tobacco during adolescence. Therefore, they are good targets for sales campaign by tobacco industry to secure their profit by making a large reservoir of smokers. Tobacco industry's tactics are very ingenious. It conducts many kinds of hidden advertisement. It supports many activities of youth and nonprofit organizations. Therefore, our effort should also put targets on adolescents. Adolescence is a unique stage of development and it is important to know its characteristics for effective approach to prevent starting and to facilitate quitting smoking. It is important to make tobacco-free environment surrounding adolescents, such as school campuses and other public places.

Background: Although the therapeutic outcome of acquired aplastic anemia has improved markedly with the introduction of immunosuppressive therapy using antithymocyte globulin and cyclosporine, a significant proportion of patients subsequently relapse and require second-line therapy. However, detailed analyses of relapses in aplastic anemia children are limited., Design and Methods: We previously conducted two prospective multicenter trials of immunosuppressive therapy for children with aplastic anemia: AA-92 and AA-97, which began in 1992 and 1997, respectively. In this study, we assessed the relapse rate, risk factors for relapse, and the response to second-line treatment in children with aplastic anemia treated with antithymocyte globulin and cyclosporine., Results: From 1992 to 2007, we treated 441 children with aplastic anemia with standard immunosuppressive therapy. Among the 264 patients who responded to immunosuppressive therapy, 42 (15.9%) relapsed. The cumulative incidence of relapse was 11.9% at 10 years. Multivariate analysis revealed that relapse risk was significantly associated with an immunosuppressive therapy regimen using danazol (relative risk, 3.15; P=0.001) and non-severe aplastic anemia (relative risk, 2.51; P=0.02). Seventeen relapsed patients received additional immunosuppressive therapy with antithymocyte globulin and cyclosporine. Eight patients responded within 6 months. Seven of nine non-responders to second immunosuppressive therapy received hematopoietic stem cell transplantation and five are alive. Eleven patients underwent hematopoietic stem cell transplantation directly and seven are alive., Conclusions: In the present study, the cumulative incidence of relapse at 10 years was relatively low compared to that in other studies mainly involving adult patients. A multicenter prospective study is warranted to establish optimal therapy for children with aplastic anemia.

The present study aimed to identify optimal treatment intensity in children with mosaic Down syndrome (DS) and acute megakaryoblastic leukemia (AMKL). A retrospective review of AMKL patients was undertaken to identify mosaic DS children. Between November 1992 and November 2007, seven children were diagnosed as mosaic DS and AMKL. The median age at diagnosis was 29 months (range 4-34 months). Three patients had a past history of transient abnormal myelopoiesis. UPN1-4 were treated with intermediate-dose cytarabine and UPN4 received additional one course of high-dose cytarabine. All of these patients were remained in first CR. UPN5-7 were treated with high-dose cytarabine according to the AML99 protocol. UPN5 with GATA1 mutation suffered from acute pneumonia and pancreatitis and discontinued chemotherapy. UPN7 relapsed after cessation of chemotherapy and was rescued with allo-PBSCT. The cumulative doses of cytarabine were 3.5-10.65 g/m(2) in the UPN1-4 and 40.4-78.4 g/m(2) in the UPN5-7. The 8-year overall survival was 100% and the 8-year event-free survival 85.7%, respectively. Our retrospective study reveals that patients with mosaic DS and AMKL have a good prognosis. Reduction in intensity may work in patients with mosaic DS as well as with AML-DS.

Background: We evaluated the clinical pictures, outcome for childhood idiopathic thrombocytopenic purpura (ITP) and the trends of the choice of management for childhood ITP in Japan., Method: Every year, questionnaires were sent to all institutions that employ the active members of the Japanese Society of Pediatric Hematology. The questionnaires included age, sex, date of diagnosis, platelet count at diagnosis, the presence or absence of antecedent infection, hemorrhagic symptoms, initial management, and the outcome of all patients newly diagnosed with ITP., Results: A total of 986 newly diagnosed as ITP patients were reported between January 2000 and December 2005. The occurrence of ITP peaked in boys less than 1 year of age, and at 1 year of age in girls. The male-to-female ratio was 1.24:1. Wet purpura was observed in more than half of the patients with platelet counts of <10,000/microL. The initial treatment varied among the patients with different platelet counts at diagnosis; most of the patients with platelet counts <20,000/microL received intravenous immunoglobulin or oral corticosteroids. Conversely, cases without any aggressive treatment increased to a larger degree in patients with > or =20,000/microL of platelet., Conclusions: These findings indicate that overall compliance to the Japanese guideline is considered to be relatively good in Japan.

The p300 protein shows a striking homology with cyclic-AMP-response-element-binding-protein binding protein (CBP) and both proteins form a family of DNA-binding transcriptional coactivators/histone acetyltransferases. The authors, herein, report a therapy-related acute myeloid leukemia with MLL-p300 fusion gene. Spectral karyotyping clarified that chromosome 11 is involved in complex t(1;22;11)(q44;q13;q23), and is fused to the chromosome 22, and direct sequencing revealed the fusion of exon 8 of MLL and exon 15 of p300 in this case. This is only the second reported case of leukemia with an MLL-p300 fusion gene, and the other case with MLL-p300 was also a therapy-related leukemia. Considering that the MLL-CBP fusion gene is also found almost exclusively in therapy-related leukemia, the association of MLL-p300 and MLL-CBP with therapy-related leukemia rather than de novo leukemia is thereby suggested.

The authors report a rare case of acute myeloid leukemia (AML) M1 with faggot formation in mature neutrophils and metamyelocytes. Although Auer rods in mature neutrophils are occasionally experienced, they are usually found in AML M2, M3, or M4 cases, but not in M1 cases. In addition, faggot formation in mature neutrophils, as seen in this case, is considered to be particularly unusual because most previously reported cases tended to show simple Auer rods except for AML M3 cases. This case also showed trisomy 4 in its karyotype, although its relationship with faggot formation remains unclear.

We conducted a prospective multicenter study to compare the efficacy of repeated immunosuppressive therapy (IST) with stem-cell transplantation (SCT) from an alternative donor in children with acquired aplastic anemia (AA) who failed to respond to an initial course of IST. Patients with severe (n = 86) and very severe disease (n = 119) received initial IST consisting of antithymocyte globulin (ATG) and cyclosporine. Sixty patients failed to respond to IST after 6 months from the initial IST and were eligible for second-line treatment. Among them, 21 patients lacking suitable donors received a second course of IST. Three patients developed an anaphylactoid reaction to ATG and could not complete the second IST. A trilineage response was seen in only 2 of 18 (11%) evaluable patients after 6 months. Thirty-one patients received SCT from an alternative donor. At 5 years from the initiation of second-line therapy, the estimated failure-free survival (FFS), defined as survival with response, was 83.9% (+/- 16.1%, SD) in the SCT group compared with 9.5% (+/- 9.0%) in the IST group (P = .001). These results suggest that SCT from an alternative donor offers a better chance of FFS than a second IST in patients not responding to an initial IST.

Proteins are modified and folded within the endoplasmic reticulum (ER). When the influx of proteins exceeds the capacity of the ER to handle the load, the ER is "stressed" and protein biogenesis is affected. We have previously shown that the induction of ER stress by ATP depletion in podocytes leads to mislocalization of nephrin and subsequent injury of podocytes. The aim of the present study was to determine whether ER stress is associated with proteinuria in vivo and whether the immunosuppressant mizoribine may exert its antiproteinuric effect by restoring normal nephrin biogenesis. Induction of nephrotic-range proteinuria with puromycin aminonucleoside in mice increased expression of the ER stress marker GRP78 in podocytes, and led to the mislocalization of nephrin to the cytoplasm. In vitro, mizoribine, through a mechanism likely dependent on the inhibition of inosine 5'-monophosphate dehydrogenase (IMPDH) activity in podocytes, restored the intracellular energy balance by increasing levels of ATP and corrected the posttranslational processing of nephrin. Therefore, we speculate that mizoribine may induce remission of proteinuria, at least in part, by restoring the biogenesis of slit diaphragm proteins in injured podocytes. Further understanding of the ER microenvironment may lead to novel approaches to treat diseases in which abnormal handling of proteins plays a role in pathogenesis.

We recently cloned the human Na(+)-independent system L neutral amino acid transporter LAT3. The aim of the present study was to characterize the molecular nature of mouse LAT3 at the protein level. Isolated mouse LAT3 showed 83% identity to human LAT3. Xenopus oocytes injected with mouse LAT3 cRNA showed the same functional property as human LAT3. Reverse transcriptase-polymerase chain reaction revealed apparent transcripts of mouse LAT3 in the liver, skeletal muscle, and pancreas, an expression pattern identical to that found in humans. Antibody generated against mouse LAT3 detected both approximately 58-kd and 48-kd bands in the sample from liver and only a 48-kd band in skeletal muscle and pancreas. Immunohistochemical study showed its clear localization in the plasma membrane of liver and skeletal muscle, whereas it was only detectable in the endoplasmic reticulum and in crystalline inclusions in pancreatic acinar cells. Starvation induced up-regulation of mouse LAT3 protein and mRNA in both liver and skeletal muscle but not in pancreas. These results suggest that LAT3 may indeed function as an amino acid transporter, transporting branched-chain amino acids from liver and skeletal muscle to the bloodstream and thereby participating in the regulatory system of interorgan amino acid nutrition.

Tyrosine kinase 2 (Tyk2) is a nonreceptor tyrosine kinase that belongs to the Janus kinase (Jak) family. Here we identified a homozygous Tyk2 mutation in a patient who had been clinically diagnosed with hyper-IgE syndrome. This patient showed unusual susceptibility to various microorganisms including virus, fungi, and mycobacteria and suffered from atopic dermatitis with elevated serum IgE. The patient's cells displayed defects in multiple cytokine signaling pathways including those for type I interferon (IFN), interleukin (IL)-6, IL-10, IL-12, and IL-23. The cytokine signals were successfully restored by transducing the intact Tyk2 gene. Thus, the Tyk2 deficiency is likely to account for the patient's complex clinical manifestations, including the phenotype of impaired T helper 1 (Th1) differentiation and accelerated Th2 differentiation. This study identifies human Tyk2 deficiency and demonstrates that Tyk2 plays obligatory roles in multiple cytokine signals involved in innate and acquired immunity of humans, which differs substantially from Tyk2 function in mice.

Background: The treatment outcome of multifocal childhood Langerhans cell histiocytosis (LCH) has not been satisfactory and has resulted in poor therapeutic responses with high mortality and a high incidence of reactivation with late sequelae. To overcome these issues, the Japan LCH Study Group-96 (JLSG-96) protocol was conducted prospectively from 1996 to 2001 in Japan., Methods: Newly diagnosed children with multifocal LCH were classified into 2 groups: a single-system multisite (SS-m) group and a multisystem (MS) group. All patients initially were treated on Protocol A, which consisted of 6 weeks of induction therapy with combined cytosine arabinoside, vincristine (VCR), and prednisolone (PSL) followed by 6 months of maintenance therapy. Patients who had a poor response to the induction of Protocol A were switched to a salvage regimen (Protocol B), which consisted of an intensive combination of doxorubicin, cyclophosphamide, VCR, and PSL., Results: In total, 91 patients were treated, including 32 patients in the SS-m group and 59 patients in the MS group. At the median 5-year follow-up, 96.9% of patients in the SS-m group and 78.0% of patients in the MS group had good response status. Diabetes insipidus developed in 3.1% of patients in the SS-m group and in 8.9% of patients in the MS group. The overall survival rate at 5 years for the SS-m and MS groups was 100% and 94.4% +/- 3.2%, respectively., Conclusions: The JLSG-96 protocol attained very low mortality for pediatric patients with multifocal LCH., (Copyright 2006 American Cancer Society.)

Background: To determine useful biochemical markers in Langerhans cell histiocytosis (LCH), we analyzed the serum levels of soluble CD154 (sCD154), IL2 receptor (sIL2-R), receptor activator of NF-kappaB ligand (sRANKL), and osteoprotegerin (OPG)., Procedure: Our study included 46 newly diagnosed LCH patients (single-system multi-site (SM type): n = 20, and multi-system multi-site (MM type): n = 26) who were treated with the JLSG-02 protocol between 2002 and 2004. The median age of the patients was 3.8 years old (range 0-18). sCD154, sIL2-R, sRANKL, and OPG were measured by ELISA at diagnosis (n = 46) and after 6-weeks of induction therapy (n = 14)., Results: The values of sCD154, sIL-2R, sRANKL, and OPG, and the sRANKL/OPG ratio in sera were significantly higher in patients with LCH compared with controls (1.83 +/- 1.38 vs. 0.22 +/- 0.16 ng/ml, P < 0.001; 1,600 +/- 1,060 vs. 420 +/- 160 pg/ml, P < 0.001; 1.72 +/- 1.20 vs. 1.04 +/- 1.09 pmol/L, P = 0.019; 6.34 +/- 2.94 vs. 3.71 +/- 2.03 pmol/L, P < 0.001; and 0.40 +/- 0.45 vs. 0.16 +/- 0.17, P = 0.023, respectively). Serum levels of sIL-2R were significantly elevated in the MM type compared with the SM type (2,050 +/- 1,060 vs. 870 +/- 340 pg/ml, P < 0.001). Serum OPG levels were also significantly elevated in the MM type compared with the SM type (7.58 +/- 2.72 vs. 5.13 +/- 2.69 pmol/L, P = 0.008) and negatively correlated with the number of bone lesions (r = -0.56, P = 0.007). In contrast, the sRANKL/OPG ratios were significantly higher in the SM type than the MM type (0.57 +/- 0.54 vs. 0.19 +/- 0.14, P = 0.002) and positively correlated with the number of bone lesions (r = 0.34, P = 0.040). In patients who responded to the induction therapy, serum levels of sIL-2R, sRANKL, and OPG, and the sRANKL/OPG ratio decreased significantly after the therapy (1,170 +/- 600 vs. 730 +/- 290 pg/ml, P = 0.029; 2.19 +/- 1.06 vs. 1.24 +/- 0.66 pmol/L, P < 0.001; 6.13 +/- 2.40 vs. 4.72 +/- 2.03 pmol/L, P = 0.040; and 0.57 +/- 0.52 vs. 0.41 +/- 0.37, P = 0.02, respectively). In the three patients who did not respond to the induction therapy, the serum levels of sCD154 increased significantly after the therapy (1.3 +/- 1.1 vs. 2.7 +/- 1.2, P = 0.004)., Conclusions: Serum levels of sIL-2R and sCD154 could be useful as indicators of inflammation and sRANKL/OPG ratios as markers of osteolytic activity in LCH patients.

A practice guideline aimed at standardizing the treatment for childhood idiopathic thrombocytopenic purpura (ITP) is presented. This consensus guideline is based on a survey carried out via a questionnaire prepared by the ITP Committee of the Japanese Society of Pediatric Hematology and sent to society members. The survey questionnaire included questions on the diagnosis of ITP submitted for the purpose of revising the ITP diagnostic guideline prepared in 1990 by the Research Group for Intractable Hematopoietic Disorders; a revised diagnostic guideline also is presented.

Recent reports of myelodysplastic syndrome/acute myeloid leukemia (t-MDS/AML) developing after treatment with immunosuppressants and granulocyte colony-stimulating factor (G-CSF) has raised the question of whether previously unrecognized myelodysplastic features had been present or whether actual transformation had occurred. We undertook a multi-institutional study of 112 children with aplastic anemia diagnosed between 1976 and 1996 and then treated with immunosuppressants with or without G-CSF. In each case, bone marrow specimens were tested at study entry and every 6 months for 3 years to detect t-MDS/AML as defined by morphologic and molecular/cytogenetic criteria. As of December 2001, all eligible patients had been followed for a median of 3 years. Morphologic abnormalities were found in 17 cases. The patients in 4 of these cases had clonal cytogenetic abnormalities and received MDS diagnoses. The morphologic features of the patients with and without clonal cytogenetic abnormalities were indistinguishable. However, the mast cell content was lower in cases with cytogenetic abnormalities than in cases without them. An elucidation of the role of mast cells may provide information about the differences between aplastic anemia and MDS or about the transition of aplastic anemia to MDS.

Imatinib, the ABL kinase inhibitor, is used not only for Philadelphia chromosome-positive (Ph + ) chronic myelogenous leukemia, but also for Ph + acute lymphoblastic leukemia (ALL), although resistance to the drug tends to develop in an early stage of the clinical course. We describe a childhood refractory Ph + ALL patient in whom progressive resistance to imatinib was correlated with the appearance of a mutation in the BCR-ABL kinase domain and in vitro drug resistance to imatinib as determined by the methyl-thiazol-tetrazolium (MTT) assay. A missense mutation of T to C (Y253H) of the ABL gene was identified in the resistant clone, suggesting that this mutation may play an etiological role in the rapid loss of drug sensitivity.