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Background Quality of life (QOL) as a treatment outcome has not yet been evaluated among patients receiving a specific treatment regimen by treatment phase in a consistent manner. This exploratory cross-sectional study evaluated the QOL of children with acute lymphoblastic leukemia (ALL) receiving one of the most popular treatment regimens in Japan (Japan Association of Childhood Leukemia Study ALL-02 revised protocol). Methods Children aged 5–18 years with newly diagnosed B-cell precursor ALL were included. The Pediatric Quality of Life Inventory™ 4.0 Generic Core Scales (PedsQL-J) were completed by children with ALL and their siblings, as well as by age- and sex-matched healthy controls. PedsQL Cancer Module (PedsQL-C) scores were also collected from children with ALL. Results QOL in children with ALL of the consolidation phase group was significantly decreased compared with that of healthy controls, except in the area of emotional functioning. Regarding the maintenance phase group, QOL impairment was noted in the physical and school functioning, but no differences were noted in social functioning. The off-treatment group had a large effect size only for physical functioning, and the social functioning score was even better in children with ALL than in matched controls. QOL of children with ALL differed with treatment phase. Effect size varied with function and treatment phase. Conclusions QOL may change with the progression of treatment, and the timing of these changes varied according to function and problem.

Previous studies conducted on children with autism spectrum disorder (ASD) and their abilities to recognize the psychological states of others have primarily focused on visual aspects such as facial expression and perception. The aims of this study were to clarify the characteristics of auditory information processing mechanisms in individuals with ASD in order to expand our understanding of those with ASD and to contribute to improvements in their social adaptability. The behavioral characteristics of voice cognition in ASD were investigated in 12 individuals with ASD (mean age = 11.83 years) and 12 matched typical development (TD) controls (mean age = 11.58 years). Participants were asked to judge the emotional valence of vocal stimuli with happy, angry, or neutral expressions (emotion task) and select illustrations that best correspond to the semantics of the vocal stimuli (semantic task). The ASD group had significantly (p = 0.013) longer reaction times in the emotion task, suggesting that they have difficulty distinguishing emotional valence. In the semantic task, the ASD group had lower understanding of the meaning of sentences when voices were presented with angry expressions. These results suggest the importance of the emotions conveyed in verbal speech during conversations with individuals with ASD.

Reactive attachment disorder (RAD) is characterized by markedly disturbed and developmentally inappropriate social relatedness due to parental maltreatment. RAD patients often display a high number of comorbid attention deficit/hyperactivity disorder (ADHD) symptoms, and certain RAD symptoms are difficult to discriminate from ADHD. One of the core characteristics of ADHD is a decrease in neural reward processing due to dopamine dysfunction. The aim of the present study was to determine whether the brain activity involved in reward processing in RAD patients is impaired in comparison with ADHD patients and typically developed controls. Five RAD patients, 17 typically developed (TD) controls and 17 ADHD patients aged 10-16 years performed tasks with high and low monetary reward while undergoing functional magnetic resonance imaging. ADHD patients were tested before and after 3 months treatment with osmotic release oral system-methylphenidate. Before treatment, ADHD patients showed that striatal and thalamus activities only in the tasks with low monetary reward were lower than TD controls. RAD patients showed decrease in activity of the caudate, putamen and thalamus during both the high and low monetary reward conditions in comparison with all the other groups. In RAD patients, the activity of the putamen was associated with the severity of posttraumatic stress and overt dissociation. Reward sensitivity was markedly decreased in children and adolescents with RAD, as evidenced by a diminished neural response during reward perception. This suggests that dopaminergic dysfunction exists in these patients, and may inform future dopaminergic treatment strategies for RAD.

To determine useful prognostic factors in treating childhood acute lymphoblastic leukemia (ALL), we correlated conventional risk factors and bone marrow response 14 days after induction chemotherapy. Our study included 116 precursor B-cell (n = 104) and T-cell (n = 12) ALL patients treated with our protocol between 1988 and 1999. The patients were classified into 3 initial risk groups on the basis of conventional risk factors (56 in the low-risk, 33 in the high-risk, and 27 in the very high-risk groups). All patients received similar systemic chemotherapy regimens before the evaluation of their bone marrow on day 14. We evaluated the marrow of 69 patients as M1 (less than 5% blasts), 25 as M2 (5%-25% blasts), and 22 as M3 (more than 25% blasts). Although all patients attained an initial complete remission (CR), relapse was noted in 33 of the 116 patients, and 15 patients died. All of the M1 marrow patients, irrespective of the initial risk group, showed the best event-free survival rate (85.1% +/- 3 4.4%), the lowest relapse rate (14.5%), and the highest attainment of a second CR (100%); they were defined as the new R1 prognostic group. The low-risk patients with M2 or M3 marrow (R2 group) had a relatively high relapse rate, but all of these relapsed patients were treated successfully with subsequent therapy. High- or very high-risk patients with M2 or M3 marrow (R3 group) had the worst prognosis. Our new prognostic definition (R1, R2, R3) incorporating day 14 marrow findings is useful to tailor early-phase treatments for better therapeutic results in childhood ALL.

We report the case of a 3-year-old Japanese boy with phosphoglycerate kinase 1 (PGK1) deficiency (Online Mendelian Inheritance in Man entry 311800). The patient had anaemia and jaundice at birth, necessitating exchange transfusions for 2 d. After one red blood cell transfusion at age 2 months, his Hb level was 8-9 g/dl, his reticulocyte counts were 300-500 x 109/l, and his total bilirubin level was 25.65-42.75 micro mol/l. The patient suffered two episodes of respiratory infection-associated haemolytic crisis and rhabdomyolysis during early infancy. At age 3.0 years, his developmental milestones (developmental quotients measured using the Tsumori-Inage methods) score was 49% (normal 74-131%), and his height was below average by -2.0 standard deviations. The diagnosis of PGK1 deficiency was made based on his remarkably low ( C) PGK1 gene mutation. This mutation results in the Ala-353Pro amino acid substitution, which has been designated PGK Kyoto. The patient developed the full clinical symptoms of PGK1 deficiency including haemolytic anaemia, myopathy, central nervous system disorder and growth retardation, which is unusual.

Background Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH), also known as EBV-associated hemophagocytic syndrome, develops mostly in children and young adults and may be fatal. Early etoposide treatment has been confirmed to be effective in children. However, it is unclear whether the same treatment is useful in adults. Procedure To assess whether etoposide is effective in treating young adult cases, we retrospectively studied the therapeutic measures taken and outcomes in 20 young adult cases of EBV-HLH. Eleven cases were registered in our HLH study center in Kyoto and nine derived from the literature. The patients were between 17 and 33 years old and eight were males. The influence of gender, cell lineage (T- or natural killer-), EBV serology pattern, jaundice and treatment on the outcome was assessed. Results and Conclusions Patients receiving etoposide within four weeks after diagnosis had a good prognosis as five of the seven patients survived compared to one of 13 not treated with etoposide or treated late (chi-square test for survival, P = 0.0095). The Kaplan–Meier analysis showed the 2.5-year survival of 85.7 ± 13.2% in the early etoposide-treated patients, compared to 10.3 ± 9.4% in the remaining patients (log-rank test, P = 0.0141). Thus, early etoposide treatment is effective in treating EBV-HLH in young adults as well as in children. Med Pediatr Oncol 2003;41:103–109. © 2003 Wiley-Liss, Inc.

A rare association of Epstein-Barr virus-associated T- and B-lymphoproliferative disease (EBV(+) T- and EBV(+) B-LPD) in a patient with WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is reported. A 26-year-old Japanese female, who had been treated for WHIM syndrome since early childhood, developed hemophagocytic syndrome associated with EBV(+) T-LPD at the lymph nodes and spleen. The disease rapidly resolved in response to prednisolone therapy. However, 6 weeks later, fatal EBV(+) B lymphoma unresponsive to chemotherapy occurred in the intestine and other organs. Caution must be exercised that the patient with WHIM syndrome may be at risk for EBV-LPD.

Two cases of cytomegalovirus (CMV) retinitis following bone marrow transplantation (BMT) from unrelated donors are reported. 1 patient had been treated for severe aplastic anemia (SAA) and the other for hypoplastic myelodysplastic syndrome (MDS). Because first line therapy with antithymocyte globulin (ATG) and cyclosporin A (CsA) had failed, BMT was performed following a conditioning regimen of ATG, cyclophosphamide, and total lymphoid irradiation. Treatment for CMV retinitis was successfully carried out with gancyclovir (systemic and intraocular injection), foscarnet, and photocoagulation (Case 1) and gancyclovir and foscarnet (Case 2). Both patients also developed Epstein-Barr virus-associated lymphoproliferative disease (EBV-LPD). We compared these 2 cases with 14 SAA patients who did not develop CMV retinitis after BMT using marrow from either HLA-identical siblings (n = 9) or from unrelated donors (n = 5). Unlike the retinitis patients, the latter 5 patients received ATG only once. The retinitis patients had significantly lower CD4+ T-cell levels in their peripheral blood than the 14 patients who did not develop CMV retinitis. We believe that repeated treatment with ATG and transplantation from unrelated donors may lead to immune dysfunction that could increase the likelihood of CMV retinitis, as well as LPD. For such BMT patients, regular ophthalmic examinations and careful testing for CMV antigenemia are recommended.

Latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) is considered to be an oncoprotein because it is crucial for B-lymphocyte transformation. Since a 30 base pair (bp) deletion in the carboxy-terminal portion of the LMP1 gene was found in a CAO cell line derived from nasopharyngeal carcinoma containing EBV, an association between EB viral genetic alteration and tumorigenicity has been postulated. In this study we have analyzed LMP1 DNA isolated from 10 Japanese patients with EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH). In all HLH patients, we found the 30 bp deletion and 4-8-tandem repeats of the sequence DNGPQDPDNTD in the LMP1 gene. Furthermore, detailed amino acid (aa) sequence analysis revealed that 7 aa substitutions identical to those found in CAO-LMP1 but not in B95.8 cell line-LMP1 were found in all the HLH cases. NF-kappaB assay revealed that HLH-LMP1 activated NF-kappaB significantly more than that of B95.8-LMP1 (p=0.032). We conclude that EBV from all of our HLH cases shared common genetic characteristics with EBV obtained from the CAO cell line, which is distinct from the wild-type EBV isolated from the B95.8 cell line. These data suggest that the mutational changes of the LMP1 gene may play an important role in the pathogenesis of these fatal EBV-related disorders.

腎炎の進展に血小板の関与が考えられている。代表的な腎炎である溶連菌感染後急性糸球体腎炎 (AGN) において血小板数 (PLT) を観察し，腎炎を併発しなかった溶連菌感染症 (ST) と比較した。症例はAGN26例とST80例で初診時と初診1週後の，AGNではその後初診3週後，5週後，11週以後でPLTを見た。白血球数 (WBC)，補体値，CRPとの相関も見た。この結果，AGNではPLTは初診時から初診1週後で増加する傾向にあり，3週で低下しその後は微増した。STのPLTは同様に初診時から初診1週後にかけて増加した。WBCは両疾患とも初診時では初診1週後に比較して多いがSTの増加の程度は強かった。PLTとWBCの関連ではSTにおいて好中球との関連を認めたがAGNでは認めず，初診1週後PLTと初診時，初診1週後リンパ球との間に有意の相関を認めた。またAGNの初診1週後でCH50とPLTに有意の相関を認めた。初診時CRPと初診1週後PLTは両者とも相関を認めた。これらのことは制御に関わるサイトカインが異なっていることを示唆すると思われ，腎炎発症のメカニズムを推測する上で参考になると思われた。

The clinical practice of child and adolescent psychiatry includes encounters with disorders not particular to childhood and adolescence, but seen in adulthood as well. For example, among the neurotic disorders, obsessive-compulsive disorder can be seen from around 3 years of age, with rapid rise in prevalence from around age 10. Increase is also seen in cases of anorexia nervosa from around age 11. This report examines the association between disorders in childhood and adolescence, in comparison to that in adulthood, with focus on obsessive-compulsive disorder. To start with, the characteristics of childhood onset cases with onset under age 7 were reviewed, revealing a relatively large proportion of subjects with experience of separation anxiety. Analyses revealed the possibility of anticipating obsessional tendencies in the parents of such subjects. Further clarification of the features of such early onset cases is hoped for in future. Next, we conducted a literature review comparing the characteristics of child and adolescent obsessive-compulsive disorder with that in adulthood. It has been determined that obsessive-compulsive symptoms in childhood and adolescence have a relatively unyielding 4-factor construct that persists through life, namely: 1) symmetry factor, 2) forbidden thoughts factor, 3) cleaning factor, and 4) hoarding factor. Of these, children with primary symptoms of hoarding are said to have poorer long-term diagnoses than children with other symptoms. Another point of note is the presence of large disparity regarding the prognosis of cases with concomitant tics. While the prognosis of childhood-obsessive compulsive disorder is generally favorable in many reports, the need for caution has also been noted regarding the possibility of transition on to schizophrenia in more than just a few cases.

We report here the first case with Diamond-Blackfan anemia (DBA) who responded to rituximab. The patient is an 8-yr-old Japanese girl with refractory DBA accompanied by complex congenital heart disease. She received two doses of rituximab, 375 mg/m(2)/wk. She became transfusion independent 6 months after the treatment without any serious side effect. However, after 8 months of transfusion-free period, her condition returned to the pretreatment level with recovery of peripheral B cells. Rituximab may be a successful therapy for refractory DBA where B cells play a crucial role in the pathogenesis of the severe anemia.

The glutathione-S-transferase (GST) polymorphism may affect the outcome of treatment of leukemia because GSTs play an important role in detoxifying the chemotherapeutic agents used to kill leukemia cells. However, results of previous reports have been controversial. This study was undertaken to clarify the influence of GST polymorphism on the outcome of childhood B-precursor acute lymphoblastic leukemia (ALL).Eighty-two patients with childhood B-precursor ALL treated during 1988-1999 with our ALL protocol (median follow-up time 89.5 months, range 31 -169 months) were examined for GST gene patterns. The effect of GSTM1 and GSTT1 deletion genotypes on the clinical features and therapeutic results was analyzed.All patients attained complete remission but 12 had an early relapse (within 30 months of the initiation of treatment). In univariate analysis, early relapse of ALL was correlated significantly with the presence of the t(9;22)(q34;q11) cytogenetic abnormality (p=0.0003), high white blood cell counts (p=0.015) and double null genotype (p=0.027). Multivariate analysis revealed that the GST double null genotype was the only significant independent predictor of early relapse (p=0.018).The simultaneous deletion of both the GSTM1 and GSTT1 genes is more predictive than any other parameter of early relapse of childhood B-precursor ALL.

We report the case of a 3-year-old Japanese boy with phosphoglycerate kinase 1 (PGK1) deficiency (Online Mendelian Inheritance in Man entry 311800). The patient had anaemia and jaundice at birth, necessitating exchange transfusions for 2 d. After one red blood cell transfusion at age 2 months, his Hb level was 8-9 g/dl, his reticulocyte counts were 300-500 x 109/l, and his total bilirubin level was 25.65-42.75 micro mol/l. The patient suffered two episodes of respiratory infection-associated haemolytic crisis and rhabdomyolysis during early infancy. At age 3.0 years, his developmental milestones (developmental quotients measured using the Tsumori-Inage methods) score was 49% (normal 74-131%), and his height was below average by -2.0 standard deviations. The diagnosis of PGK1 deficiency was made based on his remarkably low (10% of normal) erythrocyte PGK enzyme activity level and the identification of a novel missense (1060G--C) PGK1 gene mutation. This mutation results in the Ala-353Pro amino acid substitution, which has been designated PGK Kyoto. The patient developed the full clinical symptoms of PGK1 deficiency including haemolytic anaemia, myopathy, central nervous system disorder and growth retardation, which is unusual.

We studied the impact of etoposide on the prognosis of 81 patients (77 of whom were children

PURPOSE: We sought to identify the clinical variables most critical to successful treatment of Epstein-Barr virus (EBV)–associated hemophagocytic lymphohistiocytosis (HLH). PATIENTS AND METHODS: Among the factors tested were age at diagnosis (< 2 years or ≥ 2 years), time from diagnosis to initiation of treatment with or without etoposide-containing regimens, timing of cyclosporin A (CSA) administration during induction therapy, and the presence or absence of etoposide. RESULTS: By Kaplan-Meier analysis, the overall survival rate for the entire cohort of 47 patients, most of whom had moderately severe to severe disease, was 78.3% ± 6.7% (SE) at 4 years. The probability of long-term survival was significantly higher when etoposide treatment was begun less than 4 weeks from diagnosis (90.2% ± 6.9% v 56.5% ± 12.6% for patients receiving this agent later or not at all; P < .01, log-rank test). Multivariate analysis with the Cox proportional hazards model demonstrated the independent prognostic significance of a short interval from EBV-HLH diagnosis to etoposide administration (relative risk of death for patients lacking this feature, 14.1; 95% confidence interval, 1.16 to 166.7; P = .04). None of the competing variables analyzed had significant predictive strength in the Cox model. However, concomitant use of CSA with etoposide in a subset of patients appears to have prevented serious complications from neutropenia during the first year of treatment. CONCLUSION: We conclude that early administration of etoposide, preferably with CSA, is the treatment of choice for patients with EBV-HLH.

An attractive hypothesis is that in utero exposure of hematopoietic cells to oncogenic agents can induce molecular changes leading to overt acute lymphoblastic leukemia (ALL) in infants and perhaps older children as well. Although supported by studies of identical infant twins with concordant leukemia, and of nontwined patients withMLL gene rearrangements, this concept has not been extended to the larger population of B-lineage ALL patients who lack unique nonconstitutive mutations or abnormally rearranged genes. We therefore sought to demonstrate a prenatal origin for 7 cases of B-cell precursor ALL (either CD10+ or CD10−) that had been diagnosed in infants and children 14 days to 9 years of age. Using a polymerase chain reaction–based assay, we identified the same clonotypic immunoglobulin heavy-chain complementarity determining region or T-cell receptor VD2-DD3 sequences in the neonatal blood spots (Guthrie card) and leukemic cell DNAs of 2 infants with CD10− ALL and 2 of the 5 older patients with CD10+ ALL. Nucleotide sequencing showed a paucity of N or P regions and shortened D germ line and conserved J sequences, indicative of cells arising from fetal hematopoiesis. Our findings strongly suggest a prenatal origin for some cases of B-cell precursor ALL lacking specific clonotypic abnormalities.