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Children with acute myeloid leukemia (AML) commonly develop extramedullary disease (EMD), which comprises central nervous system (CNS) lesions and myeloid sarcoma (MS). In this retrospective analysis, we aimed to determine the effect of EMD on the outcomes of allogeneic hematopoietic cell transplantation (HCT) in 678 pediatric patients with de novo AML (median age, 7 years; range, 0.3-15 years) between 2006 and 2016. We compared the outcomes between patients with (EMD group, n = 158; CNS lesion, n = 47, CNS lesion + MS, n = 9, and MS, n = 102) and without EMD at diagnosis (non-EMD group, n = 520). Survivors were followed for a median of 4.5 years, and the 4-year overall survival (OS) rates were 60.6% and 56.4% in the EMD and non-EMD groups, respectively (P = 0.60). No significant differences in OS were observed with respect to the EMD site, except bone lesions, which were associated with poor OS after HCT in a non-remission status. A multivariate analysis revealed that EMD did not affect the outcomes of HCT. In conclusion, the study findings suggest that EMD should not be considered a poor prognostic factor in HCT for children with AML.

We herein report a 10-month-old female infant with a 4-month history of diarrhea with electrolyte abnormalities and growth impairment. A 4-cm right adrenal tumor was detected by computed tomography. No metastasis or accumulation on I123 -metaiodobenzylguanidine scintigraphy was recognized in the tumor. A vasoactive intestinal peptide-secreting neuroblastic tumor was suspected, and octreotide was started, but the diarrhea persisted. Tumor extirpation was laparoscopically performed. After tumor removal, the symptoms improved immediately, and her growth caught up by 9 months after surgery. A minimally invasive approach for pediatric solid tumor is difficult, especially for neuroblastoma, but may be beneficial for the patient's recovery.

Japan Children’s Cancer Group (JCCG) is the only national clinical research group for childhood cancer in Japan, which was established in December 2014. In this paper, the JCCG describes its efforts in Japan and Asia and shares its current goals for enhancing the effective treatment of childhood cancer. International collaborative research is necessary for expeditious meaningful clinical outcomes because childhood cancers are relatively rare. The purpose of JCCG’s international committee is to facilitate smooth international cooperation based on the JCCG Constitution to support the exchange of domestic and foreign research results, strengthen international cooperation in paediatric cancer treatments. At this moment, two clinical trials are ongoing, including JPLT4: PHITT for pediatric hepatic tumor and ASIA DS-ALL 2016 for acute lymphoblastic leukaemia in children with Down syndrome. Other than JCCG activity, several activities will be introduced including Japan Heart. Finally, the Global Initiative for Childhood Cancer was launched with a goal of at least a 60% survival rate for children with cancer by 2030. The international committee of JCCG is one of the members of leading this activity in Japan. It began working with the International Committee of The Japanese Society of Pediatric Hematology/Oncology to participate in this effort on behalf of paediatric cancer care in Japan.

Escherichia albertii is a recently recognized human enteropathogen that is closely related to Escherichia coli. As E. albertii sometimes causes outbreaks of gastroenteritis, rapid strain typing systems, such as the O- and H-serotyping systems widely used for E. coli, will be useful for outbreak investigation and surveillance. Although an O-genotyping system has recently been developed, the diversity of E. albertii H-antigens (flagellins) encoded by fliC genes remains to be systematically investigated, and no H-serotyping or genotyping system is currently available. Here, we analyzed the fliC genes of 243 genome-sequenced E. albertii strains and identified 73 sequence types, which were grouped into four clearly distinguishable types designated E. albertii H-genotypes 1–4 (EAHg1–EAHg4). Although there was a clear sign of intraspecies transfer of fliC genes in E. albertii, none of the four E. albertii H-genotypes (EAHgs) were closely related to any of the 53 known E. coli H-antigens, indicating the absence or rare occurrence of interspecies transfer of fliC genes between the two species. Although the analysis of more E. albertii strains will be required to confirm the low level of variation in their fliC genes, this finding suggests that E. albertii may exist in limited natural hosts or environments and/or that the flagella of E. albertii may function in a limited stage(s) in their life cycle. Based on the fliC sequences of the four EAHgs, we developed a multiplex PCR-based H-genotyping system for E. albertii (EAH-genotyping PCR), which will be useful for epidemiological studies of E. albertii infections.

Purpose: Patients with strong pulmonary vascular occlusive lesions are at risk of developing postoperative pulmonary hypertension (PH). We aimed to evaluate preoperative right ventricular (RV) function in patients with ventricular septal defect (VSD) who required cardiac surgery during infancy and consequently developed postoperative PH and to determine whether we could preliminarily evaluate postoperative PH in these patients.Methods: We retrospectively analyzed 55 infants with VSD who underwent cardiac surgery between March 2014 and April 2020. We evaluated the measurements of preoperative atrial/ventricular general function and 2D atrial/ventricular strain between these two groups: a group with postoperative PH (post-PH) and a group without postoperative PH (post-NPH). Results: Post-PH patients had a significantly lower tricuspid annular plane systolic excursion (TAPSE) (11.2 mm) and TAPSERA (the proportion of TAPSE due to RA contraction alone) (6.6 mm) than the post-NPH patients (14.1 mm, 8.5 mm). Furthermore, the post-PH group had a significantly lower peak right atrial (RA) longitudinal strain (PRALS) (31.0%) than the post-NPH group (43.0%). Multivariate logistic regression analysis identified that PRALS and TAPSERA were independent echocardiographic parameters for the presence of post-PH. The sensitivity and specificity of predicting post-PH for ≤38% of the PRALS were 83.0% and 100.0%, respectively, with an area under the curve of 0.94 (p < 0.01).Conclusion: Preoperative RA function and RV diastolic function decreased in the post-PH group. The RA strain and TAPSERA could be useful factors for predicting postoperative PH.

Although concurrent bacteremia in siblings is rare, serotype 24F Streptococcus pneumoniae was isolated from the blood of twin 1-year-old girls within a 3-day interval, supporting the high invasive potential of this serotype. As the prevalence of childhood serotype 24F-invasive pneumococcal diseases increases in Europe and the Western Pacific Region, investigation and surveillance of this serotype are necessary.

Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH) is highly prevalent in Japan. To date, no standard treatment for EBV-HLH has been established owing to the diversity in treatment response and the difficulty in assessing prognostic factors. The present prospective study recruited 27 children with EBV-HLH who were also part of the HLH-2004 study. EBV load in the peripheral blood was monitored at diagnosis and 2, 4, and 8 weeks after treatment initiation. Additionally, T-cell receptor (TCR) clonality and other laboratory data were evaluated. TCR clonality was positive in 14 patients at diagnosis. Seven of 27 patients experienced recurrences after treatment. No correlation was noted among any clinical data at diagnosis of patients with and without recurrence. However, the recurrence rate was significantly higher in patients aged 2 years and/or those with a high plasma EBV load of 10

Herein, we describe a 14-year-old female patient with B-cell precursor acute lymphoblastic leukemia who relapsed in early consolidation. Minimal residual disease-negative complete remission was obtained after 1 cycle of inotuzumab ozogamicin therapy. She underwent HLA-haploidentical peripheral blood stem cell transplantation after a myeloablative conditioning regimen. Posttransplant cyclophosphamide, tacrolimus, and mycophenolate mofetil were administered for the prophylaxis of graft-versus-host disease. At 23 months, she was in complete remission. Although the administration of inotuzumab ozogamicin followed by haploidentical peripheral blood stem cell transplantation with posttransplant cyclophosphamide has been limited in children, this strategy may be an effective treatment for pediatric refractory acute lymphoblastic leukemia.

Background This study aims at determining the health-related quality of life (HRQOL) of children with acute lymphoblastic leukemia (ALL) after the induction therapy, assessing the agreement between child self-reports and family proxy-reports HRQOL, and determining the factors related to this agreement, especially child age, family attendance, and children’s social relationships beyond the family. Methods We analyzed questionnaire data (2012–2017) from the Japanese Pediatric Leukemia/Lymphoma Study Group’s clinical study (ALL-B12). Participants were children with B-cell precursor ALL aged 5–18 and their family members, who mostly took care of the child during hospitalization. Participants answered the Pediatric Quality of Life Inventory™ (PedsQL™) Generic Core Scales (PedsQL-G), and Cancer Module (PedsQL-C) to measure pediatric HRQOL. We calculated the differences between child self-reported and family proxy-reported subscale scores along with intraclass correlation coefficients (ICC). We conducted multiple regression analyses according to all participant pairs and age groups (young children, school age, and adolescents), with ICCs for all PedsQL-G subscales (ICC-G) and all PedsQL-C subscales (ICC-C) as the outcome variables. Results Five hundred twenty-two pairs of children and their families were analyzed. We observed a moderate level of agreement on most PedsQL subscales between child self-reports and family proxy-reports; however, worry had the weakest agreement for all PedsQL subscales (ICC = .32, 95% confidence interval = .24–.40). The agreement of ICC-C was positively related to family attendance in the hospitalization, only for the young children group (B = .185, p = .003). Conclusions We observed some differences between child self-reports and family proxy-reports of HRQOL of children with ALL. Both child self-reports and family proxy-reports captured HRQOL in the induction therapy. We suggest that attending to young children’s hospitalization affects the level of agreement between reports on their HRQOL.

The appropriateness of allogeneic hematopoietic stem cell transplantation (HSCT) in children and adolescents with leukemia in whom complete remission is not possible remains unclear. This retrospective analysis aimed to investigate the outcomes associated with HSCT, and the risks of HSCT in children and adolescents with nonremission acute lymphoblastic leukemia (ALL).Data from the Japan Society for Hematopoietic Cell Transplantation registry on 325 patients with nonremission ALL (aged21 years, with blasts in the peripheral blood and/or bone marrow) who had undergone HSCT between January 2001 and December 2015 were evaluated. To assess survival, we developed a scoring system using significant adverse pre-HSCT variables.Overall, 247 patients died. The median length of follow up among survivors was 1145 days, and the 3-year overall survival was 22% (95% confidence interval [CI]: 18-27%). A low performance score, presence of25% bone marrow blasts, T-cell phenotype, poor-risk or normal cytogenetics, and history of HSCT were predictors of a poor outcome. Patients scoring 0-1 (n = 109), 2 (n = 91), and 3-7 (n = 125) had a 3-year overall survival of 41% (95% CI: 31-51%), 21% (95% CI: 13-31%), and 7% (95% CI: 3-12%), respectively.These results support HSCT in certain nonremission patients. Even in patients without complete remission, outcomes differed according to pre-HSCT factors. A scoring system could help determine the appropriateness of HSCT in children and adolescents with nonremission ALL.

Induction deaths (ID) remain a critical issue in the treatment of pediatric patients with acute lymphoblastic leukemia (ALL). The reported rate of ID in this population is 1% or higher. We speculate that this proportion might be lower in Japan because of mandatory hospitalization during induction therapy to manage complications. We retrospectively analyzed the incidence of ID among children with ALL enrolled in 4 Japanese study groups between 1994 and 2013. Among 5620 children, 41 (0.73%) cases of ID were noted. The median age was 6.5 years; 24 children were female, and 7 had T-cell ALL. Infection was the most common cause of ID (n=22), but the incidence (0.39%) was lower than that reported in western countries. Mortality within 48 hours from the onset of infection was low, comprising 25% of infection-related deaths. The incidence of infections caused by Bacillus species was low. Only 1 patient died because of Aspergillus infection. Fatal infections mostly occurred during the third week of induction therapy. Our findings suggest that close monitoring, stringent infection control, and immediate administration of appropriate antibiotics through hospitalization might be important strategies in reducing the rate of infection-related ID in pediatric patients with ALL.

Weight gain is often observed in children with acute lymphoblastic leukemia (ALL) who undergo chemotherapy including steroids. An increase in body mass index (BMI)-standard deviation score (SDS) during induction therapy is reported as a risk factor for obesity after treatment. However, risk factors of an increase in BMI-SDS during induction therapy are not known. Ninety-six patients with ALL who were treated at our hospital between 1996 January and September 2013 were analyzed retrospectively. Daily body weight measurement was initiated in July 2005 in an attempt to control weight. Fifty-four patients were boys and 42 were girls. The median age at onset was 5.1 years (0.5-16.6 y), and 7.3% of patients were overweight/obese at onset. BMI-SDS increased +0.1% (-3.3% to +3.2%) during induction therapy. BMI-SDS increased by 1 and 2 or more SDs in 20% and 3% of patients, respectively. In multivariate analysis, non-high-risk treatment and earlier treatment start date (before daily body weight measurement) were independent risk factors. Ten percent of patients were overweight/obese at 3 years after completion therapy, and high BMI-SDS after induction therapy was a risk factor. Daily body weight measurement might prevent excess weight gain during induction therapy, resulting in patients maintaining a healthy weight after ALL treatment.

We are conducting a nationwide multicenter Phase II/III trial in children and adolescents with newly diagnosed B-cell precursor acute lymphoblastic Leukemia in Japan., B-cell precursor acute lymphoblastic leukemia is the most common pediatric malignancy, but its treatment needs to be modified to cause low acute toxicity and few late complications with a high cure rate. In this trial, we will stratify patients with B-cell precursor acute lymphoblastic leukemia into standard, intermediate and high risk groups according to prognostic factors. In addition, we will establish an evaluation system for minimal residual disease that will enable us to stratify patients based on minimal residual disease in subsequent clinical trials. We will clarify the impact of dexamethasone/vincristine pulse therapy during maintenance therapy in the standard risk group, and intensive l-asparaginase therapy in the intermediate risk group. In the high risk group, usefulness of vincristine intensification will be assessed. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000009339 [http://www.umin.ac.jp/ctr/].

We report the first case of liver abscess due to Sterigmatomyces halophilus. Because this pathogen grows poorly in culture medium without added salts, it was identified by sequencing analysis targeting the rRNA gene internal transcribed spacer (ITS) region. This method could be useful for pathogens that cannot be cultured using standard methods.

We describe the case of a 23-month-old male infant with Epstein-Barr virus (EBV)-associated lymphoproliferative disorder, which mimicked the recurrence of EBV-associated hemophagocytic lymphohistiocytosis. Chemotherapy with dexamethasone, etoposide, and cyclosporine resolved fever, hepatosplenomegaly, and pancytopenia. However, on day 81 of illness, the patient developed similar symptoms. Plasma EBV-DNA levels markedly increased again, but no T-cell clonality was observed. B cells were identified to be infected with EBV. He was successfully treated with rituximab, dexamethasone and etoposide. When recurrence of EBV-associated hemophagocytic lymphohistiocytosis is suspected, performing tests to identify the infected cells will enable accurate understanding of the clinical condition, resulting in proper treatments.

Background: T-cell acute lymphoblastic leukemia (T-ALL) accounts for approximately 10-15% or 25% of cases of pediatric or adolescent and young adult (AYA) ALL, respectively. The use of pediatric protocols can improve outcomes in AYA T-ALL. Furthermore, nelarabine (NEL) has been shown to be effective for patients with relapsed or refractory T-ALL. This nationwide, multicenter, prospective, phase II trial for T-ALL was conducted to assess the feasibility and efficacy of NEL, intensive L-asparaginase (L-asp), and protracted intrathecal therapy (IT) when incorporated in the AIEOP-BFM-ALL 2000 based pediatric treatment for patients Patients & Methods: From December 2011 to November 2017, 364 patients with newly diagnosed T-ALL, age 0-24 (median 9.6 years), were enrolled in the JPLSG ALL-T11/JALSG T-ALL-211-U (ALL-T11) trial conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group and the Japan Adult Leukemia Study Group. Patients were stratified into three groups according to their prednisone (PSL) response, initial central nervous system (CNS) status, and PCR-based minimal residual disease (MRD) at the end of induction consolidation protocol IB (TP2). Good or poor PSL responses were defined as Results: Fifteen patients were excluded having not meeting inclusion criteria. Of 349 evaluable patients, 238 (68.2%) were male, the median white blood cell count was 45 × 10 9/L (range 0.4-1375), and 73.4% were HR by NCI criteria. Twenty-eight patients (8.0%) had CNS3 status. PCR-MRD could be evaluated in 208 patients. Among 310 stratified patients, 168 (54.2%), 103 (33.2%), and 39 (12.6%) were SR, HR, and VHR, respectively. HSCT was performed in 35 patients (10.0%). The composite CR (CR+CR in suppression) rate after IA, and the CR rate after IB were 85.4% and 90.5%, respectively. With a median follow-up of 5 years 2 months, the 3-year event-free survival (EFS) and overall survival (OS) of the whole cohort was 85.6% (95% CI: 81.5-89.9) and 91.4% (87.9-93.9), respectively (Figure 1), and the 3-year cumulative incidence of relapse was 8.9% (5.9-12.1). Induction death was seen in 14 patients (4.0%), and 3-year non-relapse mortality of the whole cohort was 0.6% (0.1-2.1). Three-year EFS and OS for each risk group were 90.4% (84.9-94.0) and 95.8% (91.4-98.0) in SR, 91.3% (83.9-95.4) and 95.1% (88.6-97.9) in HR, and 87.2% (71.9-94.5) and 87.2% (71.9-94.5) in VHR respectively. Three-year EFS and OS were 90.1% (86.1-93.0) and 95.7% (92.7-97.5), and 55.6% (30.5-74.8) and 66.7% (40.4-83.4) in MRD-negative and MRD-positive patients (p < 0.001 and p < 0.001), respectively. Grade 3 or higher peripheral motor and sensory neuropathies were seen in 9 (8.7%) and 6 (5.8%) in HR and 2 (5.1%) and 0 in VHR, respectively. Clinical allergic reaction, anaphylaxis, and pancreatitis were reported in 10 (2.9%), 16 (4.6%), and 31 (8.9%) patients, respectively. Conclusions: The addition of NEL, intensified L-asp, and protracted IT in AIEOP-BFM-ALL 2000 based treatment showed encouraging outcomes with acceptable toxicities despite the limited use of CRT and HSCT. Figure 1 Figure 1. Disclosures Hatta: Bristol-Myers Squibb: Honoraria; Novartis KK: Honoraria; Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical.: Honoraria. Imai: Juno Therapeutics: Patents & Royalties: chimeric receptor with 4-1BB signaling domain. Saito: Toshiba corporation: Research Funding. Kiyoi: Astellas: Honoraria; celgene: Honoraria; Daiichi Sankyo: Honoraria; Dainippon Sumitomo: Honoraria; Eisai: Honoraria; Fijifilm: Honoraria; Kyowa Kirin: Honoraria; Otsuka: Honoraria; Perseus Proteomics: Honoraria; Pfizer: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Zenyaku Kogyo: Honoraria. Matsumura: Nippon Shinyaku: Research Funding; Ono: Research Funding; Bristol-Myers Squibb: Speakers Bureau; Daiichi Sankyo: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Chugai: Research Funding; Asahi Kasei: Research Funding; Japan Blood Products Organization: Research Funding; Mundipharma: Research Funding; Amgen: Speakers Bureau; AYUMI Pharmaceutical: Research Funding; Eli Lilly Japan: Research Funding; Sumitomo Dainippon: Research Funding; Takeda: Research Funding; Astellas: Speakers Bureau; Kyowa Kirin: Research Funding; Taiho: Research Funding; Nihon Pharmaceutical: Research Funding; Janssen: Speakers Bureau; Mitsubishi Tanabe: Research Funding; Eisai: Research Funding; Otsuka: Consultancy, Research Funding, Speakers Bureau; MSD: Research Funding; Shionogi: Research Funding; Addvie: Research Funding. Miyazaki: Chugai: Honoraria; Kyowa-Kirin: Honoraria; Astellas: Honoraria; Novartis: Honoraria; Abbvie: Honoraria; Sumitomo-Dainippon: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria; Eisai: Honoraria; Janssen: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Nippon-Shinyaku: Honoraria; Takeda: Honoraria; Sanofi: Honoraria.

In wire EDM process, it is important to smoothly exclude debris and bubbles generated in the working gap for keeping stable performance. Much debris stagnation in the gap would cause frequent occurrence of discharge concentration and secondary discharge, which results in unstable machining performance, such as frequent wire breakage, low removal rate, and low shape accuracy. Therefore, a jet flushing of working fluid using upper and lower jet nozzles has been conventionally applied for excluding the debris and bubbles from the machined kerf. Nevertheless, it is well known that the wire often breaks when the machined kerf length is a few mm from the start hole in 1st-cut wire EDM. The influence of machined kerf length on the flow field, the debris exclusion, and the wire behavier caused with hydrodyanamic force by the jet flushing should be made clear.In this study, variations of flow field in the kerf, the debris accumulation state and the wire deflection caused jet flushing with machined length were analytically investigated by CFD (computational fluid dynamics) and structural analysis when 1st-cut wire EDM was done from a small start hole. Moreover, the effects of machined kerf length on the wire deflection and wire breakage were discussed. Wire breakage frequency experiments showed that wire tended to frequently break at a certain machined kerf length, where the wire deflection rapidly increased and the debris particle residence time in the gap became long.

Background The dose-limiting toxic effect of cyclophosphamide (CY) is cardiotoxicity. The pathogenesis of myocardial damage is poorly understood, and there is no established means of prevention. In previous studies, we suggested that for CY-induced cardiotoxicity, whereas acrolein is the key toxic metabolite, carboxyethylphosphoramide mustard (CEPM) is protective. We sought to verify that acrolein is the main cause of cardiotoxicity and to investigate whether aldehyde dehydrogenase (ALDH), which is associated with greater CEPM production, is involved in the protective effect for cardiotoxicity. We also evaluated the protective effect of N-acetylcysteine (NAC), an amino acid with antioxidant activity and a known acrolein scavenger. Methods H9c2 cells were exposed to CY metabolites HCY (4-hydroxy-cyclophosphamide), acrolein or CEPM. The degree of cytotoxicity was evaluated by MTT assay, lactate dehydrogenase (LDH) release, and the production of reactive oxygen species (ROS). We also investigated how the myocardial cellular protective effects of CY metabolites were modified by NAC. To quantify acrolein levels, we measured the culture supernatants using high performance liquid chromatography. We measured ALDH activity after exposure to HCY or acrolein and the same with pre-treatment with NAC. Results Exposure of H9c2 cells to CEPM did not cause cytotoxicity. Increased ROS levels and myocardial cytotoxicity, however, were induced by HCY and acrolein. In cell cultures, HCY was metabolized to acrolein. Less ALDH activity was observed after exposure to HCY or acrolein. Treatment with NAC reduced acrolein concentrations. Conclusions Increased ROS generation and decreased ALDH activity confirmed that CY metabolites HCY and acrolein are strongly implicated in cardiotoxicity. By inhibiting ROS generation, increasing ALDH activity and decreasing the presence of acrolein, NAC has the potential to prevent CY-induced cardiotoxicity.

Improvement in the outcomes associated with acute lymphoblastic leukemia (ALL) in Down syndrome (DS-ALL) has been delayed. However, as the clinical characteristics of DS-ALL, including leukemogenesis, are elucidated, strategies for improving the outcomes are being considered and implemented. As host side problems, infectious complications and complication deaths due to immunodeficiency and mucosal disorders are problematic. Close control of infection using prophylactic antibiotics and intravenous immunoglobulin replacement should assist in overcoming these problems. DS-ALL is commonly associated with a poor prognosis for gene abnormality, similar to Ph-like ALL. While selecting appropriate treatment for DS-ALL, minimal residual disease (MRD) is determined to assess the disease status and calculate the risk. DS-ALL is considered as a good indication for immunotherapy, such as inotuzumab ozogamicin, blinatumomab, and chimeric antigen receptor T cell therapy, because of less adverse events than those of anticancer drugs. CRLF2-JAK abnormalities are frequently observed in DS-ALL, and specific therapies targeting them are also being developed. As mentioned above, it is thought that improvements in the treatment of DS-ALL outcomes will lead to similar improvements in other ALL. This review will point out the current and future direction of DS-ALL to clinicians treating DS-ALL and those doing research on DS-ALL.

Fludarabine/cyclophosphamide-based conditioning regimens are standard in bone marrow transplantation (BMT) for acquired bone marrow failure in children, however, graft failure may occur. Using the data from a nationwide transplantation registry, we compared the outcomes of children aged

Lymphatic malformation (LM) is a congenital disorder resulting from an abnormal development of lymphatic vessels. LM may result in problems of cosmesis and functional impairment, including airway compression. An 11-year-old girl was referred to our department with increasing dysphagia caused by a large left cervical LM with a long history of treatment. Because of the LM location, surgical resection was not an option, and various therapies, including use of picibanil, had proven ineffective. Celecoxib treatment (100 mg/day) was initiated for local pain management. Softening of the lesion was observed 2 weeks after treatment initiation, and the dose was increased to 200 mg/day with additional shrinking of the LM over the next 2 weeks. With parental consent, celecoxib was continued, with a 65% reduction in volume achieved at 6 months. The patient discontinued treatment at 12 months, and the LM volume increased. Control over the LM was achieved with resumption of celecoxib treatment. After 2 years of treatment, the LM persists, but the size of the malformation is significantly smaller. No adverse effects of celecoxib treatment were observed. The anti–cyclooxygenase-2 effect of celecoxib prevented lymphatic vessel growth through an inhibition of cyclooxygenase-2 activity in the conversion of prostaglandin to prostaglandin E2. In conclusion, celecoxib may be a promising therapeutic agent for LM management.

Pediatric anaplastic large-cell lymphoma (ALCL), which is characterized by strong expression of CD30, is usually responsive to multidrug chemotherapy. Brentuximab vedotin (BV) which is an anti-CD30 antibody-drug conjugate is a promising drug with effects on relapsing or refractory ALCL. However, its effects may not be sufficient for the central nervous system disease. The authors herein reported an 11-year-old boy with ALCL that progressed as central nervous system disease receiving intensive induction chemotherapy has achieved and maintained remission by BV and high-dose methotrexate administrated alternately. Alternate therapy with high-dose methotrexate may complement these shortcomings of BV to provide safe treatment without worsening adverse events.

Background Nelarabine has been used for the treatment of T-cell malignancies including T-acute lymphoblastic leukemia (T-ALL)/T-lymphoblastic lymphoma. However, the mechanisms that underlie the susceptibility or resistance to nelarabine have not been fully elucidated. The aim of this study was to determine the significance of nelarabine transport and metabolism in the context of nelarabine cytotoxicity. Procedure The expression profiles of six genes in the nelarabine pathway were analyzed in blast cells from six patients with T-ALL as well as in three T-ALL cell lines. In vitro cytotoxicity (LC50 of 9-β-d-arabinofuranosylguanine [ara-G]) was evaluated. Results The mRNA expression of ENT1, DCK, CDA, NT5C2, RRM1, and RRM2 in patients showed inter-individual variability and was not correlated with the LC50 of ara-G. However, the ratio of (ENT1 × DCK)/(CDA × RRM1) expression was significantly correlated with LC50 (r = –0.831, P = 0.0405). Conclusions Chemosensitivity to nelarabine is influenced by the balance of the expression of these four genes, and the ratio of their expression predicts the response of T-cell malignancies to nelarabine.

A phase 1 study was conducted to evaluate the safety, pharmacokinetics (PK), efficacy and pharmacogenetic characteristics of clofarabine in seven Japanese pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL). Patients in Cohort 1 received clofarabine 30 mg/m(2)/day for 5 days, followed by 52 mg/m(2)/day for 5 days in subsequent cycles. Cohort 2 patients were consistently treated with 52 mg/m(2)/day for 5 days. No more than six cycles were performed. Every patient had at least one ≥Grade 3 adverse event (AE). AEs (≥Grade 3) related to clofarabine were anaemia, neutropenia, febrile neutropenia, thrombocytopenia, alanine aminotransferase increased, aspartate aminotransferase increased, haemoglobin decreased, and platelet (PLT) count decreased. C max and AUC of clofarabine increased in a dose-dependent fashion, but its elimination half-life (T 1/2) did not appear to be dependent on dose or duration of treatment. Clofarabine at 52 mg/m(2)/day shows similarly tolerable safety and PK profiles compared to those in previous studies. No complete remission (CR), CR without PLT recovery, or partial remission was observed. Since clofarabine is already used as a key drug for relapsed/refractory ALL patients in many countries, the efficacy of clofarabine in Japanese pediatric patients should be evaluated in larger study including more patients, such as by post-marketing surveillance.

Stenotrophomonas maltophilia causes pneumonia and CVC-CRBSI in HSCT. However, there are few reports of pyomyositis due to S. maltophilia. We report a patient with CRBSI and pyomyositis due to S. maltophilia after allogeneic HSCT who was successfully treated by removing the CVC and antibiotics without surgical drainage. Removing the CVC and the combined antibiotics without preventing the neutrophil engraftment could avoid surgical drainage in pyomyositis due to S. maltophilia when detected in an early stage.

The early-onset form of carnitine palmitoyltransferase (CPT) II deficiency has severe outcomes; patients typically die during the newborn period. We report a case of neonatal-onset CPT II deficiency with prolonged survival, exceeding 24 months. The patient was successfully treated by continuous hemodialysis (CHD), which enabled her to overcome repeated crises. We suggest that early intensive treatment, including CHD, is a key for prolonged survival in patients with neonatal-onset CPT II deficiency.

We examined 3 pediatric patients with bilineal acute leukemia. Patient 1 with B-cell acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML) with B-ALL dominance responded well to prednisolone and ALL-type induction therapy. Patients 2 and 3 with T-ALL and AML with AML dominance responded poorly to prednisolone. Patient 2 was resistant to AML-type therapy; patient 3 was resistant to ALL-type induction therapy until day 15. However, all 3 patients eventually achieved complete remission after ALL-type induction therapy. Thus, ALL-type induction therapy should be initiated for bilineal acute leukemia even with AML-dominant, poor prednisolone response, or poor early response features.

Recent advances in intensive chemo- and immunotherapy have contributed to the outcome of hemophagocytic lymphohistiocytosis (HLH); however, the prognosis of HLH in children differs by HLH subtype. In Japan, secondary HLH, particularly Epstein-Barr virus-associated HLH (EBV-HLH), is the most common HLH subtype. The prognosis of HLH has improved in recent years. We here conducted a prospective study of 73 patients who were treated with HLH-2004 protocol in Japan. EBV-HLH, familial HLH (FHL), and HLH of unknown etiology were seen in 41, 9, and 23 patients, respectively. Patients with resistant or relapsed disease after HLH-2004 treatment and those with FHL received hematopoietic stem cell transplantation (HSCT). The induction rate after initial therapy was 58.9%, and the 3-year overall survival (OS) rate of all patients was 73.9% and differed significantly among those with EBV-HLH, FHL, and HLH of unknown etiology. Of the 17 patients who received HSCT, the 3-year OS rates of those with and without complete resolution before HSCT were 83.3% and 54.5%, respectively. Outcomes in children with HLH who were treated with the same protocol differed among HLH subtypes. Appropriate strategy for each subtype should be established in future studies.

BACKGROUND Fatal adverse effects or relapse can occur with excessive or insufficient busulfan exposure in hematopoietic stem cell transplantation. Given that busulfan is mainly metabolized by glutathione S-transferase (GST), we investigated the influence of GST polymorphisms on busulfan pharmacokinetics in Japanese pediatric patients. METHODS Blood samples were taken from patients receiving high-dose i.v. busulfan as the first dose. Plasma busulfan concentration was measured using high-performance liquid chromatography. The area under the plasma busulfan concentration-time curve (AUC) was calculated. The genotype of GSTA1 was determined on polymerase chain reaction (PCR)-restriction fragment length polymorphism. Multiplex PCR was used to detect the presence or absence of GSTM1 and GSTT1 in the genomic DNA samples. RESULTS Twenty patients were consecutively enrolled. Phenotype prediction was defined as follows: poor metabolizer (n = 4), one or more GSTA1*B haplotype or GSTM1/GSTT1 double-null genotypes; and extensive metabolizer (n = 16), other genotypes. GSTA1, M1, and T1 independently had no significant differences in AUC0-∞ , clearance or elimination rate constant. For the infant with unexpectedly high AUC0-∞ (2,591 μmol/L min), the GSTA1, M1, and T1 polymorphisms were wild type. On further analysis, the poor metabolizer group had lower clearance and higher AUC0-∞, except for the aforementioned patient, compared with the extensive metabolizer group (1,531 vs 1,010 μmol/L min; P < 0.01). CONCLUSIONS GST polymorphisms may have affected busulfan pharmacokinetics, but these effects were obscured by other factors, such as underlying disease, systemic conditions, treatment history, and race.

Infantile hemangiomas (IH) are the most common in the head and neck region.1 They can occur anywhere in the skin, however, urethral hemangiomas are very rare. We describe a case report of a 3-year-old boy with extensive lesions of IH in the anterior urethra. Urethral IH were disappeared during 1 year of oral administration of propranolol though it brought on urinary retention. This is the first report about oral propranolol treatment in a child with urethral IH. Oral administration of propranolol may be effective for urethral IH and beneficial especially for lesions requiring extensive surgical resection and reconstruction.

In a previous study of childhood acute lymphoblastic leukemia (ALL) by the Kyushu-Yamaguchi Children's Cancer Study Group, ALL-96, we achieved a 72.1 % 5-year event-free survival (EFS) and an 84.8 % 5-year overall survival (OS). In a subsequent study, ALL-02, we adopted a vincristine dexamethasone (VCR/DEX) pulse regimen as maintenance therapy in the context of the ALL-96 study using the same risk classification and treatment schedule. A total of 156 pediatric cases of ALL were treated with ALL-02. All of the patients were classified as standard-risk or high-risk. Risk stratification was based on white cell counts, immunophenotype, the presence of central nervous system (CNS) disease at diagnosis, organomegaly, and early treatment response (day 14 bone marrow status). The 7-year EFS and OS rates were 77.7 % (95 % CI 70.6-84.8 %) and 89.5 % (95 % CI 84.6-94.4 %), respectively. CNS 3 status [hazard ratio (HR) = 5.0, p = 0.009] and high white blood cell count at diagnosis (HR = 2.6, p = 0.047) were risk factors for poor EFS in multivariate analysis. Our strategies to categorize patients into two risk groups, and to treat with a VCR/DEX pulse were feasible and reasonably effective treatments for pediatric ALL.

EDM finishing technology has progressed recently, and very small surface roughness can be obtained by controlling the electrical discharge conditions. Also, EDM using powder mixed fluids can improve the surface characteristics. Therefore, the EDM finished surface is highly expected to be applied as a final metal mold surface. In that case, the characteristics of EDMed surface influence the molding performance and the life of metal molds. As a new surface finishing method by EDM, the characteristics of EDMed surface using a nickel powder mixed fluid was experimentally discussed in this study, since nickel coatings have been widely applied to improve the corrosion resistance and the mold releasability of metal molds. Experimental analysis clarified that the resolidified layer containing nickel content could be formed on the surface by EDM in nickel powder mixed fluid. Also, the water repellency and the releasability of molded resin from the EDM finished surface could be improved.