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The outcomes for relapsed and metastatic Ewing sarcoma (EWS) is extremely poor. Therefore, it is important to identify the tumor‐specific targets in these intractable diseases. High focal adhesion kinase (FAK) transcript expression levels in EWS cell lines are known. TAE226 is a dual inhibitor of FAK and insulin‐like growth factor‐I receptor (IGF‐IR), while PF‐562,271 is a dual inhibitor of FAK and proline‐rich tyrosine kinase 2. We compared the cytotoxicity of TAE226 and PF‐562,271 toward three EWS cell lines. TAE226 strongly inhibited proliferation of three cell lines when compared with PF‐562,271. Furthermore, we investigated the efficacy of TAE226 as well as its mechanism of action against EWS. A stable EWS cell line with FAK and IGF‐IR knocked down was established, and microarray analysis revealed dysregulated expression in various pathways. TAE226 treatment of EWS cell lines induced cell cycle arrest, apoptosis, AKT dephosphorylation, and inhibition of invasion. We demonstrated that TAE226 drastically inhibits the local growth of primary tumors and metastasis in EWS using mouse models. Furthermore, the combination of TAE226 and conventional chemotherapy proved to exert synergistic effects. TAE226 may be a candidate single agent or combined therapy drug to be developed for patients who have relapse and metastatic EWS tumors in future., Systemic TAE226 treatment potently reduced the size of local tumors and inhibited micrometastasis in vivo through cell cycle inhibition, induction of apoptosis, and inhibition of AKT signaling. Furthermore, combined therapy with TAE226 and conventional anticancer drugs for EWS has synergistic anticancer effects. Overall, the results of the present study suggest that TAE226 is a candidate single agent or combined therapy drug to be developed for patients who have relapse and metastatic EWS tumors in future.

Here, we report the case of a 9-year-old girl with acute myeloid leukemia (AML) developed from systemic mastocytosis (SM). She experienced bladder and rectal disturbance due to an extramedullary nodule in the paraspinal region of the sacrum. Cytogenetic and genetic analyses of leukemic cells revealed the KIT D816Y mutation besides t (8;21) (q22:q22) /RUNX1-RUNX1T1. Despite receiving proton beam therapy after conventional chemotherapy, the patient relapsed after 2 months. As SM-AML with the KIT D816 mutation in adults exhibits a poor prognosis, hematopoietic stem cell transplantation is recommended. Owing to a few reports of SM-AML in children, the standard therapy for pediatric cases has not been established to date. Based on our experience and the related literature, the prognosis of childhood SM-AML could be as poor as in adults. Hence, further investigation, including mutational analyses of the KIT gene, is warranted to establish a risk-oriented strategy for managing childhood SM-AML.

Liquid crystals (LCs) have a large anisotropy of refractive index in the visible light region and the microwave region. With the increasing use of mobile communication systems, electrically controllable phase shifters that use LCs for the dielectric layer have gained considerable attention. In this chapter, we first introduce the fundamental characteristics of LCs in the microwave region. In this study, we describe a complex dielectric constant in the microwave region. Next, we describe the microwave phase shifter loaded with LCs. Furthermore, we explain the new antenna technology for satellite communications, which uses LCs as a dielectric material of the variable capacitor for microwave metamaterials.

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder caused by survival motor neuron gene mutations. Variant forms of SMA accompanied by additional clinical presentations have been classified as atypical SMA and are thought to be caused by variants in as yet unidentified causative genes. Here, we presented the clinical findings of two siblings with an SMA variant followed by progressive cerebral atrophy, and the results of whole-exome sequencing analyses of the family quartet that was performed to identify potential causative variants. We identified two candidate homozygous missense variants, R942Q in the tubulin-folding cofactor D (TBCD) gene and H250Q in the bromo-adjacent homology domain and coiled-coil containing 1 (BAHCC1) gene, located on chromosome 17q25.3 with an interval of 1.4 Mbp. The in silico analysis of both variants suggested that TBCD rather than BAHCC1 was likely the pathogenic gene (TBCD sensitivity, 0.68; specificity, 0.97; BAHCC1 sensitivity, 1.00; specificity, 0.00). Thus, our results show that TBCD is a likely novel candidate gene for atypical SMA with progressive cerebral atrophy. TBCD is predicted to have important functions on tubulin integrity in motor neurons as well as in the central nervous system.

Inversion of chromosome 16 [inv(16)] has a good prognosis in acute myeloid leukemia (AML), but additional genetic aberrations influence the outcome. We herein describe the case of a 15-year-old Japanese boy with inv(16) harboring a low-allelic burden internal tandem duplication of FLT3 (FLT3-ITD) and KIT mutations. Conventional chemotherapy eradicated a clone with a low-allelic burden FLT3-ITD mutation, although another clone with a KIT mutation occurred 17 months later. Further investigation is necessary to identify AML with inv(16) conferring poor prognosis, to facilitate appropriate treatment with additional drugs, such as dasatinib or gemtuzumab ozogamicin.

Background:The current event-free survival rates of children with acute myeloid leukemia (AML) approach 60%, with hematopoietic cell transplantation (HCT) as an effective second-line therapy and improvements in supportive care; however, the overall survival rates of children with relapsed AML still remains 70%, which is an unsatisfactory situation that urgently needs to be solved. Patients & Methods:In order to identify prognostic factors and improve their prognosis, we analyzed 111 patients with relapsed disease after treatment with the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 protocol, who were registered in the retrospective JPLSG AML-05R study. We collected the following data: age at relapse, time from the diagnosis to relapse, site of relapse, FAB classification, chromosomal analysis results, reinduction chemotherapy regimen, rate of achieving a second complete remission (CR2) after initial reinduction therapy, detailed information on HCT, outcome and cause of death. Moreover, ninety-three leukemic samples obtained from 111 patients at the time of their diagnosis were available for a genetic analysis. Mutational analyses ofFLT3-ITD,KIT, N-andK-RAS, NPM1,WT1,andKMT2A-partial tandem duplication were performed. Screening ofNUP98-NSD1was also performed. The high or low expression ofMECOMandPRDM16were determined based on theABL1ratio. Results:The 5-year overall survival rate was 36.1%. t(8;21) was found in 27 patients and inv(16) was found in 5 patients.KMT2Arearrangement was found in 23 patients (24.7%).KITmutations were found in 17 patients (17.5%). The following mutations were also detected:FLT3-ITD (n=10),N-RAS(n=10),WT1(n=7),K-RAS(n=4),NUP98-NSD1(n=2),KMT2A-PTD (n=2), andNPM1(n=2). The high expression ofMECOMandPRDM16was found in 24 (25.8%) and 32 (34.4%) patients, respectively. A genetic analysis revealed the prognostic significance ofFLT3-ITD as a poor prognostic marker (p=0.04) and core binding factor-AML, t(8;21) and inv(16), as a good prognostic marker (p Conclusions:Achieving CR2 prior to HCT by intensive reinduction chemotherapy, ECM, or FLAG, is important for improving the prognosis of patients with relapsed pediatric AML. Liposomal daunorubicin or 3 fractionated doses of gemtuzumab ozogamicin is an attractive option which is under consideration for addition to FLAG. Moreover, recent molecular targeted therapeutics, such as FLT3 inhibitors, may contribute to improving the prognosis of these patients. Larger prospective investigations are needed in order to establish individualized treatment strategies for patients with relapsed childhood AML. Disclosures No relevant conflicts of interest to declare.

Lasing stability in dye-doped cholesteric liquid crystal (ChLC) lasers largely depends on repetition frequency of the pumping laser, and therefore stabilization of output power under quasi-continuous-wave operation with high repetition frequency greater than 1 kHz is a tough challenge. In this study, a significant improvement of lasing stability in dye-doped ChLC lasers is obtained by lowering dye concentration, increasing cell gap, and moving LC cells with a piezo stage. Considering the balance between lasing stability and slope efficiency, the optimal conditions regarding cell gap and dye concentration in a ChLC laser doped with Pyrromethene 597 are determined to be 50 μm and 0.3 wt%, respectively. Under severe conditions of high repetition frequencies of 1 kHz and 10 kHz, the optimized ChLC laser demonstrates durability retaining 100% and more than 72% against the initial output power for 30 min, respectively.

Electrically fine tuning is demonstrated in a cholesteric liquid crystal (ChLC) laser based on the polymer composite system. Photo-polymerization in the mixture of LC monomer and LC hardly causes phase separation due to miscibility, forming a microscopically well-mixed polymer-LC composite structure like gel. Light scattering in the polymer-LC composite system decreases with increasing the polymer component, and the composite of equal parts of the polymer and LC exhibits high transparency in electric modulation of the selective reflection band, resulting in high-quality tuning of lasing wavelength in ChLC laser. In tuning operation, the ChLC laser retains a high slope efficiency greater than 19%, a low threshold smaller than 3 nJ/pulse, and a spectral linewidth narrower than 0.13 nm, while the change in lasing wavelength is fully continuous and reaches 13 nm.

We report a 38-month-old Japanese male with premature chromatid separation/mosaic variegated aneuploidy syndrome bearing biallelic BUB1B germline mutations who suffered from bilateral Wilms tumor. After right nephrectomy, dactinomycin monotherapy was administered for the left Wilms tumor; however, severe adverse reaction prevented the patient from receiving further chemotherapy. Left nephrectomy was then performed without postoperative chemotherapy. The patient survived for 15 months after bilateral nephrectomy without peritoneal relapse, metastasis of Wilms tumor, or the occurrence of rhabdomyosarcoma and maintained a good quality of life while receiving peritoneal dialysis at home.

Recently, the modern technique of comprehensive genomic analysis has identified both somatic mutations originating from tumor cells and germline mutations as causative genes of inherited familial leukemias among which Fanconi anemia and Li-Fraumeni syndrome are well known. Pathogenic germline mutations occur in various pathways, affecting DNA repair, ribosome biogenesis, telomere biology, hematopoietic transcription factors, tumor suppressors, neutrophil development, and other critical cellular processes. The clinical manifestations of germline mutations present a wide phenotypic spectrum of patients displaying congenital anomalies, early-onset myelodysplastic syndrome, or no medical problems until the developing leukemia. The use of genetic tests to identify these affected persons will significantly benefit cancer surveillance and subsequent therapeutic interventions. Although familial leukemia treatment usually focuses on children, it is important for clinicians to recognize that familial leukemias can occur at any age, even among older adults. Genetic counseling after diagnosis is essential, and an immediate referral to experts in each disease is recommended.

The prognosis of paediatric acute myeloid leukaemia (AML) with primary induction failure (PIF) is extremely poor, and effective treatment strategies have not been established. We investigated the clinical and biological features of paediatric AML patients with PIF registered to the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-05 study. The 3-year overall survival rate of the 41 PIF patients was 19.0%. High leucocyte count, M7 morphology, and unfavourable genetic aberrations, such as FLT3-internal tandem duplication, NUP98-NSD1 and high MECOM or PRDM16 expression, were risk factors for PIF. More effective treatment strategies based on leukaemia biology need to be urgently explored.

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.

We report the long-term morbidity and mortality of 105 pediatric patients who developed chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). According to the consensus criteria of the National Institutes of Health, the global severity of cGVHD was mild in 26 patients (25%), moderate in 30 patients (29%), and severe in 49 patients (47%). Patients with severe cGVHD had a significantly lower cumulative incidence of cGVHD remission and higher probability of continuing cGVHD at 8 years from cGVHD diagnosis compared with those with mild or moderate cGVHD. The 10-year cumulative incidence of nonrelapse mortality in severe cGVHD patients was significantly higher and the probability of disease-free survival was significantly lower than those among patients with mild and moderate cGVHD. Of the 59 patients who survived for more than 5 years, 20 (34%) (4 with moderate and 16 with severe cGVHD) had persistent functional impairment caused by cGVHD with a Karnofsky/Lansky performance score of 90% in 3 patients, 80% in 4 patients, and below 70% in 13 patients at the time of relapse, death, or last follow-up. Better therapeutic strategies are needed to lower the incidence of severe cGVHD, considering the longer life expectancy of pediatric HSCT survivors.

Background On the basis of results of previous Japanese trials for myeloid leukemia in Down syndrome (ML-DS), the efficacy of risk-oriented therapy was evaluated in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-D05 study. Procedure All patients received induction chemotherapy that consisted of pirarubicin, intermediate-dose cytarabine, and etoposide. Patients who achieved complete remission (CR) after initial induction therapy were stratified to the standard risk (SR) group and received four courses of reduced-dose intensification therapy. Patients who did not achieve CR were stratified to the high risk (HR) group and received intensified therapy that consisted of continuous or high-dose cytarabine. Results A total of 72 patients were eligible and evaluated. One patient died of sepsis during initial induction therapy. Sixty-nine patients were stratified to SR and two patients to HR. No therapy-related deaths were observed during intensification therapy. The 3-year event-free and overall survival rates were 83.3% ± 4.4% and 87.5% ± 3.9%, respectively. Age at diagnosis less than 2 years was a significant favorable prognostic factor for risk of relapse (P = 0.009). Conclusions The attempt of risk-oriented prospective study for ML-DS was unsuccessful, but despite the dose reduction of chemotherapeutic agents, the overall outcome was good, and further dose reduction might be possible for specific subgroups.

The viscosity properties of an electrolyte solution, which consists of 1-methyl-3- propylimidazolium iodide (MPI-I) as an electrolyte and ethylisopropylsulfone (EiPS) as a solvent, using the shear horizontal (SH) wave device are investigated. The viscosities with several concentrations of the electrolyte in solutions are measured. The viscosity increases with increasing concentration of the electrolyte. The viscosity also increases with increasing applied voltage and depends on not applied voltage but applied electric field. Furthermore, the analytical solutions of the physical properties of the SH wave propagation are derived.

As past studies of adolescent and young adults (AYA) with acute myeloid leukemia (AML) reported conflicting results, we conducted a retrospective analysis using data from three Japanese pediatric AML studies. Among the 782 patients with de novo AML, 44 were classified as AYA (age ≥15 years at diagnosis), 164 as infants (0-1 year), 413 as younger children (2-11 years), and 161 as older children (12-14 years). While the 5-year event-free survival rate of AYA was not different among the groups, the five-year survival rate (54.7 %) was significantly lower than that of the other three groups (P = 0.019): 68.7 % for infants, 73.2 % for younger children, and 75.5 % for older children. No difference in the 5-year cumulative incidence of relapse was observed, but treatment-related death (TRD) of AYA was significantly higher (29.4 %) than that in infants (14.8 %), younger children (10.2 %), and older children (13.8 %). Multivariate analysis showed age ≥15 years old at diagnosis was associated with both poor survival rate and high TRD. Adolescents with AML had inferior survival due to a higher incidence of TRD, especially after failure of initial frontline treatment.

BACKGROUND: With a large number of children surviving cancer worldwide, numerous investigations have assessed psychological and social adjustment among childhood cancer survivors. According to these studies, it is unclear whether childhood cancer survivors adjust their daily lives after being discharged from the hospital, especially for adolescent and young adult survivors who have unique needs and concerns. The primary aim of this study was to grasp the factors underlying psychosocial difficulties faced by adolescent and young adult survivors in their daily lives after being discharged from the hospital. METHODS: Semi-structured interviews were conducted. Twenty-five childhood cancer survivors were recruited from two regional cancer institutions in Japan. Content analysis was applied to the responses. RESULTS: Nineteen attributes were extracted and classified into four categories as follows: physical difficulties, interpersonal difficulties, behavioral difficulties, and uncertainty about the future. The attributes indicated by over 50% of the participants were "I am worried about not feeling well," "I have difficulty continuing a treatment in daily life," "I have difficulty moving my body," "I have to be absent from school or work because of illness," and "I am left behind academically." CONCLUSIONS: This study grasped important factors of psychosocial daily difficulties. Clinically, these results suggest that it is important to watch for these signs and to provide early support to survivors so that their daily lives and developmental process are not hindered by the treatment and its side effects and to offer long-term support focusing on individual patient characteristics such as sex, age, and cancer history. Language: en

Background The combination of fludarabine (Flu), high-dose cytarabine (Ara-C) and granulocyte colony-stimulating factor (G-CSF; FLAG), with anthracyclines has become standard chemotherapy for refractory acute myeloid leukemia (AML) in European children and adults. To clarify the efficacy and the safety of FLAG-idarubicin (IDA) for children prospectively, we planned a multicenter phase II study (AML-R11) by the Japanese Pediatric Leukemia/Lymphoma Study Group. Methods Patients with AML aged between 2 and 20 years old, who had the first bone marrow (BM) relapse or induction failure, were enrolled. The FLAG-IDA regimen consisted of Flu 30 mg/m2 for 5 days, Ara-C 2 g/m2 for 5 days, G-CSF (lenograstim) 5 μg/kg for 6 days and IDA 10 mg/m2 for 3 days. The primary endpoint was remission rate after therapy. Results Due to drug supply issues, the trial was suspended after the inclusion of seven eligible patients. There were six cases of early relapse within 1 year of the first remission. All seven patients completed the therapy and no early death was observed. Hematological toxicity was common, and one patient developed grade 4 non-hematological toxicity of bacterial meningitis. Although only one patient with late relapse achieved complete remission, minimal residual disease was positive on both flow cytometry and Wilms' tumor 1 mRNA. Two patients were alive in remission following hematopoietic stem cell transplantation, whereas the other five patients died of either the disease or treatment-related causes. Conclusion FLAG-IDA might be tolerable for children with refractory AML although the efficacy should be further investigated.

The outcome of treatment-refractory and/or relapsed pediatric T cell acute lymphoblastic leukemia (T-ALL) is extremely poor, and the genetic basis for this is not well understood. Here we report comprehensive profiling of 121 cases of pediatric T-ALL using transcriptome and/or targeted capture sequencing, through which we identified new recurrent gene fusions involving SPI1 (STMN1-SPI1 and TCF7-SPI1). Cases positive for fusions involving SPI1 (encoding PU.1), accounting for 3.9% (7/181) of the examined pediatric T-ALL cases, showed a double-negative (DN; CD4-CD8-) or CD8+ single-positive (SP) phenotype and had uniformly poor overall survival. These cases represent a subset of pediatric T-ALL distinguishable from the known T-ALL subsets in terms of expression of genes involved in T cell precommitment, establishment of T cell identity, and post-β-selection maturation and with respect to mutational profile. PU.1 fusion proteins retained transcriptional activity and, when constitutively expressed in mouse stem/progenitor cells, induced cell proliferation and resulted in a maturation block. Our findings highlight a unique role of SPI1 fusions in high-risk pediatric T-ALL.

The outcomes of children with relapsed acute myeloid leukemia (AML) are known to be poor, but remain obscure. We retrospectively analyzed 71 patients who had relapsed following first-line treatment under the AML99 protocol. We investigated the time and site of recurrence, response to re-induction therapy, and performance of hematopoietic stem cell transplantation (HSCT) in relapsed cases, and performed a multivariate analysis to identify prognostic factors. The 5-year overall-survival (OS) rate after relapse was 37 %. Of 71 patients, three died without any anti-leukemic therapy and two underwent allogeneic HSCT. The remaining 66 patients received re-induction chemotherapy, and 33 (50 %) achieved second CR (CR2). Twenty-two of 25 (88 %) late relapse patients and 11 of 41 (27 %) early relapse patients achieved CR2 (P < 0.001). Twenty-nine CR2 cases and 35 non-CR2 cases underwent allogeneic HSCT. The 5-year OS rate was significantly higher in patients who underwent HSCT in CR2 than those in non-CR2 (66 vs. 17 %, P < 0.000001). Multivariate analysis indicated that early relapse (P < 0.05) and the positivity of the FMS-like tyrosine kinase 3—internal tandem duplication (P < 0.05) were adverse prognostic factors for survival. In conclusion, the etiology of relapsed pediatric AML needs to be elucidated and effective chemotherapy should be administered to obtain CR2.

This present study sought to analyze acute lymphoblastic leukemia (ALL) patients with hemophagocytic lymphohistiocytosis (HLH) registered in Kyushu-Yamaguchi Children's Cancer Study Group studies conducted between 1996 and 2007. Four of 357 patients, including two of 318 patients with B cell precursor acute lymphoblastic leukemia (BCP-ALL) and two of 39 of those with T cell acute lymphoblastic leukemia (T-ALL), were identified. HLH was observed more frequently in the T-ALL patients than in the BCP-ALL patients (P = 0.061). The mean age of 13.0 years at the diagnosis of leukemia in the HLH + ALL group was significantly higher than the 6.05 years observed in the remaining ALL groups (P = 0.001). A female predisposition was noted, as all four patients were female (P = 0.043). In two of four patients, the leukemic cells exhibited deletions on the long arm of chromosome 6 (P = 0.003). Three patients suffered from HLH during maintenance therapy. Parvovirus B19 infection and cytomegalovirus reactivation were identified as causes of HLH in one and two patients, respectively. All four patients are currently in complete remission, although one developed relapse of leukemia after receiving maintenance therapy. Based on the genetic analyses, non-synonymous single nucleotide polymorphisms (SNPs) in UNC13D, syntaxin 11, and STXBP2 were identified in all patients. Clinicians should therefore be aware of the risk of HLH during maintenance therapy, especially in older T-ALL patients with SNPs in familial HLH causative genes.

Objective Disseminated intravascular coagulation (DIC) is a clinical condition with high mortality that is characterized by the systemic activation of coagulation pathways resulting in multiple organ failure. Although no standard treatment for DIC has been established, recent reports have indicated that recombinant human soluble thrombomodulin (rTM) is effective against DIC. Methods To elucidate the clinical characteristics and outcomes of DIC, we retrospectively analyzed 92 DIC patients who were treated with rTM at Miyazaki Prefectural Hospital over a 4-year period (62 patients had infectious diseases and 30 patients had hematological diseases). A diagnosis of DIC was made based on the diagnostic criteria of the Japanese Association for Acute Medicine (JAAM) and Japanese Ministry of Health and Welfare (JMHW) for infectious diseases and hematological diseases, respectively. In addition to treating the underlying disease, rTM was administered for six consecutive days. Results In this study, 49 of the 92 DIC patients (53.3%) experienced resolution of DIC seven days after administration (46.8% patients with infectious disease and 66.7% with hematological disease). A higher survival rate was observed after a 28-day observation period in 69 of the 92 patients (75.0%) (72.6% of the patients with infectious disease and 80.0% of the patients with hematological disease). A lower DIC score at the initiation of rTM treatment was closely related to a higher rate of resolution of DIC. Conclusion Our findings indicate that rTM therapy is an effective, safe and feasible treatment for DIC patients. Furthermore, making an accurate and early diagnosis of DIC and providing subsequent immediate treatment with rTM may improve the resolution of DIC.

Background: Myeloid leukemia in Down syndrome (ML-DS) is associated with good response to chemotherapy thus results in a favorable outcome. However, relapsed and refractory cases are rarely salvageable, regardless of receiving hematopoietic stem cell transplantation. Several factors such as certain chromosomal abnormalities and age at diagnosis are somewhat prognostic, but no universal prognostic factor has been found to date. In order to identify a subgroup with high risk of treatment failure, the role of minimal residual disease (MRD) with three methods were explored in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) trial AML-D11. Procedure: AML-D11 is a nationwide single-arm clinical trial for children (4 months to 17 years old) with ML-DS. All patients received an identical chemotherapy to the previous AML-D05 study (Taga T. Pediatr Blood Cancer 2016). MRD was evaluated at two time points, one after the induction therapy and another at the end of whole chemotherapy, using 3 different methods; flow cytometric MRD (FCM-MRD), deep sequencing MRD of mutant GATA1 (GATA1-MRD) and PCR MRD of WT1 mRNA expression (WT1-MRD). WT1-MRD was measured in both bone marrow (BM) and peripheral blood (PB) samples, while FCM- and GATA1-MRD were measured only in BM samples. Results: A total of 78 patients were eligible and followed-up with a median of 47.6 months (range, 8 to 68.8 months). Seventy-six patients were stratified to the standard risk (SR) and one patient to the high risk (HR) group by morphological response. One patient died of sepsis during initial induction therapy. Three-year event-free survival (EFS) and overall survival (OS) rates were 87.2% (95%CI, 77.5 to 92.9%) and 89.7% (95%CI, 80.5 to 94.7%), respectively. FCM-MRD and GATA1-MRD after initial induction therapy were positive in 5/65 and 7/59 patients, respectively, which were both significantly prognostic (Fig.1). Prognostic significance of WT1-MRD could not be evaluated due to a limited number of collected samples. Conclusions: MRD detections by FCM and targeted deep sequencing of GATA1 after initial induction therapy are both significant prognostic factors for predicting relapse. Risk stratification using FCM-MRD is currently incorporated in the on-going Japan Children's Cancer Group ML-DS trial (AML-D16; jrct.niph.go.jp, jRCTs041190047). Figure 1 Disclosures No relevant conflicts of interest to declare.

Non-radiative dielectric (NRD) waveguides are known as a type of transmission line with advantages such as the restriction of undesired radiation at curved sections and discontinuities. A new type of terahertz phase shifter which uses liquid crystal as the dielectric material in an NRD waveguide is presented for the first time. The phase change is very large but the decay time is extremely long. By inserting a PET sheet into a nematic liquid crystal-loaded NRD waveguide, the thickness of the liquid crystal layer is reduced. Although the phase change decreases, the decay time is greatly improved, and the availability of the partial use of nematic liquid crystal in the dielectric material of an NRD waveguide is confirmed. By comparing dielectric response results of the ordinary sandwiched cells with the experimental results of nematic liquid crystal-loaded NRD waveguides, it is confirmed that the response time does not depend on the kind of device.

Infants (

Clear cell sarcoma of tendons and aponeuroses (CCS) is a rare malignant tumor with no effective treatment. This study demonstrates the efficacy of BNCT with the use of human CCS-bearing nude mice. Groups A and C were administered saline, and groups B and D were injected with p-borono- l -phenylalanine-fructose complex. Groups C and D were then irradiated with thermal neutrons. The tumors in only group D disappeared, demonstrating that BNCT is a potentially new option for the treatment of human CCS.

We describe a case of a 5-year-old girl with central nervous system relapse of neuroblastoma after high-dose chemotherapy and autologous stem cell transplantation. Although the brain metastasis was surgically removed, she had a second relapse in the same region with leptomeningeal dissemination despite receiving irinotecan. Administration of temozolomide in addition to irinotecan led to her third complete response and the patient has been in complete response for >24 months. The tumor had no expression of the O -methylguanine methyltransferase (MGMT) gene due to promoter methylation. Temozolomide is an attractive candidate treatment in neuroblastoma with methylated MGMT, especially in central nervous system relapsed cases.

Major facilitator superfamily domain containing 2a (Mfsd2a) is a member of the major facilitator superfamily. Mfsd2a functions as a transporter for docosahexaenoic acid and also plays a role in the unfolded protein response (UPR) upon tunicamycin (TM) exposure. UPR is involved in the pathogenesis of various human diseases. TM and thapsigargin are representative experimental reagents that induce UPR. To elucidate the detailed function of Mfsd2a in UPR in vivo, we generated Mfsd2a-deficient mice and investigated the role of Mfsd2a during UPR induced by TM or thapsigargin. Phenotypically, Mfsd2a-deficient mice were small and short-lived. No gross anatomical abnormalities in Mfsd2a-deficient mice compared with the wild-type mice were exhibited. Embryonic fibroblasts derived from Mfsd2a-null mice failed to show induction of GRP78 and DDIT3 expressions upon TM exposure but not upon Tg exposure. This phenomenon could not be overcome despite the exposure under high TM concentration. Reconstitution of Mfsd2a in Mfsd2a-null MEF showed hypersensitivity to TM. Furthermore, we examined the physiological role of Mfsd2a against TM using an in vivo mouse model. DDIT3 induction by TM was drastically attenuated in both the liver and brain of Mfsd2a-deficient mice. These results reveal that Mfsd2a plays a critical role in UPR upon TM exposure.

ASXL2 is an epigenetic regulator involved in polycomb repressive complex regulation or recruitment. Clinical features of pediatric acute myeloid leukemia (AML) patients with ASXL2 mutations remain unclear. Thus, we investigated frequencies of ASXL1 and ASXL2 mutations, clinical features of patients with these mutations, correlations of these mutations with other genetic alterations including BCOR/BCORL1 and cohesin complex component genes, and prognostic impact of these mutations in 369 pediatric patients with de novo AML (0-17 years). We identified 9 (2.4%) ASXL1 and 17 (4.6%) ASXL2 mutations in 25 patients. These mutations were more common in patients with t(8;21)(q22;q22)/RUNX1-RUNX1T1 (ASXL1, 6/9, 67%, P = 0.02; ASXL2, 10/17, 59%, P = 0.01). Among these 25 patients, 4 (27%) of 15 patients with t(8;21) and 6 (60%) of 10 patients without t(8;21) relapsed. However, most patients with relapse were rescued using stem cell transplantation irrespective of t(8;21). The overall survival (OS) and event-free survival (EFS) rates showed no differences among pediatric AML patients with t(8;21) and ASXL1 or ASXL2 mutations and ASXL wild-type (5-year OS, 75% vs. 100% vs. 91% and 5-year EFS, 67% vs. 80% vs. 67%). In 106 patients with t(8;21) AML, the coexistence of mutations in tyrosine kinase pathways and chromatin modifiers and/or cohesin complex component genes had no effect on prognosis. These results suggest that ASXL1 and ASXL2 mutations play key roles as cooperating mutations that induce leukemogenesis, particularly in pediatric AML patients with t(8;21), and these mutations might be associated with a better prognosis than that reported previously.

Myeloid leukemia in Down syndrome (ML-DS) is associated with good response to chemotherapy and favorable prognosis. Because little research has been focused on refractory/relapsed (R/R) cases, we conducted a retrospective analysis for R/R ML-DS. Among ML-DS patients diagnosed between 2000 and 2010 in Japan, 26 relapsed (25 in the BM and 1 in the skin), and 3 refractory patients were enrolled. The male/female ratio was 18/11. The median age at initial diagnosis of ML-DS was 2 years, and the median time to relapse was 8.6 months. Each patient initially had been treated with ML-DS–specific protocols. Thirteen of the 26 patients achieved complete remission with various kinds of reinduction chemotherapies; 2 of 8 survived without further recurrence after receiving allogeneic hematopoietic stem cell transplantation, and 4 of 5 maintained complete remissions with chemotherapy alone. Treatment failures mostly were associated with disease progression rather than treatment-related toxicities. The 3-year OS rate was 25.9% ± 8.5%. A longer duration from initial diagnosis to relapse was a significant favorable prognostic factor (P < .0001). We conclude that clinical outcome for patients with R/R ML-DS generally are unfavorable, even in those receiving hematopoietic stem cell transplantation. Novel methods to identify poor prognostic factors for ML-DS are necessary.

We performed a retrospective population-based cohort study of acute myeloid leukemia (AML) in Miyazaki Prefecture, Japan. Over 6 years, we diagnosed 221 patients (211 adults and 10 children) with AML, indicating an incidence of AML in Miyazaki Prefecture of 3.2 per 100,000 per year. In 193 adult patients with non-acute promyelocytic leukemia (APL), the proportion of patients with myelodysplasia, unfavorable risk karyotypes, antecedent hematologic diseases, prior chemotherapy for other malignancies, and small proportion of blasts in the marrow was higher in patients ≥65 years, and patients with poor performance status (PS) and higher WBC counts at diagnosis were more prevalent among patients ≥75 years. One-third of the adult non-APL patients met the inclusion criteria usually applied in clinical trials: de novo AML, age ≤64 years with PS 0-2 and no key organ dysfunction. The 5-year overall survival (OS) rate of adult non-APL patients was 21.1 % (patients ≤64 years, 33.8 %; 65-74 years, 21.6 %; ≥75 years, 0 %). Multivariate analysis revealed that French-American-British subtypes M0, M6, and M7, poor PS (3, 4), unfavorable risk karyotypes, and higher WBC counts at diagnosis were independent adverse prognostic factors associated with OS. This analysis provides real world data.

Homogenous alignment of smectic liquid crystal is demonstrated by applying bidirectional shear with controlled amplitude and frequency. For shear amplitudes smaller than 10 μm and at the frequency of 100Hz, the smectic layer was found to align in the direction of shear. The quality of alignment was evaluated from the contrast ratio obtained when the sample was placed between crossed polarizers and set at 0° and 45° to the transmission axes. A monotonic increase in the alignment quality was found with increasing shear amplitude.

We describe a 6-month-old infant with classic medulloblastoma. Gross total resection of the left cerebellar tumor was performed; however, relapse occurred during the administration of intrathecal and intravenous methotrexate-based chemotherapy. After undergoing resection, high-dose chemotherapy was administered consisting of topotecan, melphalan, and cyclophosphamide with autologous peripheral stem cell rescue followed by local irradiation and intrathecal topotecan, which resulted in a complete response for more than two years. The administration of high-dose chemotherapy followed by intrathecal topotecan as maintenance therapy is an effective strategy, without losses in the cognitive function, for avoiding the use of whole-brain irradiation for infantile classic medulloblastoma. Pediatr Blood Cancer 2014;61:2316-2318. © 2014 Wiley Periodicals, Inc.

Leukemia cells survive and proliferate under conditions of metabolic stress by acquiring mutations that increase energy metabolism. Here, we aimed to identify a specific metabolic inhibitor and examine transcription factor-enhanced changes in energy metabolism by refractory leukemia cells. Overexpression of Ecotropic Virus Integration site 1 protein homolog (EVI1) in adults and children with mixed lineage leukemia-rearrangement acute myeloid leukemia (MLL-r AML) has a very poor prognosis. We focused on metabolic reprograming of MLL leukemia cells expressing EVI1, since the metabolic relationship between MLL and EVI1 is unclear. We used an extracellular flux analyze to examine metabolic changes during leukemia development in a mouse model of MLL-r AML expressing high levels of EVI1 (EVI1+). To examine whether EVI1 regulates energy metabolism in MLL-rearranged leukemia cells, we used transgenic mice expressing EVI1 (TG) in LSK and GMP cells model in which AML is driven by the MLL-AF9 oncogene. We measured oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) using a flux analyzer. TG MLL-AF9 mice showed a significantly higher basal and capacity of OCR than WT MLL-AF9 mice ex vivo. EVI1+ cells showed accelerated oxidative phosphorylation (OXPHOS) prior to activation of glycolysis, and higher dependency on glutamine as an energy source. To identify the metabolic pathways regulated by EVI1, we performed capillary electrophoresis time-of-fight mass spectrometry-based metabolome profiling of WT and TG MLL-AF9 leukemia cells. We found significant differences between the cells in terms of the amounts of metabolites derived from the glycolytic and TCA cycles. Fructose 1,6-bisphosphate and lactate were up-regulated in TG MLL-AF9 cells, implying activation of glycolysis. Moreover, the amounts of fumarate and malate (metabolites of the TCA cycle) were significantly higher in TG MLL-AF9 cells. EVI1 played a role in glycolysis as well as driving expression of genes engaged in the tricarboxylic acid cycle. Next, we tested whether pharmacological inhibition of glycolysis and glutaminolysis suppresses MLL-AF9. L-asparaginase (ASP) [which catalyzes hydrolysis of asparagine (Asn) and glutamine (Gln) to asparatic acid or glutamic acid, respectively] markedly suppressed proliferation of TG MLL-AF9 cells, EVI1highAML cell lines. To examine the therapeutic potential of ASP in vivo, we treated secondary recipients of TG MLL-AF9 AML cells with ASP or control (vehicle), beginning 5 days post-transplantation. Mice then received intraperitoneal injections (five times per week) of distilled water or ASP (1000 U/kg). ASP led to a significant reduction in the number of GFP+ AML cells in the peripheral blood and increased the survival of recipient mice. Next, we examined an AML xenograft model. Two groups of NOG mice were injected subcutaneously with UCSD/AML1 cells and then treated with ASP or control. ASP -treated mice showed a significant reduction in the growth of AML tumors. Overall, these findings indicate that ASP -mediated inhibition of OXPHOS is a potential treatment for AML. We clarified that increased glutamine dependency by MLL-r AML cells showing high EVI1 expression makes them sensitive to ASP. We found that the energy advantage of AML cells is acquired via transcription factor-mediated activation of mitochondrial metabolism, leading to a poor prognosis. Furthermore, we show that new therapeutic options can be identified by examining the energy-based metabolic characteristics of leukemia cells. Disclosures No relevant conflicts of interest to declare.

The authors report continue tuning of the lasing wavelength in cholesteric liquid crystals (ChLCs) by an applied electrical fields. Although the pitch length and the corresponding lasing wavelength is sensible to external fields, only a discrete shift in the pitch is observed in the conventional cell configuration where the helix axis is lying the cell-normal direction, since the molecules are anchored to a single direction at the substrate interfaces. In this study, continuous wavelength tuning is achieved by laying the helix in the cell-plane direction, mitigating the effects of anchoring: this alignment is attained simply by applying an electric field while cooling the sample from the isotropic state, in a planarly rubbed sandwich cell. We also show that the tuning characteristics as that predicted based on calculations using the elastic theory.

We study optical properties of nanoimprinted gratings infiltrated with liquid crystal (LC). One-dimensional grating of a line-spacing pattern is used as a distributed feedback cavity. After filling LC into the trenches of the grating, the LC molecules align along the trench of grating and it shows uniform planar alignment. By optical pumping, laser emission occurs and the laser wavelength can be tuned by temperature control or application of voltage. We also demonstrate control of diffraction intensities from a two-dimensional grating using LC molecular reorientation in micro space.

Janus kinases are essential for signal transduction by a variety of cytokine receptors and when inappropriately activated can cause hematopoietic disorders and oncogenesis. Consequently, it can be predicted that the interaction of the kinases with receptors and the events required for activation are highly controlled. In a screen to identify phosphorylation events regulating Jak2 activity in EpoR signaling, we identified a mutant (Jak2-Y613E) which has the property of being constitutively activated, as well as an inactivating mutation (Y766E). Although no evidence was obtained to indicate that either site is phosphorylated in signaling, the consequences of the Y613E mutation are similar to those observed with recently described activating mutations in Jak2 (Jak2-V617F and Jak2-L611S). However, unlike the V617F or L611S mutant, the Y613E mutant requires the presence of the receptor but not Epo stimulation for activation and downstream signaling. The properties of the Jak2-Y613E mutant suggest that under normal conditions, Jak2 that is not associated with a receptor is locked into an inactive state and receptor binding through the FERM domain relieves steric constraints, allowing the potential to be activated with receptor engagement.

We have demonstrated lasing in cholesteric liquid crystals (CLCs) of various thicknesses oriented by acoustic streaming. Although alignment control of CLC molecules in a thick cell is difficult, acoustic streaming can change the CLC alignment from a focal conic state to a planar state by molecular flow. The molecular reorientation leads to making a large uniform CLC layer that can function as a laser cavity. Therefore, laser action cannot be observed in the untreated thick cells because of the focal conic state, while a sharp emission appears from the thick cells treated by acoustic streaming. Furthermore, lasing wavelength shifts with a small wavelength interval are realized using a large cavity.

The Propagation characteristics of a shear horizontal (SH) wave in a trilayer structure having a viscous fluid layer is analyzed from a numerical analysis. Acoustic phase changes under application of electric fields in a nematic liquid crystal cell are measured using the SH wave. The acoustic phase advances with increasing the applied electric field. This result corresponds with the viscosity change based on a molecular reorientation of the liquid crystal. In dynamic response measurement, the response times in the phase and the optical measurements are different, because the measured area of the acoustic phase is only the vicinity of the glass surface.

The acoustic phase of a shear horizontal (SH) wave propagating into a nematic liquid crystal cell is measured. To investigate the acoustic phase depending on the director angle of a liquid crystal, the two SH wave devices having different initial molecular orientations are fabricated. The acoustic phase change of the SH wave devices is measured for various applied electric fields. The numerical analyses are also performed by considering director distribution in the nematic liquid crystal layer. The experimental acoustic phase changes are well accorded with the calculated shear stresses as a viscous resistance.

Mechanical vibration distributions of freely suspended ferroelectric liquid crystal films with various thicknesses in the range from 15 nm to 12 µm induced by applying a sinusoidal electric field are observed using a laser Doppler vibrometer. Mechanical resonance profiles of the freely suspended film are represented in the form of mechanical vibration distributions. Resonance frequency increases with the number of mechanical resonance modes. Surface tension is calculated from the number of mechanical resonance modes and the resonance frequency. The surface tension is not constant and is proportional to the thickness of the freely suspended film below 1.2 µm.

The dynamic responses of an acoustic phase to liquid crystal (LC) molecular reorientation in a shear horizontal (SH) wave device with an LC cell are measured by applying a voltage. The optical responses are also observed in order to determine the molecular director distributions in the device. The response of acoustic phase by removing the applied voltage is three orders of magnitude faster than the optical response. To investigate the effective viscosity acting on the SH wave propagation, the dynamic changes in the director distribution are calculated. Using the calculated director distribution, we obtain the effective viscosity acting on the SH wave propagation, which coincides qualitatively with the measured acoustic phase change.

We experienced the case of a 3-year-old male with a very rare combination of autoimmunity, including immune thrombocytopenia, recurrent Henoch-Schönlein purpura and intestinal Behçet disease. Exome sequencing of the patient’s peripheral blood mononuclear cells identified a KRAS G13C mutation. Interestingly, the KRAS G13C mutation was observed in T and B lymphocytes, as well as natural killer cells, but not granulocytes. Our case was completely phenotypically different from RASopathies and did not meet the criteria for Ras-associated lymphoproliferative disease or juvenile myelomonocytic leukemia. This is the first reported case in which the KRAS mutation existed only in the lymphoid lineage. Based on the findings of our case and the current literature, it is clear that the RAS mutation in lymphoid cells is tightly linked with various autoimmune symptoms. The presence of the RAS mutation in lymphocytes should be reconsidered as a pathogenesis in cases of autoimmunity.

Acquired aplastic anemia is an immune-mediated disease characterized by severe defects in stem cell number resulting in hypocellular marrow and peripheral blood cytopenias. Minor paroxysmal nocturnal hemoglobinuria populations and a short telomere length were identified as predictive biomarkers of immunosuppressive therapy responsiveness in aplastic anemia. We enrolled 113 aplastic anemia patients (63 boys and 50 girls) in this study to evaluate their response to immunosuppressive therapy. The paroxysmal nocturnal hemoglobinuria populations and telomere length were detected by flow cytometry. Forty-seven patients (42%) carried a minor paroxysmal nocturnal hemoglobinuria population. The median telomere length of aplastic anemia patients was -0.99 standard deviation (SD) (range -4.01-+3.01 SD). Overall, 60 patients (53%) responded to immunosuppressive therapy after six months. Multivariate logistic regression analysis identified the absence of a paroxysmal nocturnal hemoglobinuria population and a shorter telomere length as independent unfavorable predictors of immunosuppressive therapy response at six months. The cohort was stratified into a group of poor prognosis (paroxysmal nocturnal hemoglobinuria negative and shorter telomere length; 37 patients) and good prognosis (paroxysmal nocturnal hemoglobinuria positive and/or longer telomere length; 76 patients), respectively. The response rates of the poor prognosis and good prognosis groups at six months were 19% and 70%, respectively (P