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Acute lymphoblastic leukemia expressing the gamma delta T-cell receptor (γδ T-ALL) is a poorly understood disease. We studied 200 children with γδ T-ALL from 13 clinical study groups to understand the clinical and genetic features of this disease. We found age and genetic drivers were significantly associated with outcome. γδ T-ALL diagnosed in children under 3 years of age was extremely high-risk and enriched for genetic alterations that result in both LMO2 activation and STAG2 inactivation. Mechanistically, using patient samples and isogenic cell lines, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer-promoter looping, resulting in deregulation of gene expression associated with T-cell differentiation. High-throughput drug screening identified a vulnerability in DNA repair pathways arising from STAG2 inactivation, which can be targeted by poly(ADP-ribose) polymerase inhibition. These data provide a diagnostic framework for classification and risk stratification of pediatric γδ T-ALL. Significance: Patients with acute lymphoblastic leukemia expressing the gamma delta T-cell receptor under 3 years old or measurable residual disease ≥1% at end of induction showed dismal outcomes and should be classified as having high-risk disease. The STAG2/LMO2 subtype was enriched in this very young age group. STAG2 inactivation may perturb chromatin conformation and cell differentiation and confer vulnerability to poly(ADP-ribose) polymerase inhibition., (©2024 American Association for Cancer Research.)

Background: The molecular pathogenesis of acute myeloid leukemia (AML) was dramatically clarified over the latest two decades. Several important molecular markers were discovered in patients with AML that have helped to improve the risk stratification. However, developing new treatment strategies for relapsed/refractory acute myeloid leukemia (AML) is crucial due to its poor prognosis., Procedure: To overcome this difficulty, we performed an assay for transposase-accessible chromatin with sequencing (ATAC-seq) in 10 AML patients with various gene alterations. ATAC-seq is based on direct in vitro sequencing adaptor transposition into native chromatin, and is a rapid and sensitive method for integrative epigenomic analysis. ATAC-seq analysis revealed increased accessibility of the DOCK1 gene in patients with AML harboring poor prognostic factors. Following the ATAC-seq results, quantitative reverse transcription polymerase chain reaction was used to measure DOCK1 gene expression levels in 369 pediatric patients with de novo AML., Results: High DOCK1 expression was detected in 132 (37%) patients. The overall survival (OS) and event-free survival (EFS) among patients with high DOCK1 expression were significantly worse than those patients with low DOCK1 expression (3-year EFS: 34% vs. 60%, p < .001 and 3-year OS: 60% vs. 80%, p < .001). To investigate the significance of high DOCK1 gene expression, we transduced DOCK1 into MOLM14 cells, and revealed that cytarabine in combination with DOCK1 inhibitor reduced the viability of these leukemic cells., Conclusions: Our results indicate that a DOCK1 inhibitor might reinforce the effects of cytarabine and other anti-cancer agents in patients with AML with high DOCK1 expression., (© 2024 Wiley Periodicals LLC.)

Background/objectives: The Berlin-Frankfurt-Münster (BFM)-S classification is a crucial prognostic indicator in children experiencing first-relapsed acute lymphoblastic leukemia (ALL). Early molecular response to therapy, evaluated by measurable/minimal residual disease (MRD), has a significant impact on the survival of patients with childhood ALL. Applying risk stratification based on the BFM-S classification and MRD response after induction, the first nationwide prospective multicenter study, ALL-R08, was conducted in children with first-relapsed ALL in Japan., Methods: The ALL-R08 study comprised two parts: ALL-R08-I, an observational study aimed at obtaining an overall picture of outcomes in first-relapsed childhood ALL, and ALL-R08-II, a clinical trial for the non-T-ALL S2 risk group. In ALL-R08-II, patients with an MRD level of ≥10 -3 at the end of induction therapy were assigned to undergo allogeneic hematopoietic stem cell transplantation (allo-HCT), whereas those with an MRD level less than 10 -3 and isolated extramedullary relapse continued to receive chemotherapy., Results: In total, 163 patients were enrolled in the ALL-R08 study, and 82 and 81 patients were enrolled in the ALL-R08-I and the ALL-R08-II, respectively. In ALL-R08-I, the probability of 3-year event-free survival (EFS) for patients with S1, S2, S3, S4, and post-HCT groups was 83% ± 15%, 37% ± 11%, 28% ± 8%, 14% ± 7%, and 0%, respectively. In the ALL-R08-II trial, 3-year EFS in patients with post-induction MRD less than 10 -3 and ≥10 -3 was 70% ± 9% (n = 27) and 68% ± 8% (n = 31) (p = .591), respectively., Conclusions: ALL-REZ BFM-type treatment is equally effective for children with first-relapsed ALL treated according to the Japanese frontline protocols and for children with first-relapsed ALL treated according to the BFM-type frontline protocols., (© 2024 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Background: Failure-free survival (FFS) rates of low-risk patients with rhabdomyosarcoma improved in Intergroup Rhabdomyosarcoma Study IV after the escalation of cyclophosphamide total dose to 26.4 g/m 2 . However, this dose may increase the risk of adverse events, including infertility, in some patients. The JRS-I LRA0401 and LRB0402 protocols aimed to reduce the cyclophosphamide dose to 9.6 g/m 2 and 17.6 g/m 2 , respectively, without decreasing the FFS rates., Methods: Subgroup-A patients received eight cycles (24 weeks) of vincristine, actinomycin D, and 1.2 g/m 2 /cycle cyclophosphamide. Subgroup-B patients received eight cycles (24 weeks) of vincristine, actinomycin D, and 2.2 g/m 2 /cycle cyclophosphamide, followed by six cycles (24 weeks) of vincristine and actinomycin D. Group II/III patients in both subgroups received radiotherapy., Results: In subgroup A (n = 12), the 3-year FFS rate was 83% (95% confidence interval [CI], 48-96), and the 3-year overall survival (OS) rate was 100%. Only one isolated local recurrence was observed (8.3%). There were no unexpected grade-4 toxicities and no deaths. In subgroup B (n = 16), the 3-year FFS and OS rates were 88% (95% CI, 59-97) and 94% (95% CI, 63-99), respectively. There were no unexpected grade 4 toxicities and no deaths., Conclusions: Shorter duration therapy using vincristine, actinomycin D, and lower dose cyclophosphamide with or without radiotherapy for patients with low-risk subgroup A rhabdomyosarcoma (JRS-I LRA0401 protocol) and moderate reduction of cyclophosphamide dose for patients with low-risk subgroup B rhabdomyosarcoma (JRS-I LRB0402 protocol) did not compromise FFS., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Introduction: Although the prognosis of Langerhans cell histiocytosis (LCH) is excellent, the high recurrence rate and permanent consequences, such as central diabetes insipidus and LCH-associated neurodegenerative diseases, remain to be resolved. Based on previous reports that patients with high-risk multisystem LCH show elevated levels of inflammatory molecules, we hypothesised that dexamethasone would more effectively suppress LCH-associated inflammation, especially in the central nervous system (CNS). We further hypothesised that intrathecal chemotherapy would effectively reduce CNS complications. We administer zoledronate to patients with multifocal bone LCH based on an efficacy report from a small case series., Methods and Analysis: This phase II study (labelled the LCH-19-MSMFB study) is designed to evaluate the significance of introducing dexamethasone and intrathecal chemotherapy for multisystem disease and zoledronate for multifocal bone disease in previously untreated, newly diagnosed children, adolescents (under 20 years) and adults under 40 years. The primary endpoint is the 3-year event-free survival rate by risk group of under 20 years and the 3-year event-free survival rate of 20 years and over., Ethics and Dissemination: This study was approved by the Central Review Board of the National Hospital Organisation Nagoya Medical Centre (Nagoya, Japan) on 21 January 2022 and was registered in the Japan Registry of Clinical Trials (https://jrct.niph.go.jp/en-latest-detail/jRCTs041210027). Written informed consent will be obtained from all patients and/or their guardians., Trial Registration Number: jRCTs041210027., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Abstract: Transient abnormal myelopoiesis (TAM) is a common complication in newborns with Down syndrome (DS). It commonly progresses to myeloid leukemia (ML-DS) after spontaneous regression. In contrast to the favorable prognosis of primary ML-DS, patients with refractory/relapsed ML-DS have poor outcomes. However, the molecular basis for refractoriness and relapse and the full spectrum of driver mutations in ML-DS remain largely unknown. We conducted a genomic profiling study of 143 TAM, 204 ML-DS, and 34 non-DS acute megakaryoblastic leukemia cases, including 39 ML-DS cases analyzed by exome sequencing. Sixteen novel mutational targets were identified in ML-DS samples. Of these, inactivations of IRX1 (16.2%) and ZBTB7A (13.2%) were commonly implicated in the upregulation of the MYC pathway and were potential targets for ML-DS treatment with bromodomain-containing protein 4 inhibitors. Partial tandem duplications of RUNX1 on chromosome 21 were also found, specifically in ML-DS samples (13.7%), presenting its essential role in DS leukemia progression. Finally, in 177 patients with ML-DS treated following the same ML-DS protocol (the Japanese Pediatric Leukemia and Lymphoma Study Group acute myeloid leukemia -D05/D11), CDKN2A, TP53, ZBTB7A, and JAK2 alterations were associated with a poor prognosis. Patients with CDKN2A deletions (n = 7) or TP53 mutations (n = 4) had substantially lower 3-year event-free survival (28.6% vs 90.5%; P < .001; 25.0% vs 89.5%; P < .001) than those without these mutations. These findings considerably change the mutational landscape of ML-DS, provide new insights into the mechanisms of progression from TAM to ML-DS, and help identify new therapeutic targets and strategies for ML-DS., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Asparaginase is essential for treating T-cell acute lymphoblastic leukemia (T-ALL). Despite the ongoing debate on whether T-ALL and T-cell lymphoblastic lymphoma (T-LBL) are the same disease entity or two distinct diseases, patients with T-LBL often receive the same or similar treatment protocols as those with T-ALL., Methods: The outcomes of patients with or without L-asparaginase discontinuation were retrospectively analyzed among four national protocols: Japan Association of Childhood Leukemia Study (JACLS) ALL-02 and ALL-97 for T-ALL and Japanese Pediatric Leukemia/Lymphoma Study Group ALB-NHL03 and JACLS NHL-98 for T-LBL. The hazard ratio (HR) was calculated with the Cox regression model by considering L-asparaginase discontinuation as a time-dependent variable., Results: In total, 199 patients with T-ALL, and 133 patients with T-LBL were included. L-asparaginase discontinuation compromised event-free survival (EFS) of T-ALL patients (ALL-02: HR 3.32, 95% confidence interval [CI] 1.40-7.90; ALL-97: HR 3.39, 95%CI 1.19-9.67). Conversely, EFS compromise was not detected among T-LBL patients (ALB-NHL03: HR 1.39, 95%CI 0.41-4.68; NHL-98: HR 0.92, 95%CI 0.11-7.60)., Conclusion: The effects of L-asparaginase discontinuation differed between T-ALL and T-LBL. We assume that the differential impact results from (1) the inherent differential response to L-asparaginase between them and/or (2) a less stringent assessment of early treatment response in T-LBL than in T-ALL. Given the poor salvage rate of refractory or relapsed T-ALL and T-LBL, optimization of the frontline therapy is critical, and the current study provides a new suggestion for further treatment modifications. However, larger studies in contemporary intensified treatment protocols are required., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: In children with intermediate-risk relapsed acute lymphoblastic leukemia (ALL), allogeneic hematopoietic stem cell transplantation (allo-HSCT) has markedly improved the outcome of patients with an unsatisfactory minimal residual disease (MRD) response. Total body irradiation (TBI), etoposide (ETP), and cyclophosphamide (CY) have been shown to be equivalent to or better than TBI + ETP for conditioning, so we hypothesized that even greater survival could be achieved due to recent advances in HSCT and supportive care., Procedure: We prospectively analyzed the efficacy and safety of allo-HSCT with a unified conditioning regimen of TBI + ETP + CY in children with intermediate-risk relapsed ALL, based on MRD in the bone marrow after induction, from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) ALL-R08-II nationwide cohort (UMIN000002025)., Results: Twenty patients with post-induction MRD ≥ 10 -3 and two not evaluated for MRD underwent allo-HSCT. Engraftment was confirmed in all patients, and no transplantation-related mortality was observed. The 3-year event-free survival and overall survival rates after transplantation were 86.4% ± 7.3% and 95.5% ± 4.4%, respectively., Conclusion: Allo-HSCT based on post-induction MRD with TBI + ETP + CY conditioning was feasible in Japanese children with intermediate-risk relapsed ALL., (© 2024. Japanese Society of Hematology.)

Objective: Minimal residual disease assessment of BCR-ABL messenger ribonucleic acid levels is crucial in Philadelphia chromosome-positive acute lymphoblastic leukemia for prognosis and treatment planning. However, accurately quantifying minor BCR-ABL transcripts, which comprise 70% of Philadelphia chromosome-positive acute lymphoblastic leukemia cases, lacks a national-approved method., Methods: We developed the "Otsuka" minor BCR-ABLmessenger ribonucleic acid assay kit with exceptional precision (0.00151%). Minor BCR-ABL messenger ribonucleic acid levels were analyzed in 175 adults, 36 children with acute lymphoblastic leukemia and 25 healthy individuals to evaluate the kit's performance., Results: The "Otsuka" kit showed high concordance with a commonly used chimeric gene screening method, indicating reliable detection of positive cases. Quantitative results demonstrated a robust correlation with both a laboratory-developed test and a diagnostic research product. The "Otsuka" kit performs comparably or even surpass to conventional products, providing valuable insights into Philadelphia chromosome-positive acute lymphoblastic leukemia pathology., Conclusions: The 'Otsuka" minor BCR-ABL messenger ribonucleic acid assay kit exhibits excellent performance in quantifying minor BCR-ABL transcripts in Philadelphia chromosome-positive acute lymphoblastic leukemia patients. Our results align well with established screening methods and show a strong correlation with laboratory-developed tests and diagnostic research products. The "Otsuka" kit holds great promise as a valuable tool for understanding Philadelphia chromosome-positive acute lymphoblastic leukemia pathology and guiding effective treatment strategies., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

This study investigated the effects of animated food consumption on human psychology. We developed a movable, edible robot and evaluated the participants' impressions induced by the visualization of its movements and eating of the robot. Although several types of edible robots have been developed, to the best of our knowledge, the psychological effects associated with the eating of a robot have not been investigated. We developed a pneumatically driven edible robot using gelatin and sugar. We examined its perceived appearance and the participants' impressions when it was eaten. In the robot-eating experiment, we evaluated two conditions: one in which the robot was moved and one in which it was stationary. Our results showed that participants perceived the moving robot differently from the stationary robot, leading to varied perceptions, when consuming it. Additionally, we observed a difference in perceived texture when the robot was bitten and chewed under the two conditions. These findings provide valuable insights into the practical applications of edible robots in various contexts, such as the medical field and culinary entertainment., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Nakata et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

CD25 is an aberrant marker expressed on the leukemic stem cell (LSC) surface and an immunotherapy target in acute myeloid leukemia (AML). However, the clinical prevalence and significance of CD25 expression in pediatric AML are unknown. High IL2RA/CD25 expression in pediatric AML showed a stem cell-like phenotype, and elevated CD25 expression was associated with lower overall survival (p < .001) and event-free survival (p < .001) in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 study. This finding was reproduced in AML without a core-binding factor in the Children's Oncology Group study cohort. High CD25 expression has prognostic significance in pediatric AML., (© 2023 Wiley Periodicals LLC.)

The immune system plays a crucial role in cancer development and progression. More than a century ago, mouse models showed that primary tumors suppressed the growth of newly implanted secondary tumors. This phenomenon, in which tumor-primed T cells mediate the rejection of tumor growth at a distant site, is known as concomitant tumor immunity. Here, we investigated the role of concomitant immunity in the development of breast cancer bone metastases using newly developed syngeneic immunocompetent mouse models. The presence of primary breast tumors developed by tumor cell injection into the mammary fat pads (MFPs) significantly reduced bone metastases of mouse breast cancer 4T1 and EMT6 cells induced by cell injection through the caudal artery (CA). Similar results were obtained when primary tumors were surgically resected prior to CA injection of tumor cells. In contrast, no inhibition was found when MFP and CA injections were performed using different cell combinations. Immunohistochemical studies revealed that the number of CD8 + T cells in bone metastases of 4T1 and EMT6 cells was significantly increased in the presence of primary tumors. The primary tumor-induced inhibition of bone metastases was not reproduced in T cell-deficient athymic nude mice. Furthermore, depletion of CD8 + T cells using an anti-CD8α antibody also abolished the primary tumor-induced inhibition of bone metastases. Taken together, these results suggest that immune cell priming by orthotopic breast tumors inhibits the development of breast cancer bone metastases, which is predominantly mediated by CD8 + cytotoxic T lymphocytes., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Juvenile myelomonocytic leukemia (JMML), which is classified as a myelodysplastic/myeloproliferative neoplasm, is a rare hematologic malignancy of childhood. Most patients with JMML require allogeneic hematopoietic cell transplantation (HCT) as a curative therapy. A Japanese retrospective analysis demonstrated favorable outcomes for a busulfan (BU) + fludarabine (FLU) + melphalan (MEL) regimen, with an overall survival (OS) of 72% and an event-free survival (EFS) of 53%. To further validate the efficacy and safety of this regimen, the Japan Pediatric Leukemia/Lymphoma Study Group (JPLSG) conducted a nationwide prospective study, JMML-11. Between July 2011 and June 2017, 28 patients with newly diagnosed JMML were enrolled in JMML11. Low-dose chemotherapy for tumor control before HCT was recommended, and patients treated with AML-type chemotherapy and azacitidine were excluded. The conditioning regimen comprised i.v. BU, 16 doses administered every 6 h, with dose adjustment based on pharmacokinetic (PK) studies on days -11 to -8; FLU, 30 mg/m 2 /day or 1 mg/kg/day for patients <10 kg or age <1 year on days -7 to -4; and MEL, 90 mg/m 2 /day or 3 mg/kg/day for patients <10 kg or <1 year on days -3 to -2. The donor was selected by the physician in charge. A family donor was available for 7 patients (3 HLA-matched siblings, 3 HLA-1-antigen mismatched parents, and 1 haploidentical father). Overall, 21 patients received grafts from unrelated donors, including 8 HLA-matched donors and 13 HLA-mismatched donors. The graft source was related bone marrow (BM) for 7 patients, unrelated BM for 14 patients, and unrelated cord blood for 7 patients. Neutrophil engraftment was achieved in 21 of 28 patients (75%), with a median of 20.5 days (range, 11 to 39 days) after transplantation. The 3-year OS, 3-year EFS, 3-year relapse rate, and 3-year transplantation-related mortality were 63% (95% confidence interval [CI], 42% to 78%), 52% (95% CI, 32% to 69%), 18% (95% CI, 6% to 34%), and 21% (95% CI, 9% to 38%), respectively. WBC count before the conditioning regimen (≥7.0 × 10 9 /L) was significantly associated with inferior EFS and OS. Body surface area ≥.5 m 2 , spleen size <4 cm before conditioning, and HLA-matched unrelated BM donors were significantly associated with better OS. Adverse effects related to the conditioning regimen included febrile neutropenia (86%), diarrhea (39%), hypoxemia (21%), and mucositis (18%). BU-associated toxicity, including sinusoidal obstruction syndrome (SOS) and thrombotic microangiopathy (TMA), occurred in 7 patients (25%; SOS, n = 6; TMA, n = 2). Retrospective analysis of PK data after the first BU dose in 23 patients, including 6 with SOS and 17 without SOS, did not show significant differences between groups. The JMML-11 study confirms the positive results of previous retrospective analyses. BU+FLU+MEL might become a standard conditioning regimen for patients with JMML., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Hematopoietic stem cell transplantation (HSCT) is only indicated for acute lymphoblastic leukemia (ALL) patients for whom other treatments are unlikely to be curative. However, outcomes of patients not in complete remission (CR) at HSCT remain very poor. To improve the outcomes of patients receiving HSCT, it is important to obtain detailed clinical information about patients with ALL receiving HSCT in CR and not in CR. Patients enrolled in the Japan Association of Childhood Leukemia Study ALL-02 who underwent HSCT and were not in CR (non-CR patients, n = 55) were examined. The 1-year overall survival (OS) rate of non-CR patients was 27.3%. Compared with CR patients, non-CR patients experienced very early and early relapse significantly more frequently and had poorer prognostic factors. Most interestingly, high hyperdiploid (HHD) patients showed an excellent 1-year OS of 80%. In addition, long-term survival among surviving HHD patients was longer than 5 years. All eight patients who survived after undergoing HSCT while not in CR were younger than 10 years at initial diagnosis and were negative for central nervous system involvement. While limited, these results suggest that a subset of patients may benefit from HSCT while not in CR., (© 2023. Japanese Society of Hematology.)

Association fibers connect different areas of the cerebral cortex over long distances and integrate information to achieve higher brain functions, particularly in humans. Prototyped association fibers are developed to the respective tangential direction throughout the cerebral hemispheres along the deepest border of the subplate during the fetal period. However, how guidance to remote areas is achieved is not known. Because the subplate is located below the cortical surface, the tangential direction of the fibers may be biased by the curved surface geometry due to Sylvian fissure and cortical poles. The fiber length can be minimized if the tracts follow the shortest paths (geodesics) of the curved surface. Here, we propose and examine a theory that geodesics guide the tangential direction of long association fibers by analyzing how geodesics are spatially distributed on the fetal human brains. We found that the geodesics were dense on the saddle-shaped surface of the perisylvian region and sparse on the dome-shaped cortical poles. The geodesics corresponded with the arrangement of five typical association fibers, supporting the theory. Thus, the geodesic theory provides directional guidance information for wiring remote areas and suggests that long association fibers emerge from minimizing their tangential length in fetal brains., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Purpose: Several studies have investigated good communication practices with adult patients receiving bad news about cancer. However, while communication preferences may differ between adults and adolescent and young adult (AYA) patients, these preferences have not been determined for AYA patients. The primary endpoint of this study was to describe the communication preferred by AYA patients with cancer. Methods: The study cohort consisted of 15 patients who received a cancer diagnosis at the age of 15-29 years. Patients were recruited at the National Cancer Center Hospital or through "STAND UP!!," an association of AYA patients with cancer. Semistructured interviews were conducted, and content analysis was performed to analyze the data. Results: For the preferred communication of AYA patients, 80 categories were extracted in the following five domains: (1) "Supportive setting," (2) "Method of disclosure of bad news," (3) "Information given," (4) "Emotional support," and (5) "Support for the patient's decision making." Although more than half of the categories extracted were identical to the preferred communication of adult patients, some categories specific to AYA patients were identified that physicians should consider. Preferences specific to AYA patients included mentioning generation-specific social factors, not showing excessive empathy, and communicating in a manner considering their age and cognitive development that supports their decision making. Conclusion: Although physicians should be mindful of the specific preferences of AYA patients, the basic attitude and communication preferences are similar to those of patients of other generations.

In this study, we report a case of tracheotomy using the ex utero intrapartum treatment (EXIT) procedure in a fetus that was pointed out as having bilateral giant cervical cysts at prenatal diagnosis and whose postnatal airway occlusion was predicted. The subject was a female aged 35. She was diagnosed with polyhydramnios at 28 weeks of pregnancy. The fetus was found to have a giant cervical cyst before she was referred to the department of obstetrics and gynecology of our hospital. On the second day of 37 weeks of pregnancy, oral tracheal intubation was attempted on the fetus using the EXIT procedure after the caesarean operation, but intubation was difficult resulting in a tracheotomy. The oxygenation of the fetus during the operation was maintained well without any postoperative complication. Postnatal fetal airway occlusion is a critical incident which may lead to the death of a fetus. It was assumed, however, that the airway management under the same procedure was completed by the preoperative detailed simulation with the staff of the departments of anesthesiology, obstetrics and gynecology and pediatrics as well as the operating room personnel., Competing Interests: There is no conflict-of-interest to be disclosed concerning this article.

Pediatric acute myeloid leukemia (AML) is a poor prognostic subtype of pediatric leukemia. However, the detailed characteristics of many genetic abnormalities are yet to be established in this disease. Although TP53 and RB1 are established as representative tumor suppressor genes in various cancers, alterations of these two genes, especially RB1, have not been characterized in pediatric AML. We performed next-generation sequencing in 328 pediatric AML patients from the Japanese AML-05 trial to ascertain TP53 and RB1 alterations, and their prognostic implications. We identified seven patients with TP53 alterations (2.1%) and six patients with RB1 alterations (1.8%). These alterations were found in only patients without RUNX1::RUNX1T1, CBFB::MYH11, or KMT2A rearrangements. TP53 and RB1 were frequently co-deleted with their neighboring genes PRPF8 and ELF1, respectively. Patients with TP53 alterations had significantly lower 5-year overall survival (OS; 14.3% vs. 71.4%, p < 0.001) and lower 5-year event-free survival (EFS; 0% vs. 56.3%, p < 0.001); similarly, patients with RB1 had significantly lower 5-year OS (0% vs. 71.8%, p < 0.001) and lower 5-year EFS (0% vs. 56.0%, p < 0.001) when compared to patients without these alterations. In gene expression analyses, oxidative phosphorylation, glycolysis, and protein secretion were upregulated in patients with TP53 and/or RB1 alterations. Additionally, Kaplan-Meier analysis revealed that high expressions of SLC2A5, KCNAB2, and CD300LF were related to poor OS of non-core-binding factor AML patients (p < 0.001, p = 0.001, and p = 0.021, respectively). This study will contribute to the development of risk-stratified therapy and precision medicine in pediatric AML., (© 2023 Wiley Periodicals LLC.)

The characteristics and prognosis of Japanese children with acute lymphoblastic leukemia (ALL) who fail to achieve complete remission after remission induction chemotherapy (i.e., experience induction failure) are poorly understood. Therefore, we retrospectively analyzed data of patients enrolled in Japanese clinical trials for newly diagnosed ALL between 1996 and 2009. Among 4956 participants, 89 (1.8%) experienced induction failure. With a 6.0-year median follow-up, the 5-year overall survival rate of the entire cohort was 43.0% ± 5.5%. Survival rates did not differ between patients with B-cell precursor ALL (BCP-ALL) and T-cell ALL (T-ALL). In multivariate analysis, day 15 M3 marrow (bone marrow blast count ≥ 25%) was significantly correlated with poorer survival in the whole or BCP-ALL cohorts. In T-ALL, age < 6 years was significantly associated with poor survival. However, due to the small sample size, this correlation must be further investigated. Most T-ALL and BCR-ABL-positive BCP-ALL patients underwent allogeneic stem cell transplantation (allo-SCT). Survival rates did not differ between BCR-ABL-negative BCP-ALL patients who did and did not undergo allo-SCT, possibly due to the inclusion of lower-risk patients in the latter group. In conclusion, the induction failure rate and survival after diagnosis of induction failure in our study were comparable to previously reported figures., (© 2023. Japanese Society of Hematology.)

Asparaginase is an essential drug for acute lymphoblastic leukaemia (ALL) treatment, but has several side effects, and its discontinuation often compromises patient outcomes. In the prospective Japan Association of Childhood Leukaemia Study ALL-02 protocol, two major changes were made: (1) additional chemotherapies to compensate for the reduction of treatment intensity when asparaginase was discontinued and (2) more intensive concomitant corticosteroid administration, relative to our previous ALL-97 protocol. In ALL-02 study, 1192 patients were included and L-asparaginase was discontinued for 88 (7.4%). Discontinuation due to allergy was markedly decreased relative to the ALL-97 protocol (2.3% vs 15.4%). Event-free survival (EFS) among patients with T-ALL was compromised when L-asparaginase was discontinued, as well as among patients with high-risk B-cell ALL, especially when discontinued before maintenance therapy. Moreover, multivariate analysis identified discontinuation of L-asparaginase as an independent poor prognostic factor for EFS. In the current study, additional chemotherapies failed to fully compensate for L-asparaginase discontinuation, illustrating the difficulty of replacing asparaginase with other classes of drugs, although this study was not designed to evaluate the effect of these modifications. Concomitant intensive corticosteroid treatment may help to reduce allergy to asparaginase. These results will assist in further optimization of asparaginase use., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

The secreted protein sclerostin is primarily produced by osteocytes and suppresses osteoblast differentiation and function by inhibiting the canonical Wnt signaling pathway. Genetic and pharmacological inhibition of sclerostin has been shown to increase bone formation and an anti-sclerostin antibody has been clinically approved for the treatment of osteoporosis. Canonical Wnt signaling is also involved in the progression of several types of cancers including breast cancer. Here, we studied the effects of sclerostin inhibition on the development of bone metastases of breast cancer using mouse models. TOPFLASH assay and real-time PCR analysis of AXIN2, a target of canonical Wnt signaling, revealed that, among four cell lines tested, MDA-MB-231 human breast cancer cells responded highly to the canonical Wnt ligand Wnt3a, whereas other cell lines exhibited marginal responses. Consistent with these results, treatment with an anti-sclerostin antibody significantly increased the bone metastases of MDA-MB-231 but not those of other breast cancer cells. Immunohistochemical studies demonstrated that an anti-sclerostin antibody induced intracellular accumulation of β-catenin in bone-colonized MDA-MB-231 cells. Suspension culture assays showed that Wnt3a accelerated the tumorsphere formation of MDA-MB-231 cells, whereas monolayer cell proliferation and migration were not affected. Furthermore, the numbers of osteoclasts and their precursor cells in bone metastases of MDA-MB-231 were significantly increased in mice treated with an anti-sclerostin antibody. These results collectively suggest that sclerostin blockade activates canonical Wnt signaling in ligand-responsive breast cancer cells metastasized to bone, thereby increasing bone metastases, likely to have been mediated at least in part by enhancing stem cell-like properties of cancer cells and osteoclastogenesis., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: T-cell acute lymphoblastic leukaemia has distinct biological characteristics and a poorer prognosis than B-cell precursor acute lymphoblastic leukaemia. This trial aimed to reduce the rate of radiation and haematopoietic stem-cell transplantation (HSCT) while improving outcomes by adding nelarabine, intensified L-asparaginase, and protracted intrathecal therapy in the Berlin-Frankfurt-Münster (BFM)-type treatment., Methods: In this nationwide, multicenter, phase 2 trial, we enrolled patients with newly diagnosed T-cell acute lymphoblastic leukaemia (age <25 years at diagnosis) conducted by Japan Children's Cancer Group and Japan Adult Leukemia Study Group. Patients were stratified into standard-risk, high-risk, and very-high-risk groups according to prednisolone response, CNS status, and end-of-consolidation minimal residual disease. We used the Associazione Italiana di Ematologia Oncologia Pediatrica (AIEOP)-BFM-ALL 2000-backbone chemotherapy. Nelarabine (650 mg/m 2 per day for 5 days) was given to high-risk and very high-risk patients. All patients received, until the measurement of end-of-consolidation minimal residual disease, an identical therapy schedule, which included the prednisolone pre-phase remission induction therapy with dexamethasone (10 mg/m 2 per day, for 3 weeks [for patients <10 years] or for 2 weeks including a 7-day off interval [for patients ≥10 years]) instead of prednisolone, and consolidation therapy added with Escherichia coli-derived L-asparaginase. On the basis of the stratification, patients received different intensities of treatment; L-asparaginase-intensified standard BFM-type therapy for standard risk and nelarabine-added high risk BFM-type therapy for high risk. In the very high-risk group, patients were randomly assigned (1:1) to group A (BFM-based block therapy) and group B (another block therapy, including high-dose dexamethasone) stratified by hospital, age (≥18 years or <18 years), and end-of-induction bone marrow blast percentage of M1 (<5%) or M2 (≥5%, <25%)+M3 (≥25%). Cranial radiotherapy was limited to patients with overt CNS disease at diagnosis (CNS3; >5 white blood cells per μL with blasts) and patients with no evidence of CNS disease received protracted triple intrathecal therapy. Only very high-risk patients were scheduled to receive HSCT. The primary endpoint was 3-year event-free survival for the entire cohort and the proportion of patients with disappearance of minimal residual disease between randomly assigned groups A and B in the very high-risk group. Secondary endpoints were overall survival, remission induction rate, and occurrence of adverse events. 3 years after the completion of patient accrual, a primary efficacy analysis was performed in the full analysis set and the per-protocol set. This study is registered with the Japan Registry of Clinical Trials, jRCTs041180145., Findings: Between Dec 1, 2011, and Nov 30, 2017, of 349 eligible patients (median age 9 years [IQR 6-13]), 238 (68%) were male, and 28 (8%) patients had CNS3 status. 168 (48%) patients were stratified as standard risk, 103 (30%) as high risk, 39 (11%) as very high risk, and 39 (11%) as no risk (patients who had off protocol treatment before risk assessment. The composite complete remission (complete remission plus complete remission in suppression) rate after remission induction therapy was 89% (298 of 335 patients). HSCT was performed in 35 (10%) of 333 patients. With a median follow-up of 5·2 years (IQR 3·6-6·7), 3-year event-free survival was 86·4% (95% CI 82·3-89·7%) and 3-year overall survival was 91·3% (87·7-93·8%). The proportion of minimal residual disease disappearance was 0·86 (12 of 14 patients; 95% CI 0·57-0·98) in group A and 0·50 (6 of 12 patients, 0·21-0·79) in group B. Grade 3 peripheral motor neuropathy was seen in 11 (3%) of 349 patients and sensory neuropathy was seen in 6 (2%) patients. The most common grade 3 or worse adverse event was febrile neutropenia (294 [84%] of 349 patients). Treatment-related death occurred in three patients due to sepsis, gastric perforation, or intracranial haemorrhage during remission induction., Interpretation: The ALL-T11 protocol produced encouraging outcomes with acceptable toxicities despite limited cranial radiotherapy and HSCT use., Funding: Ministry of Health, Labor and Welfare of Japan, and Japan Agency for Medical Research and Development., Translation: For the Japanese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests AS has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, and educational events from Chugai Pharmaceutical. YH has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, and educational events from Kyowa Kirin, Novartis Pharma, and Nippon Shinyaku. CI has received patent royalty in Juno Therapeutics and CURED, consulting fees from CURED and, as a filing of a new patent is being planned in CURED, has a Stock option in CURED. MK received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, and educational events from Amgen, Chugai Pharmaceutical, and Novartis Pharma, and received grants from from Otsuka Pharmaceutical. SSu has a contract from the Division of General Pediatrics and Emergency Medicine, Oita City, and also has leadership in Japan Children's Cancer Group and The Japanese Society of Pediatric Hematology and Oncology. HK has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, and educational events from Abbvie, Chugai Pharmaceutical, Astellas Pharma, and Novartis Pharma. IM has received grants from Ono Pharmaceutical, Janssen Pharmaceutical, Nippon Shinyaku, Kyowa Kirin, Sumitomo Dainippon Pharma, Shionogi & Co, Teijin Pharma, Boehringer Ingelheim, Sanofi, Chugai Pharmaceutical, Eisai, MSD, Asahi Kasei Pharma Corporation, Astellas Pharma, Takeda Pharmaceutical, Nihon Pharmaceutical, Daiichi Sankyo, AbbVie, Taiho Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Nippon Kayaku, CSL Behring, Mundipharma, AYUMI Pharmaceutical Corporation, Eli Lilly Japan, Actelion Pharmaceuticals Japan, and Amgen BioPharma. IM has also received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, and educational events from Bristol-Myers Squibb (Celgene), Novartis, Otsuka Pharmaceutical, Pfizer Japan, Janssen, Astellas Pharma, Takeda Pharmaceutical, and Daiichi Sankyo, and has received consulting fees from Otsuka Pharmaceutical. YM has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, and educational events from Novartis Pharma and Kyowa-Kirin. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

It has not been established how to assess children's and adolescents' decision-making capacity (DMC) and there has been little discussion on the way their decision-making (DM). The purpose of this study was to examine actual situation and factors related to difficulties in explaining their disease to adolescent cancer patients or obtaining informed consent (IC). The cross-sectional questionnaire survey was conducted. Physicians who have been treating adolescent cancer patients for at least five years answered a self-administered questionnaire uniquely developed about clinical difficulties in explaining, IC and factors related patient's refusal of medical treatment (RMT). Descriptive statistics for each item and a polychoric correlation analysis of the problems and factors related to the explanation were conducted. As a result, fifty-six physicians were participated (rate of return: 39%). Explaining the disease and treatment to patients (83.9%), IC to patients (80.4%), and explaining the disease and treatment to parents (78.6%) was particularly problematic. Difficulties to provide support related with patient's refusal of medical treatment and to explain disease and treatment for patient and parents were related to difficulties obtaining IC for the patient. Conclusion: There are clinically difficult to explain for the patient or parents and to obtain IC for the patient. It is necessary to establish a disease acceptance assessment tool for the adolescence generation so that it can be applied in the field., (© 2023. The Author(s).)

Introduction: Relapsed and refractory B-cell acute lymphoblastic leukaemia (R/R-B-ALL) is linked to a significant relapse rate after allogeneic haematopoietic cell transplantation (allo-HCT) in children, adolescents and young adults (CAYA). No standard treatment has been established to prevent relapse after allo-HCT for R/R-B-ALL, which is an unmet medical need. The administration of blinatumomab after allo-HCT is expected to enhance the antileukaemic effect on residual CD19-positive blasts by donor-derived CD3-positive T-cells., Methods and Analysis: The goal of this multicentre, open-label, uncontrolled, phase I-II clinical trial is to assess the safety and effectiveness of post-transplant maintenance therapy with blinatumomab for CAYA patients (25 years old or younger) with CD19-positive R/R-B-ALL who have received allo-HCT beyond first complete remission (CR) and have CR with haematological recovery between 30 and 100 days after allo-HCT. Eighty-five paediatric institutions in Japan are participating in this study. Forty-one patients will enrol within 2.25-year enrolment period and follow-up period is 1 year. The primary endpoints are the treatment completion rate for phase I study and the 1-year graft-versus-host disease-free/relapse-free survival rate for phase II study, respectively., Ethics and Dissemination: This research was approved by the Central Review Board at National Hospital Organization Nagoya Medical Center (Nagoya, Japan) on 21 January 2022 and was registered at the Japan Registry of Clinical Trials (jRCT) on 3 March 2022. Written informed consent is obtained from all patients and/or their guardians. The results of this study will be disseminated through peer-reviewed publications and conference presentations., Trial Registration Number: jRCTs041210154., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The prognosis of pediatric acute myeloid leukemia (AML) has improved via stratification therapy. However, relapse or death occurs in 30%-40% of cases. Novel genetic factors for pediatric AML need to be elucidated to improve prognosis. We detected recurrent internal tandem duplication in upstream binding transcription factor (UBTF-ITD) in 1.2% (6/503) of Japanese pediatric patients with de novo AML. No UBTF-ITD was detected in 175 adult patients with AML or in 65 cell lines that included 15 AML, 39 acute lymphoblastic leukemia, five chronic myeloid leukemia, and six neuroblastoma cell lines. All UBTF-ITDs were found in exon 13 and shared a duplicated region. UBTF-ITD was more frequently detected in patients with trisomy 8, FLT3-ITD, WT1 mutation, and/or high PRDM16 expression (trisomy 8, 3/6; FLT3-ITD, 5/6; WT1 mutation, 2/6; and high PRDM16 expression, 6/6). Gene expression patterns of patients with UBTF-ITD were similar to those of patients with NUP98::NSD1 or FUS::ERG. Survival analysis of the AML-05 cohort revealed that patients with UBTF-ITD had worse outcomes than those without UBTF-ITD (3-year event-free survival, 20% vs. 55%; 3-year overall survival, 40% vs. 74%). Moreover, among the 27 patients with trisomy 8, all three patients with UBTF -ITD had a poor prognosis resulting in early events (relapse or non-complete remission) within 1 year. Our findings suggest that UBTF-ITD may be a novel and significant prognostic factor for pediatric patients with AML., (© 2022 Wiley Periodicals LLC.)

The European Intergroup for Childhood Non-Hodgkin Lymphoma (EICNHL) was established 25 years ago with the goal to facilitate clinical trials and research collaborations in the field both within Europe and worldwide. Since its inception, much progress has been made whereby major improvements in outcomes have been achieved. In this Review, we describe the different diagnostic entities of non-Hodgkin lymphoma in children and young adults describing key features of each entity and outlining clinical achievements made in the context of the EICNHL framework. Furthermore, we provide an overview of advances in biopathology with an emphasis on the role of biological studies and how they have shaped available treatments. Finally, for each entity, we describe future goals, upcoming clinical trials, and highlight areas of research that require our focus going forward., Competing Interests: Declaration of interests LB has sat on advisory boards for the BrigaPed study for Takeda and has received support from Bristol Myers Squibb for the nivoALCL clinical trial. GAAB has received institutional payments for consultancies from Novartis, Roche, Takeda, straZeneca, and Janssen. AA has sat on a board for MSD. All other authors have no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: We aimed to study prognostic factors and efficacy of allogeneic hematopoietic stem-cell transplantation (allo-HSCT) in first remission of patients with noninfant childhood acute lymphoblastic leukemia (ALL) with 11q23/ KMT2A rearrangements treated with chemotherapy regimens between 1995 and 2010., Patients and Methods: Data were retrospectively retrieved from 629 patients with 11q23/ KMT2A -rearranged ALL from 17 members of the Ponte-di-Legno Childhood ALL Working Group. Clinical and biologic characteristics, early response assessed by minimal residual disease at the end of induction (EOI) therapy, and allo-HSCT were analyzed for their impact on outcomes., Results: A specific 11q23/ KMT2A translocation partner gene was identified in 84.3% of patients, with the most frequent translocations being t(4;11)(q21;q23) (n = 273; 51.5%), t(11;19)(q23;p13.3) (n = 106; 20.0%), t(9;11)(p21&#95;22;q23) (n = 76; 14.3%), t(6;11)(q27;q23) (n = 20; 3.8%), and t(10;11)(p12;q23) (n = 14; 2.6%); 41 patients (7.7%) had less frequently identified translocation partner genes. Patient characteristics and early response varied among subgroups, indicating large biologic heterogeneity and diversity in therapy sensitivity among 11q23/ KMT2A -rearranged ALL. The EOI remission rate was 93.2%, and the 5-year event-free survival (EFS) for the entire cohort was 69.1% ± 1.9%, with a range from 41.7% ± 17.3% for patients with t(9;11)-positive T-ALL (n = 9) and 64.8% ± 3.0% for patients with t(4;11)-positive B-ALL (n = 266) to 91.2% ± 4.9% for patients with t(11;19)-positive T-ALL (n = 34). Low EOI minimal residual disease was associated with favorable EFS, and induction failure was particularly predictive of nonresponse to further therapy and relapse and poor EFS. In addition, EFS was not improved by allo-HSCT compared with chemotherapy only in patients with both t(4;11)-positive B-ALL (n = 64 v 51; P = .10) and 11q23/ KMT2A -rearranged T-ALL (n = 16 v 10; P = .69)., Conclusion: Compared with historical data, prognosis of patients with noninfant 11q23/ KMT2A -rearranged ALL has improved, but allo-HSCT failed to affect outcome. Targeted therapies are needed to reduce relapse and treatment-related mortality rates.

Purpose: Adolescent and young adult cancer patients (AYAs) often experience profound psychological distress, with various unmet supportive care needs that can be alleviated with appropriate screening and attention by healthcare workers. The Distress Thermometer and Problem List-Japanese version (DTPL-J) is our previously developed screening tool to facilitate individual support of AYAs. This study evaluated the feasibility and preliminary effectiveness of a psychosocial support program based on the DTPL-J for AYAs in clinical practice., Methods: This multicenter, retrospective, observational study included 19 of 126 wards and 9 of 75 outpatient clinics at 8 institutions in Japan. Over 200 patients were expected to participate during the eligibility period. Patients participated in a support program at least once, and approximately once a month based on the DTPL-J results. The program was evaluated using the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) implementation framework., Results: The screening rate of the 361 participants was 90.3%, suggesting high feasibility. Distress Thermometer scores, the number of supportive care needs, and the rates of AYAs with high distress were significantly reduced 1 month after screening (p < 0.05), suggesting the preliminary effectiveness of the program. The program was continued at the 8 institutions as part of routine care after the study., Conclusion: Analysis using the RE-AIM suggested the sufficient feasibility and preliminary effectiveness of a psychosocial support program based on the DTPL-J for AYAs., Trial Registration: University Hospital Medical Information Network (UMIN CTR) UMIN000042857. Registered 25 December 2020-Retrospectively registered., (© 2023. The Author(s).)

Self-efficacy is the key factor for promoting physical activity. Older adults with low self-efficacy tend to be physical inactive than those with high self-efficacy, and an approach is needed to promote physical activity. Among several approaches, increasing the perception of green space may be an effective approach for low self-efficacy not high self-efficacy, but no study has investigated. This study investigated the association between walking and perception of green space among older adults with high and low self-efficacy, respectively. We conducted a cross-sectional study among 204 community-dwelling older adults (mean age = 78.3 years, 62.3% females). Using the median split, the participants were divided into high and low self-efficacy groups based on the median score of 12. Walking was measured using the International Physical Activity Questionnaire and 'more walking' was defined as ≥150 min of walking time per week. Perception of green space was measured using an 8-item questionnaire. We performed logistic regression analysis to investigate the association between walking and perception of green space adjusted for age, gender, years of education, living with someone and income level. For all participants, 94 participants (46.1%) fell under low self-efficacy. After adjustment, higher perception of green space is associated with more walking among older adults with low self-efficacy [adjusted odds ratio (aOR) = 1.07, 95% confidence interval (CI) = 1.00-1.15], but not among those with high self-efficacy (aOR = 1.09, 95% CI= 0.99-1.20). To increase perception of green space, experts should design/improve green spaces considering beneficiaries' characteristics., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Outdoor play (OP), which is considered important for children's development, is declining every year. Perceived physical competence (PPC) is a vital factor that promotes physical activity such as OP, sports clubs, etc., but the relationship between PPC and OP was unknown. The purpose of this research was to investigate the relationship between PPC and OP in children and consider whether there were any sex-specific changes., Methods: A cross-sectional study was conducted in Japan with 288 children (134 girls, age: 10.6 ± 1.01 years). OP was assessed using an original self-report questionnaire. Each weekday, the children reported the time of OP and were classified as "high" if they played outside for at least an hour three times. PPC was evaluated with a self-report questionnaire developed by Okazawa et al. (1996). It has 12 questions and was assessed on a 5-point Likert scale. After adjusting for age, sex, BMI, screen time, sports club participation, and the number of friends, logistic regression analyses were carried out., Results: Children with better PPC were significantly more likely to be classified as "high" [crude odds ratio (OR): 1.04; 95% confidence interval (CI): 1.00-1.08; adjusted OR: 1.04; 95% CI: 1.00-1.08]. Only girls with better PPC were significantly more likely to be classified as "high" in a sex-based stratified analysis [crude OR: 1.08; 95% CI: 1.01-1.15, adjusted OR 1.09; 95% CI: 1.02-1.17]., Conclusions: Particularly among girls, OP could be promoted as a voluntary physical activity with improved PPC.

Introduction: Adoptive cell transfer of genetically engineered T cells is a promising treatment for malignancies; however, there are few ideal cancer antigens expressed on the cell surface, and the development of chimeric antigen receptor T cells (CAR-T cells) for solid tumour treatment has been slow. CAR-T cells, which recognise major histocompatibility complex and peptide complexes presented on the cell surface, can be used to target not only cell surface antigens but also intracellular antigens. We have developed a CAR-T-cell product that recognises the complex of HLA-A*02:01 and an epitope of the MAGE-A4 antigen equipped with a novel signalling domain of human GITR (investigational product code: MU-MA402C) based on preclinical studies., Methods and Analysis: This is a dose-escalation, multi-institutional, phase 1 study to evaluate the tolerability and safety of MU-MA402C for patients with MAGE A4-positive and HLA-A*02:01-positive unresectable advanced or recurrent solid cancer. Two dose cohorts are planned: cohort 1, MU-MA402C 2×10 8 /person; cohort 2, MU-MA402C 2×10 9 /person. Prior to CAR-T-cell infusion, cyclophosphamide (CPA) and fludarabine (FLU) will be administered as preconditioning chemotherapy. Three evaluable subjects per cohort, for a total of 6 subjects (maximum of 12 subjects), will be recruited for this clinical trial. The primary endpoints are safety and tolerability. The severity of each adverse event will be evaluated in accordance with Common Terminology Criteria for Adverse Events V.5.0. The secondary endpoint is efficacy. Antitumour response will be evaluated according to Response Evaluation Criteria in Solid Tumours V.1.1., Ethics and Dissemination: This clinical trial will be conducted in accordance with the current version of Good Clinical Practice. The protocol was approved by the Clinical Research Ethics Review Committee of Mie University Hospital (approval number F-2021-017). The trial results will be published in peer-reviewed journals and/or disseminated through international conferences., Trial Registration Number: jRCT2043210077., Competing Interests: Competing interests: SO received consulting fees from T Cell Nouveau. MI received honoraria from Chugai, Eisai, MSD, Ono, Daiichi Sankyo and Eli Lilly. NK received consulting fees from Adlai Nortye and Ono, received honoraria from Eli Lilly, Ono, Bristol-Myers Squibb, MSD, Eisai and Bayer, serves on the advisory boards of Chugai and Adlai Nortye, and received research funding from Boehringer Ingelheim, Ono, Bristol-Myers Squibb, Astra Zeneca, Pfizer, Chugai, Rakuten Medical, Bayer and Adlai Nortye. KT received honoraria from Eisai, Janssen, Chugai, Ono, Eli Lilly, Otsuka and Daiichi Sankyo. HI received a research grant from Takara Bio Inc. KK received consulting fees from AbbVie, AstraZeneca, Celgene, Chugai, Eisai, Janssen, Novartis and Daiichi-Sankyo, honoraria from Takeda, MSD, Kyowa-Kirin, Janssen, Celgene, Ono, Mundi, Dainippon-Sumitomo and Bristol-Myers Squibb, and research funding from Chugai, Takeda, Kyowa-Kirin, AbbVie, Novartis, Eisai, Janssen, Celgene, Ono, Novartis and Daiichi-Sankyo. SKi received grants and personal fees from Astra Zeneca, grants and personal fees from Pfizer, grants and personal fees from Boehringer Ingelheim, personal fees from Taiho, personal fees from Novartis, grants and personal fees from MSD, personal fees from Sumitomo Pharma, grants and personal fees from Eisai, grants from Astellas, grants from Gilead Sciences, grants and personal fees from Ono, personal fees from Bristol-Myers Squibb, grants and personal fees from REGENERON, personal fees from Rakuten Medical, grants from PACT Pharma, grants from Takara Bio, personal fees from GSK, grants and personal fees from Daiichi-Sankyo, grants and personal fees from Chugai, grants from Incyte, personal fees from ImmuniT Research, personal fees from Merck KGaA and personal fees from Takeda. SKa serves on the advisory boards of Otsuka and Noile-Immune Biotech. KH received consulting fees from Pfizer and honoraria from Amgen, Chugai and Novartis. TY received a research grant from Daiichi Sankyo. Mie University holds a patent on the MAGE A4-CAR construct. YM and HS are the inventors on the patent., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Inotuzumab ozogamicin (InO) is a CD22-directed antibody conjugated with calicheamicin approved for adult relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL). This phase 1 study primarily aimed to determine the pediatric recommended doses of InO through the standard 3 + 3 design, and to evaluate the safety, tolerability, pharmacokinetic (PK) profile, immunogenicity and efficacy of InO. Dose level 1 (DL1) was 1.8 mg/m 2 (days 1, 8, and 15: 0.8, 0.5, and 0.5 mg/m 2 , respectively). Six of the seven registered patients were eligible [median age, 7.5 (2-17) years]. Although all six patients started DL1, only five completed the dose. No dose-limiting toxicity was observed. All patients experienced adverse events (AEs), including increased alanine aminotransferase and aspartate aminotransferase in four patients. Three patients experienced serious AEs, which were hepatic veno-occlusive disease (VOD), ALL, and fever. Five patients achieved complete remission (CR) or CR with incomplete blood cell recovery (CRi), among whom 3 (60%) were negative for minimal residual disease. PK findings were similar to those in adults. No patient had anti-drug antibodies to InO. In conclusion, InO was well tolerated in children and promoted similar antileukemic efficacy as in adults. Nonetheless, the risk for VOD requires attention., (© 2022. Japanese Society of Hematology.)

Background: This study investigated the effect of different components of screen time (mobile phone use, TV/video viewing, and video gaming) on cardiorespiratory fitness (CRF) development in children aged 9-12 years., Methods: This was a two-year longitudinal study conducted with 175 children (49.7% girls, mean age = 9.5) in Japan. CRF was assessed using a 20 m shuttle run test conducted at baseline and again at follow-up. Children were categorized as "Good" or "Poor" based on the change in CRF scores for each gender. Screen time was assessed using a self-reported questionnaire at baseline and termed as "high" if children reported ≥ 2 h/day. Univariate and multivariate logistic regression analyses were performed after adjusting for gender, physical activity, and time of data collection., Results: Children scoring "high" on mobile phone use had lower odds of being categorized as "Good" in CRF change (crude odds ratio (OR): 0.34; 95% confidence interval (CI): 0.15-0.90 (adjusted OR: 0.33; 95% CI: 0.12-0.91)). There were no significant effects of TV/video viewing (crude OR: 1.54; 95% CI: 0.84-2.81) and video gaming (crude OR: 0.98; 95% CI: 0.48-1.97) on changes in CRF., Conclusions: Limiting excessive mobile phone usage might be important for ensuring healthy development of CRF in children.

We investigated genome-wide DNA methylation patterns in 64 pediatric patients with acute myeloid leukemia (AML). Based on unsupervised clustering with the 567 most variably methylated cytosine guanine dinucleotide (CpG) sites, patients were categorized into 4 clusters associated with genetic alterations. Clusters 1 and 3 were characterized by the presence of known favorable prognostic factors, such as RUNX1-RUNX1T1 fusion and KMT2A rearrangement with low MECOM expression, and biallelic CEBPA mutations (all 8 patients), respectively. Clusters 2 and 4 comprised patients exhibiting molecular features associated with adverse outcomes, namely internal tandem duplication of FLT3 (FLT3-ITD), partial tandem duplication of KMT2A, and high PRDM16 expression. Depending on the methylation values of the 1243 CpG sites that were significantly different between FLT3-ITD+ and FLT3-ITD- AML, patients were categorized into 3 clusters: A, B, and C. The STAT5-binding motif was most frequently found close to the 1243 CpG sites. All 8 patients with FLT3-ITD in cluster A harbored high PRDM16 expression and experienced adverse events, whereas only 1 of 7 patients with FLT3-ITD in the other clusters experienced adverse events. PRDM16 expression levels were also related to DNA methylation patterns, which were drastically changed at the cutoff value of PRDM16/ABL1 = 0.10. The assay for transposase-accessible chromatin sequencing of AMLs supported enhanced chromatin accessibility around genomic regions, such as HOXB cluster genes, SCHIP1, and PRDM16, which were associated with DNA methylation changes in AMLs with FLT3-ITD and high PRDM16 expression. Our results suggest that DNA methylation levels at specific CpG sites are useful to support genetic alterations and gene expression patterns of patients with pediatric AML., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. As overall cure rates of childhood ALL have improved, reduction of overall treatment intensity while still ensuring excellent outcomes is imperative for low-risk patients. We report the outcomes of patients treated following the standard-risk protocol from the prospective Japan Association of Childhood Leukemia Study (JACLS) ALL-02 study, which was conducted between 2002 and 2008 for patients with newly diagnosed ALL aged 1-18 years. Of 1138 patients with B-cell precursor ALL, 388 (34.1%) were allocated to this protocol. Excellent outcomes were achieved despite the overall treatment intensity being lower than that of most contemporary protocols: 4 years event-free survival (EFS) was 92.3% and 4 years overall survival 98.2%. Patients with high hyperdiploidy (HHD) involving triple trisomy (trisomy of chromosomes 4, 10, and 17) or ETV6-RUNX1 had even better outcomes (4 years EFS 97.6% and 100%, respectively). Unique characteristics of this protocol include a selection of low-risk patients with a low initial WBC count and good early treatment response and reduction of cumulative doses of chemotherapeutic agents while maintaining dose density. In Japan, we are currently investigating the feasibility of this protocol while incorporating minimal residual disease into the patient stratification strategy., (© 2022. Japanese Society of Hematology.)

There is no established treatment for patients with acute promyelocytic leukemia (APL) refractory to targeted therapies with all-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO). We report here a case of an 8-month-old girl with APL who failed standard ATRA-combined chemotherapy. Although molecular remission was achieved after introducing ATRA/ATO combination therapy, molecular relapse occurred during the ATO consolidation courses. Subsequent molecular remission was rapidly achieved after administering 2 doses of gemtuzumab ozogamicin. She was successfully treated with unrelated cord blood transplantation using reduced-intensity conditioning. Gemtuzumab ozogamicin might be a preferable choice for patients with APL refractory to standard therapy., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: We examined the association between workplace social capital (WSC) and presence of neck pain (NP) among workers., Methods: This cross-sectional study included 595 workers. Presence of NP was assessed using Numerical Rating scale. WSC (overall, bonding, bridging, and linking) was divided into three categories (low, middle, and high) based on tertile distributions. We used logistic regression analysis to investigate the association between WSC and presence of NP., Results: Low overall, bonding, and linking social capital were significantly associated with presence of NP in comparison with each high social capital (overall: adjusted odds ratio [aOR] = 1.76, 95% confidence interval [CI] = 1.14 to 2.73; bonding: aOR = 1.78, 95% CI = 1.19 to 2.67, linking: aOR = 2.18, 95% CI = 1.32 to 3.63)., Conclusion: Lower WSC had an association with higher prevalence of NP among workers., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 American College of Occupational and Environmental Medicine.)

Aim: We aimed to determine whether SGLT2 inhibitor dapagliflozin treatment affects body composition and amino acid (AA) metabolism., Methods: Fifty-two overweight patients treated by oral antidiabetic agents were randomly assigned to dapagliflozin (Dapa) or a standard treatment (Con) and followed for 24 weeks. The primary outcome was the change in body mass (BM) between baseline and week 24. Body composition, intrahepatic triglyceride (IHTG) content, and plasma AA concentrations were examined as secondary outcomes., Results: The change in BM was significantly larger in the Dapa than in the Con group, with a difference in the mean change of -1.72 kg (95 %CI: -2.85, -0.59; P = 0.004) between the groups. Total fat mass was reduced by dapagliflozin treatment, but fat-free mass was maintained. IHTG content was significantly reduced in the Dapa than in the Con (P = 0.033). Changes in AAs showed small differences between the groups, but only serine concentrations were significantly reduced in the Dapa. Intra-group analysis showed that positive associations were observed between changes in branched chain AA concentrations and body composition only in the Dapa., Conclusions: Dapagliflozin treatment causes a reduction in BM mainly by reducing fat mass. AA metabolism shows subtle changes with dapagliflozin treatment., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The genetic basis of leukemogenesis in adults with B-cell acute lymphoblastic leukemia (B-ALL) is largely unclear, and its clinical outcome remains unsatisfactory. This study aimed to advance the understanding of biological characteristics, improve disease stratification, and identify molecular targets of adult B-ALL. Adolescents and young adults (AYA) (15 to 39 years old, n = 193) and adults (40 to 64 years old, n = 161) with Philadelphia chromosome-negative (Ph-) B-ALL were included in this study. Integrated transcriptomic and genetic analyses were used to classify the cohort into defined subtypes. Of the 323 cases included in the RNA sequencing analysis, 278 (86.1%) were classified into 18 subtypes. The ZNF384 subtype (22.6%) was the most prevalent, with 2 novel subtypes (CDX2-high and IDH1/2-mut) identified among cases not assigned to the established subtypes. The CDX2-high subtype (3.4%) was characterized by high expression of CDX2 and recurrent gain of chromosome 1q. The IDH1/2-mut subtype (1.9%) was defined by IDH1 R132C or IDH2 R140Q mutations with specific transcriptional and high-methylation profiles. Both subtypes showed poor prognosis and were considered inferior prognostic factors independent of clinical parameters. Comparison with a previously reported pediatric B-ALL cohort (n = 1003) showed that the frequencies of these subtypes were significantly higher in AYA/adults than in children. We delineated the genetic and transcriptomic landscape of adult B-ALL and identified 2 novel subtypes that predict poor disease outcomes. Our findings highlight the age-dependent distribution of subtypes, which partially accounts for the prognostic differences between adult and pediatric B-ALL., (© 2022 by The American Society of Hematology.)

RAS pathway alterations have been implicated in the pathogenesis of various hematological malignancies. However, their clinical relevance in pediatric acute myeloid leukemia (AML) is not well characterized. We analyzed the frequency, clinical significance, and prognostic relevance of RAS pathway alterations in 328 pediatric patients with de novo AML. RAS pathway alterations were detected in 80 (24.4%) of 328 patients: NF1 (n=7, 2.1%), PTPN11 (n=15, 4.6%), CBL (n=6, 1.8%), NRAS (n=44, 13.4%), KRAS (n=12, 3.7%). Most of these alterations in the RAS pathway were mutually exclusive also together with other aberrations of signal transduction pathways such as FLT3-ITD (P=0.001) and KIT mutation (P=0.004). NF1 alterations were frequently detected in patients with complex karyotype (P=0.031) and were found to be independent predictors of poor overall survival (OS) in multivariate analysis (P=0.007). At least four of seven patients with NF1 alterations had biallelic inactivation. NRAS mutations were frequently observed in patients with CBFB-MYH11 and were independent predictors of favorable outcomes in multivariate analysis (OS, P=0.023; event-free survival [EFS], P=0.037). Patients with PTPN11 mutations more frequently received stem cell transplantation (P=0.035) and showed poor EFS than patients without PTPN11 mutations (P=0.013). Detailed analysis of RAS pathway alterations may enable a more accurate prognostic stratification of pediatric AML and may provide novel therapeutic molecular targets related to this signal transduction pathway.