Acute lymphoblastic leukemia (ALL) is the most common disease in pediatric oncology. The history of developmental therapeutics for ALL began in the 1960s with the repetition of “unreliable” medical interventions against this lethal disease. By the 1990s, the development of multi-agent chemotherapy and various types of supportive care rendered ALL treatable. Highly sophisticated, molecular, diagnostic techniques have enabled highly accurate prediction of the relapse risk, and the application of risk-adapted treatments has increased the survival rate in the standard-risk group to nearly 100% in most European nations and North America. Incorporation of state-of-the-art, molecularly targeted agents and novel treatments, including cell and immunotherapy, is further improving outcomes even in the high-risk group. On the other hand, the financial burden of treating children with ALL has increased, imperiling the availability of these diagnostic and treatment strategies to patients in low- and middle-income countries (LMICs). The fundamental treatment strategy, consisting of corticosteroid and classical cytotoxic therapy, has achieved fairly good outcomes and should be feasible in LMICs as well. The present review will discuss the history of developmental therapeutics for childhood ALL in various countries through an extensive literature review with the aim of proposing a model for a treatment backbone for pediatric ALL. The discussion will hopefully benefit LMICs and be useful as a base for future clinical trials of novel treatments.

Background: The PedsQL 3.0 Cancer Module is a widely used instrument to measure pediatric cancer specific health-related quality of life (HRQOL) for children aged 2 to 18 years. We developed the Japanese version of the PedsQL Cancer Module and investigated its reliability and validity among Japanese children and their parents. Methods: Participants were 212 children with cancer and 253 of their parents. Reliability was determined by internal consistency using Cronbach's coefficient alpha and test-retest reliability using intra-class correlation coefficient (ICC). Validity was assessed through factor validity, convergent and discriminant validity, concurrent validity, and clinical validity. Factor validity was examined by exploratory factor analysis. Convergent and discriminant validity were examined by multitrait scaling analysis. Concurrent validity was assessed using Spearman's correlation coefficients between the Cancer Module and Generic Core Scales, and the comparison of the scores of child self-reports with those of other self-rating depression scales for children. Clinical validity was assessed by comparing the on- and off- treatment scores using Kruskal-Wallis and Mann-Whitney U tests. Results: Cronbach's coefficient alpha was over 0.70 for the total scale and over 0.60 for each subscale by age except for the 'pain and hurt' subscale for children aged 5 to 7 years. For test-retest reliability, the ICC exceeded 0.70 for the total scale for each age. Exploratory factor analysis demonstrated sufficient factorial validity. Multitrait scaling analysis showed high success rates. Strong correlations were found between the reports by children and their parents, and the scores of the Cancer Module and the Generic Core Scales except for 'treatment anxiety' subscales for child reports. The Depression Self-Rating Scale for Children (DSRS-C) scores were significantly correlated with emotional domains and the total score of the cancer module. Children who had been off treatment over 12 months demonstrated significantly higher scores than those on treatment. Conclusions: The results demonstrate the reliability and validity of the Japanese version of the PedsQL Cancer Module among Japanese children.

Retinoids are vitamin A derivatives and include trans-retinoic acid, isotretinoin, tamibarotene, and bexarotene, all of which are currently available for clinical use. The clinical development of retinoid therapy for neuroblastoma has a history spanning more than four decades. The most promising agent is isotretinoin, which can contribute to improving event-free survival in patients with high-risk neuroblastoma by approximately 10% when administered over six months as maintenance therapy. Although isotretinoin is regarded as an essential component in the standard clinical management of high-risk neuroblastoma, its use for this purpose in the US and EU is off-label. To promote isotretinoin use in Japan as a treatment for neuroblastoma, our clinical research team is planning to launch an investigator-initiated, registration-directed clinical trial. The present review article discusses the basic science behind retinoid therapy, pre-clinical/clinical evidence on neuroblastoma, the concept of the proposed clinical trial, and prospects for this therapy.

PURPOSE: The JCCG ALL-B12 clinical trial aimed to evaluate the effectiveness of unvalidated treatment phases for pediatric ALL and develop a safety-focused treatment framework. PATIENTS AND METHODS: Patients age 1-19 years with newly diagnosed B-ALL were enrolled in this study. These patients were stratified into standard-risk (SR), intermediate-risk (IR), and high-risk (HR) groups. Randomized comparisons assessed the effectiveness of vincristine (VCR)/dexamethasone pulses in the SR group, evaluated the effects of L-asparaginase (ASP) intensification in the IR group, and compared standard consolidation including block-type treatment with experimental consolidation with high-dose methotrexate (HD-MTX) intensified with VCR and ASP in the HR group. RESULTS: Of 1,936 patients enrolled, 1,804 were eligible for the experimental treatment. The overall 5-year event-free survival and overall survival rates were 85.2% (95% CI, 83.5 to 86.8) and 94.3% (95% CI, 93.1 to 95.3), respectively. The cumulative incidence of relapse and postremission nonrelapse mortality was 13.2% (95% CI, 11.6 to 14.8) and 0.6% (95% CI, 0.3 to 1.0), respectively. Random assignment in the SR group showed no significant benefit from pulse therapy. In the IR group, ASP intensification had limited effects. In the HR group, standard block therapy and HD-MTX yielded equivalent outcomes. CONCLUSION: The ALL-B12 trial achieved favorable outcomes in a nationwide cohort by stratifying treatment on the basis of risk and balancing treatment intensity. This study not only demonstrated that existing standard of care can be further refined but also indicated that improvement in outcomes with intensified chemotherapy has reached a plateau.

Tumor-treating fields (TTFields) are alternating electric fields applied continuously to the brain by attaching two-pair arrays on the scalp. Although TTFields therapy has demonstrated efficacy against supratentorial glioblastoma (GBM) in adults, its safety and efficacy in children have not been confirmed. Despite differences in the genetic etiology of the adult and pediatric forms of GBM, both have certain clinical behaviors in common, allowing us to test TTFields therapy in pediatric GBM. Recently, several, pediatric case-series using TTFields therapy have been published, and a few, prospective, pediatric studies are ongoing. Because GBMs are extremely rare in pediatric patients, where they comprise a wide variety of genetic subtypes, these pediatric studies are feasibility studies targeting various types of malignant brain tumor. Although they are important for confirming the safety and feasibility of TTFields therapy in the pediatric population, confirming its efficacy against each type of pediatric brain tumor, including the GBM, is difficult. Our clinical research team, therefore, planned an investigator-initiated clinical trial targeting pediatric supratentorial GBMs (as in adults) with the aim of expanding regulatory approval of TTFields therapy for pediatric GBM treatment based on safety and exploratory efficacy data in combination with the accumulated evidence on adult GBMs.

Objectives: Adverse events (AEs) represent an important cause of morbidity and mortality for pediatric inpatients; however, reports on their epidemiology in pediatrics, especially outside Western countries, are scarce. We investigated the incidence and nature of AEs in pediatric inpatients in Japan. Methods: Trained pediatrician and pediatric nurses reviewed all medical documents of 1126 pediatric inpatients in 2 tertiary care teaching hospitals in Japan, and potential incidents were collected with patients’ characteristics. Age was categorized into 6 groups (neonates, infants, preschoolers, school-aged children, teenagers, and over-aged pediatric patients), and medical care when potential incidents occurred was classified into drug, operation, procedure/examinations, nursing, management, and judgment. Physician reviewers independently evaluated all collected incidents into AEs, potential AEs, medical errors, and exclusions and assessed their severity and preventability. Results: A total of 1126 patients with 12,624 patient-days were enrolled, and 953 AEs, with an incidence of 76 (95% confidence interval, 71–80) per 1000 patient-days, were identified. Preventable AEs accounted for 23% (218/953) of AEs. The incidence of AEs tended to decrease with increasing age. The proportion of AEs that were preventable was highest in neonates (40%), and this proportion decreased as children aged. Both judgment and management-related AEs were considered preventable AEs, and judgment-related AEs were more severe AEs than no-judgment–related AEs; 43% were life-threatening. Conclusions: Adverse events were common in Japanese pediatric inpatients, and their preventability and severity varied considerably by age category and medical care. Further investigation is needed to address which strategies might most improve pediatric patient safety.