Inherited bone marrow failure syndromes (IBMFSs) are a heterogeneous group of hematological disorders characterized by impaired hematopoietic cell proliferation, differentiation, and various external malformations. IBMFSs also serve as cancer and leukemia predisposition syndromes, with a high risk of developing myelodysplastic syndrome or acute myeloid leukemia and, in some cases, solid tumors. IBMFSs account for 10–20% of childhood bone marrow failures, with Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome being the most common diseases. Differentiating IBMFSs from acquired bone marrow failures such as aplastic anemia is crucial for determining the appropriate treatment, including hematopoietic cell transplantation (HCT). IBMFS diagnosis relies on hematological examination, family history assessment, identification of specific external surface malformations, and disease-specific screening. With advancements in genetic analysis, many causative genes have been identified, facilitating the comprehensive genetic analysis and differential diagnosis of IBMFS. Allogeneic hematopoietic stem cell transplantation is a promising treatment option for addressing bone marrow disorders in patients with IBMFS. However, it is essential to note that HCT does not improve non-hematologic pathologies and may increase the risk of secondary malignancies due to inherited cancer predisposition. Therefore, careful consideration of the graft donor selection and determination of the conditioning regimen are necessary. Additionally, monitoring the late effects of HCT and age-related complications in patients with IBMFS is important to provide appropriate counseling, surveillance, and treatment.

A pediatric malignancy is a representative “rare cancer”, with a yearly incidence of only 2,000. Therefore, it is reasonable to consolidate clinical expertise in “centers of excellence” where pediatric patients can be treated appropriately. Acute lymphoblastic leukemia is the most common pediatric malignancy, and there is little disparity in treatment outcomes between facilities because of the remarkable progress in treatment, making it a representative disease for which standardization is important. Thus, while consolidation is generally necessary for pediatric malignancies, standardization is particularly important in certain cases. In the Kyushu and Okinawa regions, cooperation between facilities in each prefecture and Kyushu University Hospital as a core hospital has been established. A facility can become a Japanese pediatric hematology and oncology specialist training facility via two routes: becoming an affiliate of Kyushu University Hospital or becoming an independent parent facility, for which certified instructors in pediatric hematology and oncology and certified surgeons for pediatric malignancies are required. Furthermore, a certain number of new patients with pediatric malignancy annually is necessary. There are only two independent facilities in the Kyushu and Okinawa regions, each able to discuss cases that are difficult to deal with and share information through monthly web conferencing systems. There are no difficulties in daily practice, although the successful training of certified instructors and surgeons is necessary to increase the number of independent facilities for the management of pediatric malignancies.

Pediatric cancer treatment is gradually getting centralized. This is also true for solid tumor management. Pediatric surgeons play a remarkable role in the treatment of solid tumors. The Ministry of Health, Labor, and Welfare has designated pediatric cancer Base Hospitals and affiliated hospitals. The Base Hospitals seem to be satisfied with pediatric surgeons in terms of their quality and numbers, however, the affiliated hospitals do not. This raises concerns about regional disparities in pediatric solid tumor treatment. For pediatric surgeons, acquiring pediatric cancer treatment certification is not easy, and there is a discrepancy between the ideal, which the Ministry depicts, and the reality. The author raise issues related to centralization through the distribution of pediatric surgeons. Pediatric surgical services should be centralized in the core hospitals in every region. Creating an organization including abundant surgeons with specialties is the key to centralization and equalization on the treatment of childhood cancer.

The clinical practice for pediatric brain tumors in Japan is undergoing considerable changes. Historically, radiotherapy has been the mainstay of brain tumor treatment, with chemotherapy playing an ancillary role. However, owing to the limitations of intensified radiotherapy and the occurrence of late comorbidities, there has been a shift toward a multidisciplinary approach that includes chemotherapy. Numerous clinical trials aimed at optimizing treatment are currently being conducted in Japan and internationally. Effective collaboration among various specialists is crucial for optimizing this multidisciplinary approach. With the establishment of the Japan Childhood Cancer Group (JCCG), the infrastructure for advanced multidisciplinary treatment in multi-institutional settings has been developed. Consequently, several clinical trials have been launched in rapid succession, including the EPN1501 trial for ependymoma, MB19 trial for medulloblastoma, AT20 trial for atypical teratoid rhabdoid tumors, and CNSGCT2021 trial for germ cell tumors of the central nervous system. All these trials aim to optimize treatment to minimize late complications associated with radiotherapy while maintaining treatment intensity by chemotherapy. In addition, the development of molecular targeted agents, particularly for gliomas, is advancing. The approval of NTRK inhibitors, followed by BRAF and MEK inhibitors, has broadened treatment options. The importance of early and aggressive genetic testing has increased. In future, it will be essential to determine how to effectively integrate novel targeted therapies with conventional treatments. In this paper, we provide an overview of the current status and prospects for optimizing the multidisciplinary treatment of pediatric brain tumors.

The number of reports on the importance of genetic predisposition in pediatric thrombosis is increasing. We defined early-onset thrombophilia (EOT) as thrombosis occurring at ≤20 years of age associated with a genetic predisposition. An EOT registry, comprising cases diagnosed by genetic testing and obtained from a literature review, was established to identify the genetic and clinical characteristics of EOT. Anticoagulant activity levels can detect EOT with high sensitivity using an age-dependent reference range. However, the specificity is low, and genetic testing is necessary for the diagnosis of EOT. In neonates and infants, protein C (PC) deficiency, which causes purpura fulminans and/or intracranial thrombosis/hemorrhage, is common, and protein S/antithrombin (AT) deficiency increases with age. These results indicate the need for the prophylaxis and treatment of thrombosis based on age and genetic predisposition. Neonatal PC-deficient patients with PROC biallelic variants experience severe neurological sequelae, including visual impairment. Novel management strategies from early diagnosis and fetal treatment to postnatal treatment are required to reduce neurological sequelae. Genetic testing of the parents of patients with EOT (32 families) revealed a de novo variant in only one family with PC deficiency. In three families (two with PC deficiency and one with AT deficiency), the mother and neonate developed thrombosis concurrently, indicating the possibility of screening for genetic predisposition to protect them from thrombosis.

With the recent development of next-generation sequencing technology, causative genes of relatively rare vascular anomalies have been identified. Vascular anomalies, which are classified as vascular tumors and malformations, are caused by genetic abnormalities in the RAS/MAPK or PI3K/AKT/mTOR signaling pathways and are called RASopathies and PIKopathies, respectively. Somatic activating mutations, such as GNAQ and GNA11 in congenital hemangiomas, GNA14 in tufted hemangiomas, TEK (TIE2) in venous malformations, GNAQ in capillary malformations, PIK3CA in lymphatic malformations, and MAP2K1 in arteriovenous malformations, have been reported as causative genes. We performed next-generation sequencing analysis of formalin-fixed, paraffin-embedded tissue specimens from patients with Klippel-Trenaunay syndrome. We detected PIK3CA missense mutations in 86% of the cases. The identification of common causative genes in vascular anomalies associated with cancer is expanding the application of anticancer drugs through drug repositioning.

Hematopoietic stem cell transplantation (HSCT) for pediatric and adult hematological diseases significantly differ regarding target diseases and complications. Although new technologies and drugs have emerged for prevention, diagnosis, and treatment in adults, caution is needed in applying these technologies to children. This study presents examples of pediatric hematological cancer treatments and provides recent information on the diagnosis and treatment of VOD/SOS, a severe post-HSCT complication. Moreover, it discusses updates on the prevention and treatment of GVHD by introducing new treatments, such as ibrutinib and ruxolitinib. Furthermore, long-term health management and follow-up of post-HSCT patients are crucial, with tools available to support these aspects.

Disseminated intravascular coagulation (DIC) is an etiology of microangiopathic hemolytic anemia characterized by microthrombus formation due to persistent coagulation activation in the presence of specific underlying diseases. If therapeutic interventions are not promptly implemented, consumptive reduction of coagulation/fibrinolysis (C/F)-related factors and thrombocytopenia can be fatal. The degree of fibrinolysis varies with the underlying disease. For instance, in acute promyelocytic leukemia, the degree of fibrinolysis exceeds coagulation, leading to bleeding symptoms (enhanced-fibrinolysis DIC), whereas in sepsis, the suppression of fibrinolysis results in a procoagulant state, causing frequent microthromboses and organ damage (suppressed-fibrinolysis DIC). In clinical practice, accurate assessment of the balance between C/F potential is challenging, which is compounded by the existence of varying diagnostic criteria for DIC. The Japanese Ministry Health and Welfare DIC scoring system, which has been most employed in Japan, has adequate specificity while exhibiting insufficient sensitivity for the early diagnosis of DIC. The Japanese Association for Acute Medicine’s acute-stage DIC diagnostic criteria are the next most used. The International Society on Thrombosis and Haemostasis’s DIC diagnostic criteria also exhibit issues with early diagnosis. The Japanese Society on Thrombosis and Hemostasis published the diagnostic criteria for DIC in its 2017 edition. The Guideline of Diagnosis and Clinical Management for Neonatal DIC 2016 has been implemented for neonates. Although the primary focus is on treating the underlying disease, an awareness of the balance between C/F potential is crucial in DIC treatment, as a precise understanding of this balance can lead to effective treatment.

Supportive care is essential in pediatric oncology. It significantly enhances the quality of life for both patients and their families by alleviating and preventing physical, emotional, and psychological distress caused by the cancer itself, as well as by diagnostic procedures, interventions, and treatments. This care extends beyond therapeutic interventions, by adopting a holistic approach that incorporates a multidisciplinary medical framework alongside educational and awareness initiatives.

However, compared with adult populations, there is limited evidence on supportive care practices for pediatric cancer patients. In Japan, clinical research focusing on supportive care in pediatric oncology remains nascent. A recent survey by the Supportive Care Committee of the Japan Children’s Cancer Group highlighted a combination of evidence-based supportive care practices and those tailored to institutional norms, some of which were excessively intensive. Conversely, supportive care was often administered within a fragile framework owing to staff shortages, leading to inadequate multidisciplinary collaboration.

This review consolidates current evidence on critical aspects of supportive care, such as infection control and chemotherapy-induced nausea and vomiting, for pediatric cancer patients. Additionally, it explores the significance of interdisciplinary collaboration in supportive care delivery, including the utilization of sedation and analgesia during painful procedures, oral care, and nutritional management. Finally, strategies for enhancing evidence generation in supportive care for pediatric oncology are discussed.

To improve outcomes in childhood cancer, it is important to evaluate the safety and efficacy of treatments through clinical trials. The Japan Children’s Cancer Group has been conducting late-phase clinical trials to establish standards of care. However, compared to Europe and the United States, which have requirements for pediatric drug development, Japan lacks an adequate framework for early-phase clinical trials and pediatric drug development, leading to the delay of drug approval. Participation in international clinical trials could be an option to avoid this delay, although there are some challenges. This article shows the results of the retrospective survey about the implementation of academic international clinical trials in childhood cancer patients and describes the preparation for participation in the Interfant-21 trial. In addition, by referencing clinical research support systems in Europe and the United States, frameworks to facilitate participation in international trials have been discussed.

The Japanese Society for Pediatric Hematology/Oncology established a committee to support the activities of female physicians in 2020 during the coronavirus pandemic with the aim of enabling all members of society to be active in a gender-free manner. One of the activities of this committee is to organize a symposium to support the empowerment of female physicians at annual meetings. The third symposium was held at the 65th annual meeting. Dr. Takao Deguchi and Dr. Takako Miyamura were the chairpersons, and four female physicians presented their experiences as symposium speakers.

Several factors likely drive the recent emphasis on supporting decision-making in medicine, including the focus on self-determination in healthcare, rising complexity in societal demands on healthcare, and challenges healthcare professionals face. At this core, we cannot choose to be born, to avoid illness, or to escape death. Therefore, in healthcare, what is it we genuinely decide when we make a “decision”? Can medicine help individuals maintain dignity and shape their identity? What do we, as health professionals, commit to with terms such as patients’ dignity, best interests, respect for autonomy, and suffering? This study will explore the decision-making process for children in healthcare by examining discussions in adult medicine. Rather than accepting ambiguous concepts at face value, we will focus on the actual lives of children, recognizing them as unique individuals. Through continuous, fact-based discussions grounded in authentic experiences, we aim to promote a society that respects all lives equally, free from judgments based on existing values.

Although the approaches to obtaining informed consent in clinical research have diversified, a method for long-term follow-up research of childhood cancer survivors remains to be established. Typically, legal guardians provide consent for children’s participation in childhood cancer research. However, for long-term follow-up research, obtaining informed consent directly from the participants once they have reached the age of autonomous decision-making is essential. Achieving this necessitates considering a method that enables obtaining non-face-to-face informed consent. Specifically, implementing “informed consent by electronic method,” as outlined in the Ethical Guidelines for Medical and Health Research Involving Human Subjects, would be desirable, depending on the research content and security strength of the electronic system used. Moreover, obtaining informed consent through electronic data capture entails the management of personal information within an electronic system, thereby necessitating robust information security infrastructure. In this context, we developed a “Safe Server” to ensure data security. To address the abovementioned issues, we, “the Long-term Follow-up Matsumoto Group,” are in the process of establishing a nationwide long-term follow-up system as part of the Comprehensive Research Project for the Promotion of Cancer Control. In this paper, we propose an approach for obtaining informed consent and describe the information security system that underpins this proposal.

Inotuzumab ozogamicin (InO) was approved in Japan in March 2024 to treat pediatric patients with CD22-positive relapsed/refractory B-cell precursor acute lymphoblastic leukemia (R/R BCP-ALL). In this study, we investigated the efficacy and safety of InO in nine patients with R/R BCP-ALL. Eight patients in non-remission and one patient in remission received InO as bridging therapy. Of the eight patients, five achieved complete remission (CR), whereas three were refractory. Of the five patients with CR, the disease eventually relapsed in four; however, InO was re-administered in two of these patients, and both patients achieved CR again. Nonhematologic toxicities of common terminology criteria for adverse events grade ≥3 included febrile neutropenia, infusion reaction, elevated aspartate transaminase/alanine aminotransferase, and sinusoidal obstruction syndrome in one patient. InO is an effective treatment option for remission induction therapy in patients with CD22-positive R/R BCP-ALL. Re-administration of InO may be effective, particularly in patients with prior InO administration.

Hemophilia A (HA) is a representative hemorrhagic disorder caused by X-linked recessive inheritance. In Japan, there are >5,000 patients with HA, mostly men. Conversely, heterozygous females with pathogenic alleles who lack hemorrhagic symptoms were recognized as “hemophilia carriers.” Recent studies have demonstrated that “hemophilia carriers” can be symptomatic and those who have significantly decreased coagulation activity should be referred as women/girls with hemophilia. Here, we report the case of a girl with non-severe HA without inhibitors that was effectively treated with emicizumab. A limited number of Japanese women/girls with HA have been reported and were mainly treated with factor VIII concentrates. Since “hemophilia carriers” have varying degrees of hemorrhagic tendencies, individualized management should be considered. More experience and evaluation of emicizumab use in “hemophilia carriers” are needed.

Myeloid sarcoma (MS), a rare extramedullary manifestation of acute myeloid leukemia (AML), may present concurrently with, precede, or occur during bone marrow lesion relapse. We report the case of a patient with acute abdomen associated with primary appendiceal pathology that developed during remission induction therapy. The patient was a 2-year-old boy who relapsed eight months after completing chemotherapy for AML (M5 subtype). The patient underwent surgical resection and was diagnosed with appendiceal MS. Bone marrow examination after chemotherapy indicated remission, and the patient underwent bone marrow transplantation. An extramedullary lesion was detected in the patient’s intestinal tract 5 months after transplantation. Appendiceal MS is rare even in adults. Herein, we report the youngest pediatric patient with appendiceal MS in Japan to date.

Antithrombin (AT) deficiency is an inherited form of thrombophilia. Little is known about the efficacy of direct oral anticoagulants (DOACs) in children with AT deficiency. Information on the primary prevention of thromboembolism using DOACs are limited. We present patients with AT deficiency and their family members across five generations. A 7-year-old boy, weighing 19.4 kg, had 51% AT activity with a splice variant of SERPINC1. During the trial with 15 mg/day rivaroxaban, the shortened coagulation time was compared to that of healthy individuals. The maximum coagulation acceleration after rivaroxaban administration was lower than that in healthy individuals. Thrombin generation is elevated during COVID-19 and that under administration was lower than that of healthy individuals, providing reference information for the dosage of rivaroxaban. Accumulation of pediatric cases is required to establish an optimal dosage of DOACs for the prophylaxis and treatment of thrombophilia.

Despite significant improvements in the overall survival of pediatric patients with Langerhans cell histiocytosis (LCH), relapse is common, and a truly effective treatment for relapsed LCH has not yet been established. Hydroxycarbamide has been widely used for many years; however, thus far, few pediatric patients with LCH have received hydroxycarbamide therapy. Here, we present cases of two pediatric patients with relapsed LCH who received hydroxycarbamide with or without methotrexate therapy. In these two cases, the therapeutic response to hydroxycarbamide with or without methotrexate therapy was comparable to that to the conventional treatment for relapsed LCH in pediatric patients. No serious adverse events were observed, and dose reduction was unnecessary. Such an oral regimen reduces the physical and mental stress associated with painful injections in children, in addition to reducing the number of clinic visits and medical costs. It provides great benefits to pediatric patients with LCH who are likely to have repeat recurrences.