I was the first president of the Japanese Society of Pediatric Hematology and Oncology (JSPHO), between 2012 and 2014. During this period, all JSPHO board members made a concerted effort regarding financial reconstruction and office relocation, the introduction of a specialist education system to provide more appropriate medicine for hematology and oncology patients throughout Japan, the promotion of physician-initiated clinical studies regarding childhood cancer together with JCCG, collaboration studies with other Asian countries for globalization, the promotion of the study of fetal and adolescent and young adult (AYA) medicine, and the construction of a system of long-term follow-up for cancer survivors.

Despite several unfinished themes, we believe most were successfully achieved during my tenure.

For integrating academic societies, the main themes for vision consideration were membership composition, specialist system, relationship with study groups, pediatric oncology education, and internationalization efforts. The importance of aiming for an organization that emphasizes total care, like the International Society of Pediatric Oncology, was recognized as the organization’s philosophy. During my tenure as president, the reforms necessary to achieve this vision were performed. These include restructuring the organization from a specified non-profit organization to a general incorporated association, publication of a textbook for pediatric hematology and oncology, holding educational seminars for doctors involved in pediatric hematology and oncology through lectures and case presentations in seven regional blocks nationwide, establishment of the liaison council for pediatric, adolescent, and young adult cancer-related academic societies, conclusion of a contract to make the Pediatric Blood & Cancer an official journal, conclusion of an academic/researcher exchange business agreement with the Korean Society of Pediatric Hematology and Oncology, the e-mail distribution of JSPHO news, and the online journalization of the Journal of JSPHO. It is hoped that long-term follow-up and transitional medical care systems will be developed in the future and that international collaboration will be further strengthened. Furthermore, in light of the accelerated practical application of telemedicine due to the evolution of ICT, it is hoped that academic activities will focus on a new era of pediatric hematology and oncology, including a review of the medical system that considers the QOL of patients and their families.

I served as the third president of the Japan Society of Pediatric Hematology and Oncology (JSPHO). On the 10th anniversary of its establishment, I would like to thank the members who cooperated with the JSPHO activities when I was president and leave a record of this era as described in the following three points, including my messages for future direction.

The first is the growth of the Society itself, including the merger of the Japanese Society of Pediatric Oncology and the Japanese Society of Japan Pediatric Hematology, the change from an NPO corporation to a general incorporated association, the operation of a training project commissioned by the Ministry of Health, Labour, and Welfare, especially the Lifetime Care and Support for Child, Adolescent, and Young Adult Cancer Survivors (LCAS), and the process of approval as a subcommittee of the Japan Association of Medical Science. In this regard, I would like to proceed the stabilization of the economic foundation of academic societies and create a system to involve doctors and medical staff from multiple fields. Furthermore, the JSPHO should become an academic society to create guidelines and guidance for pediatric cancers and hematology.

The second was the establishment of a pediatric cancer control committee in the Cancer Control Promotion Plan (Pediatric Cancer Expert Committee) and of pediatric cancer core hospitals in collaboration with related academic societies. In this regard, it is necessary to promote human resource development in the pediatric hematology/oncology field, collaboration with JCCG, patient and family associations, and multidisciplinary academic societies, especially in fields other than pediatrics and pediatric surgery.

The third is cooperation with other countries. This involved an exchange of the Korean Society of Pediatric Hematology and Cancer (KSPHO), a joint symposium at mutual academic societies, and adoption of Pediatric Blood and Cancer (PBC) as the official journal of JSPHO. In the future, I would like to promote academic activities as the center of Asian countries and collaboration with Europe and the United States, and then to grow further as an academic society with a presence outside Japan.

It was an honor to serve as the 4th Chairman of the Board of the Japanese Society for Pediatric Hematology/Oncology (JSPHO) from June 2018 to June 2020. I would like to highlight three of the most memorable events during my term: 1) Revision of the structure between the Board and the Committees for better performance, 2) continuing the “Lifetime Care and Support for Child, Adolescent, and Young Adult Cancer Survivors” project commissioned by the Ministry of Health, Labor and Welfare, including devising the seminar system, and 3) the 60th Annual Meeting 2018 in Kyoto, for which I served as the president of the meeting, as well as the chairman of the society.

The slogan of the meeting was “Children First! To a Brighter Future for the World: Lessons from Children Fighting Intractable Diseases.” A description of this concept has been retained in a section of our website, thanks to my successor, Dr. Shoichi Ohga, present Chairman of the Board of JSPHO.

I would also like to express my sincere gratitude to Tsugumichi Koshinaga, the president of the 64th Annual Meeting, and Masahiro Hirayama, the Editor-in-Chief of the Journal of the Japanese Society and all the people involved for their kind support in planning this program and this article on the journal.

Last but not least, I would like to congratulate the JSPHO on its 10th anniversary.

Cancer immunotherapy has emerged as the fourth major treatment method for various cancers and has become a central component in patient care. Its approach involves targeting tumor cells by activating immune cells already present in the body or using genetically modified immune cells. Significantly, if it elicits responses targeted at tumor cells while sparing normal cells, it can serve as an excellent treatment modality with fewer adverse effects. Over time, several cancer immunotherapy methods have been developed and applied in clinical settings, including immune checkpoint inhibitors, genetically modified T cells, and cancer vaccines. However, their effectiveness has shown limitations, prompting continuous efforts to improve anti-tumor immune responses. Recently, researchers have made progress in developing cancer immunotherapies for pediatric cancers, particularly pediatric solid tumors. While these treatments are still immature compared to those for adult cancers, ongoing scientific and medical research is generating more evidence, making them potentially promising strategies for managing intractable and recurrent cancers in children. This study aims to provide an overview and discussion of current status and future prospects of cancer immunotherapies, focusing on pediatric cancers.

Hematologists should consider t(17;19)-positive ALL because patients with this rare type of common ALL have extremely poor prognosis when administered standard chemotherapy, even in combination with stem cell transplantation. TCF3::HLF (E2A-HLF) fusion transcription factor, produced by 17;19 translocation, protects leukemic cells from apoptosis, causing the extremely refractory nature of ALL harboring this translocation despite a relatively low WBC count at diagnosis. Clinicians must pay attention to the chromosomal analysis report because patients with 17;19 translocation are frequently misdiagnosed as having a normal karyotype. TCF3::HLF aberrantly induces the expression of many genes, including those encoding apoptosis regulators, LMO2, CD33, and ANNEXIN II. Consequently, more than half the patients with t(17;19)-ALL express CD33 on the surface of leukemic cells and have hypercalcemia or coagulopathy, all of which are relatively rare in common ALL. Thus, RT-PCR to detect TCF3::HLF chimeric transcript should be performed for patients with common ALL with normal karyotype, particularly for those who have the above-mentioned clinical features. Patients positive for TCF3::HLF chimeric fusion transcript should undergo powerful cutting-edge treatments, including CAR-T cell therapy and blinatumomab.

Translocation 17;19 is a rare type of translocation in childhood acute lymphoblastic leukemia (ALL), and the prognosis of t(17;19)-positive ALL is extremely poor. Both primary samples and cell lines showed a significant resistance to vincristine and cytarabine in vitro. Indeed, high levels of minimal residual disease are commonly observed after remission induction therapy, and early relapses are frequently confirmed during or after early consolidation therapy with low-dose cytarabine. Besides the TCF3::HLF fusion gene, the TCF4::HLF and TCF3::TEF fusion genes are also identified in childhood ALL. The anti-apoptotic activity of TCF3::HLF itself is directly associated with a poor prognosis. Additionally, the overexpression of P-glycoprotein and mutations in the RAS pathway genes are background factors for poor prognosis. Of note, hypercalcemia is developed at diagnosis in approximately 40% of cases. Accompanying osteolytic bone lesions may disrupt the hematopoietic environment and result in a delayed recovery of normal hematopoiesis after chemotherapy, which is another background for refractoriness. In the graft-versus-leukemia effect after allogeneic hematopoietic stem cell transplantation, donor-derived cytotoxic T cells induce cell death of the targeted leukemia cells via cytotoxic factors, including TRAIL. In t(17;19)-positive ALL, TCF3::HLF upregulates gene expression levels of the death receptors for TRAIL; as a result, leukemia cells are highly sensitive to the anti-leukemic activities of TRAIL. Furthermore, TRAIL mediates the anti-leukemic activities of blinatumomab and CAR-T cell therapy. Recently, the prognosis of patients with t(17;19)-positive ALL has been improving due to allogeneic hematopoietic stem cell transplantation after control of the residual disease using blinatumomab or CAR-T cell therapy.

A five-year-old boy with B-precursor acute lymphoblastic leukemia relapsed after early intensified therapy and was found to be positive for TCF3::HLF. The administration of blinatumomab (BLI) resulted in a second remission, but osteolytic lesions appeared in areas such as the skull and clavicle. While remission in the bone marrow continued, lymphoblastic cells were found in a computed tomography-guided clavicle biopsy stamp specimen, and the patient was diagnosed with a second relapse. Anti-CD19 chimeric antigen receptor T-cell (CD19-CAR-T) therapy was planned, and lymphocyte apheresis was promptly performed. Inotuzumab ozogamicin was ineffective as a bridging therapy, but chemotherapy based on vincristine, prednisolone, and L-asparaginase was effective, followed by CD19-CAR-T therapy. The bone marrow was in remission at two months after CD19-CAR-T administration when a related HLA half-matched peripheral blood stem cell transplantation was performed as a consolidation therapy. An evaluation of extramedullary lesions, including osteolytic lesions, was performed using whole-body magnetic resonance imaging, which was useful for evaluating temporal changes and detecting new lesions. BLI and CD19-CAR-T therapy were effective in controlling the disease in this case.

Germ cell tumors (GCTs) are a group of tumors that arise not only from the gonads but also from various organs, mainly around the midline. The histological subtypes differ depending on the age and the primary site, as do the response to the treatment. As the GCTs treated by pediatric oncologists are highly diverse, they must evaluate the tumor based on the appropriate tumor staging system and find the best option for the patient. Typical tumor markers include lactate dehydrogenase, alfa-fetoprotein, and human chorionic gonadotropin. Recently, serum miRNAs (miR371-373, miR302-367 clusters) have been reported to impact the treatment of GCTs significantly.

In 2015, the Malignant Germ Cell International Consortium (MaGIC) proposed a new pediatric extracranial germ cell tumor risk stratification with age ≥11 years, extragonadal origin, and Stage IV as risk factors. Based on this new stratification, a clinical trial, AGCT1531, is now underway worldwide to evaluate the usefulness of active surveillance for the low-risk group and carboplatin for the standard-risk group. In addition to the above-mentioned serum miRNA, analysis of genetic information of tumors is also gradually accumulating knowledge, and stratification based on these is expected in the future. The prognosis of GCTs has improved the most among the malignant tumors during the 20th century. However, the standard therapy for immature teratomas or high-risk patients has not yet been established, and we must develop new treatments. Furthermore, GCTs are rare, and tackling them with multi-disciplinary collaboration like MaGIC in Japan is necessary.

The Platelet Committee of the Japanese Society of Pediatric Hematology/Oncology published the Guidelines for Childhood Immune Thrombocytopenia in 2022. These comprehensive and practical guidelines were developed according to the recommendations of the Medical Information Distribution Service in Japan. They are as follows: 1) idiopathic thrombocytopenic purpura is converted to immune thrombocytopenia (ITP); 2) thrombocytopenia is defined as a platelet count of less than 100×10³/μL; 3) the traditional classification of “acute” and “chronic” ITP is divided into the new nomenclatures of “newly diagnosed”, “persistent”, and “chronic”; and 4) the modified Buchanan’s bleeding score is adopted to stratify bleeding risks. However, we recommend that the management of children with ITP be based on their bleeding scores, regardless of their platelet counts. Additionally, we suggest that the choice of treatment strategy accommodates each patient’s values and preferences, quality of life, and accessibility to health care. We equally recommend corticosteroids and intravenous immunoglobulin as first-line treatments. Thrombopoietin-receptor agonists and rituximab should be used as second-line treatments. Furthermore, it is proposed that splenectomies be considered with caution. The following clinical questions and recommendations were included: vaccination-related ITP, eradication of Helicobacter pylori, post-splenectomy control of infections, vaccination during or after treatments with corticosteroids/rituximab, management of newborn infants born from mothers with ITP, emergency management of severe bleeding, and management of daily activities. We have clearly described the differences in the pathogenesis and ITP treatments between children and adults, and we hope that these guidelines will contribute to the management of childhood ITP and ultimately improve patient well-being.

Idiopathic thrombosis developing in childhood has increased in incidence because of advances in medical technology and improved disease recognition. The genetic predisposition of pediatric thrombosis (thrombophilia) primarily consists of protein C, protein S, and antithrombin deficiencies. Evidence of thrombolysis, specific replacement, or anticoagulant therapy for these disorders does not exist. Moreover, trials for direct oral anticoagulants and specific replacement therapy for non-hereditary idiopathic thrombosis have also not proceeded. Hereditary thrombosis occurring in childhood leads to poor outcomes. Repetitive purpura fulminans require life-long anticoagulant therapy; however, a specific treatment strategy does not exist. Pregnancy and delivery of unaffected carriers could trigger maternal and infant thrombosis. Herein, we established a research project, “Establishment of a clinical algorithm for idiopathic thrombosis that develops from neonates to adults,” supported by the Japan Agency for Medical Research and Development in 2020–2022. This study proposed thrombosis underlying genetic predispositions as early-onset thrombosis/thrombophilia (EOT) and aimed to present a clinical guideline for EOT. In this symposium, we showed the progress of the EOT registry and the guideline.

Many pediatric tumors arising in the abdominopelvic region are radiosensitive, and radiotherapy plays an important role in multidisciplinary treatment. Proton beam therapy, which demonstrates better dose distribution compared with photon radiotherapy, is expected to reduce radiation toxicities. However, irradiating the entire tumor sufficiently when organs are at risk, such as those in the gastrointestinal tract and the kidneys, adjacent to the tumor is difficult even for proton beam therapy. In that case, surgical spacer placement, which provides a space between the tumor and the organ at risk, is useful to increase the radiation dose to the tumor. Moreover, as organs in children are developing and radiosensitive, tolerance doses are lower than those of adults, and a possibility of growth disorder exists in children even if the irradiated is lower than the tolerance dose. Therefore, we should consider the as low as reasonably achievable (ALARA) principle when treating pediatric patients.

A bioabsorbable spacer has been developed, and after a successful clinical trial, the product was released as Neskeep^® in June 2019. Moreover, the product was covered by public health insurance together with surgical spacer placement in December 2019. As childhood cancer survivors have a longer life expectancy than adult survivors, the bioabsorbable spacer is more useful. The non-absorbable spacer remains in the patient’s body for a lifetime and can cause functional and/or growth disorders of the organs along with infection. Removal of the non-absorbable spacer is occasionally performed; however, the burden on the patient increases.

Pediatric renal tumors, with Wilms tumor (nephroblastoma) being most prevalent, hold significant clinical importance. This article aims to provide a succinct overview of the historical progression in clinical studies, treatment milestones achieved so far, and contemporary treatment strategies, primarily focusing on Wilms tumor. Additionally, owing to its didactic nature, this paper incorporates insightful commentaries and educational lectures accompanying each chapter to enhance its applicability to real-world clinical scenarios. This paper, which presents a brief history of clinical research with practical articles, will help us deepen our understanding of pediatric renal tumors. Although the recently initiated Umbrella protocol holds intricate details that must be perused by study participants, its ongoing implementation promises to propel biological research to new heights. With this, I encourage the utilization of the knowledge herein for effective clinical practice starting from the immediate future.

Cancer remains a leading cause of death in children. A “drug lag” with regard to the introduction of standard therapeutic drugs into the Japanese market has been a long-standing concern, particularly with regard to pediatric solid tumors. Legislation to promote pediatric drug development has been enforced in the United States since 2003, and the “Research to Accelerate Cures and Equity for Children Act” was legislated in 2017. This Act mandates that pharmaceutical companies test agents used for treatment of adult cancers as anticancer agents in children in cases in which a shared molecular target is observed. Since 2017, development of molecular targeted drugs for pediatric cancer has been accelerated in the United States, which has led to a subsequent increase in the lag in Japan, following partial improvement observed previously with regard to therapy of hematological malignancies. The slow progress of pediatric cancer drug development in Japan is attributable to (a) small market size but high burden of development costs and legal obligations (for example, stable drug supply, safety monitoring) for companies, (b) shortage of experienced institutions and human resources for pediatric trials, (c) difficulties in acquisition of research funds owing to limited public budget allocation for investigator-initiated pediatric drug development, and (d) difficulties in recruitment of patients in trials considering rarity of diseases in this patient population. The existing system is inefficient in promoting pediatric cancer drug development, and a major reform of the model is warranted. Additionally, it is important to establish strategies to facilitate access to these drugs before they are approved for children diagnosed with cancer.

Blinatumomab (BLIN) is a therapeutic option available for CD19-positive relapsed or refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). We retrospectively investigated the efficacy and safety of BLIN based on medical record data of 10 children and young adults admitted to our hospital. Among the 10 patients investigated, nine showed relapse and one had refractory disease. Six of the seven patients in whom immunoglobulin/T-cell receptor polymerase chain reaction documented-minimal residual disease (MRD) primer was detected showed MRD positivity at initiation of BLIN therapy, and five of these patients subsequently achieved MRD-negative status after the second BLIN cycle. The aforementioned seven patients and one patient in whom PCR-MRD primer was not detected achieved morphological complete remission and underwent hematopoietic cell transplantation. Fever was the only BLIN therapy-induced nonhematological adverse event categorized as ≥grade 3 based on the Common Terminology Criteria for Adverse Events system. We conclude that BLIN may be safe and effective in patients with r/r B-ALL.

Inherited thrombocytopenia is a heterogeneous disorder characterized by mutations in various genes. It is often misdiagnosed as chronic immune thrombocytopenia (cITP). A two-year-old boy was admitted to our hospital because of a fever and petechiae. His family had four individuals with thrombocytopenia, and a genetic analysis of his father conducted 20 years ago showed no abnormalities. A blood examination of the patient showed a platelet count of 16×10⁹/L and anti-cardiolipin antibodies of 12 U/mL. His follow-up platelet counts transiently increased to 396×10⁹/L on the 6th day, even without specific treatment. However, subsequent platelet counts ranged between 50×10⁹ and 60×10⁹/L. Genetic analyses of the patient and his parents performed at 3y11m after approval of the ethics committee showed ANKRD26 c.-134 G>A variant in both the patient and his father. Finally, we diagnosed the boy with Thrombocytopenia 2 (THC2). Diagnosing Inherited thrombocytopenia can be challenging, particularly as it is often mistaken for ITP. Therefore, precise identification requires a thorough evaluation, including genetic analysis.