Medicine and medical research are interrelated, with medical challenges providing a basis for research and development, which ultimately leads to advances in medicine. Particularly, in the fields of hematology and oncology, medical treatment and research are closely linked; perspectives on medical treatment accelerate research, and the research findings, in turn, advance medical treatment. However, misconceptions related to research have resulted in a shift away from research. Advances in genome analysis technology, particularly next-generation sequencing, have led to the spread of data-driven research, from which hypotheses can be derived after results are obtained. Such large-scale analyses have led to the production of novel results that, otherwise, would not have been observed previously. However, this approach has already been applied to several diseases and is almost saturated, and issues that cannot be elucidated using such an approach remain unresolved. Translational research that focuses on clinical outliers is, therefore, an option to solve this challenge. Hypothesis- and curiosity-driven research, which begins with observations in clinical practice, can lead to new discoveries by taking advantage of advanced technologies. Hence, it is essential to believe in one’s potential and share the joy of learning to aim for new breakthroughs through intellectual curiosity and imagination.

In Japan, cancer is the leading cause of death, accounting for approximately 380,000 deaths annually. Although treatment methods for cancer are advancing, therapy-resistant clones remain, resulting in a poor prognosis. The presence of therapy-resistant cancer stem cells (CSCs) is a major cause of recurrence. However, the detection of these cells is difficult, and no detection method for CSCs has been established clinically. Recently, the authors found that if cancer cells were placed on a hydrogel, cancer cell spheroids were rapidly formed within 24 h, and the expression of stem cell markers, such as SOX2, increased, leading to the creation of CSCs. This phenomenon is called “hydrogel activated reprogramming (HARP),” meaning that reprogramming is induced in cancer cells by the gel. Eventually, we expect to discover new CSC markers based on the HARP phenomenon and apply them in the development of CSC therapeutics.

Radiotherapy comprises of curative and palliative treatments. Palliative radiotherapy is an effective treatment method for reducing various symptoms caused by cancer lesions and improving quality of life. All cancer symptoms are indicated for radiotherapy, especially painful bone metastases, metastatic spinal cord compression, tumor hemorrhage, airway narrowing, and brain metastases. Furthermore, radiotherapy should be considered for painful bone metastases, regardless of the STEP of drug therapy. Palliative irradiation is not widely used in Japan; therefore, it is necessary to promote and educate the public about the benefits of palliative radiotherapy. In 2019, the JASTRO established the Palliative Radiotherapy Committee to promote and educate the public and patients regarding palliative irradiation. To promote palliative irradiation, it is necessary to: 1) collaborate with medical institutions in the region regarding the diagnosis and treatment of bone metastases, 2) collaborate with multiple disciplines within the hospital, and 3) educate the public on palliative radiotherapy. Furthermore, we have introduced activities to promote palliative irradiation.

Palliative radiation therapy is an effective way to maintain the quality of life of patients with cancer. There are fewer opportunities to provide palliative radiation therapy in pediatric patients with cancer than in adults, and the indications for palliative radiation therapy vary greatly among institutions. The natural history of cancer and the treatment strategies differ between pediatric and adult cancers. Some indications and goals of palliative radiation therapy in pediatric cancer patients are unique. An insufficient understanding of the characteristics of palliative radiation therapy and the absence of established treatment guidelines based on these characteristics are among the factors that limit palliative radiation therapy for pediatric cancers. Moreover, this system poses a barrier to facilitating pediatric palliative radiation therapy. Furthermore, insufficient understanding among patients and referring physicians hinders the provision of palliative radiation therapy for pediatric cancers. Addressing these issues, including palliative radiation therapy, will help improve the palliative care for pediatric patients with cancer.

Lung metastasis is a critical factor that influences hepatoblastoma prognosis. Herein, an aggressive metastasectomy was performed for 22 patients, and when the primary tumor could be treated with conventional liver resection, there was no need to change the surgical method due to the presence of lung metastases. However, for some patients, liver transplantation must be considered for complete resection of the primary tumor. We encountered eight patients with lung metastases who received liver transplants, five of whom succumbed to the disease. The causes of death included uncontrolled pulmonary and extrapulmonary metastases. Although simple comparison was not possible, 14 of 18 patients with lung metastases who underwent liver resection but not transplantation and attained positive outcomes. Controlling metastasis and recurrence in the transplant cohort was difficult. Although there have been several reports on the outcomes of liver transplantation in patients with lung metastases, no treatment conclusions have been reached. Therefore, our policy is to perform extreme hepatectomy to avoid liver transplantation, if safety can be ensured. For instance, for a right lobe tumor with a tumor thrombus in the main trunk of the portal vein, right lobectomy should be performed using a meso-Rex shunt, and if the tumor is in contact with the residual hepatic vein, ICG fluorescence should be used to remove the tumor from the vein wall.

Hematopoietic stem cell transplantation (HSCT) has been used for inherited metabolic diseases (IMDs) since the early 1980s and has been attempted for various types of these diseases during the first two decades. In recent years, indications for HSCT have included mucopolysaccharidosis (MPS-I, MPS-II, and MPS-IVA), adrenoleukodystrophy, metachromatic leukodystrophy, Krabbe disease, and I-cell disease. HSCT for IMDs is considered a high-risk treatment because of the increased incidence of engraftment failure and transplant-related complications such as graft-versus-host disease. However, it has become progressively safer owing to the selection of appropriate transplant sources by advancing human leukocyte antigen -typing technology, world-standard transplant preparation regimens, including intravenous busulfan, and improvements in supportive care for infectious diseases. In future, newborn mass screening will include some IMDs; therefore, it will be necessary to establish a transplant network. There is a need to establish collaboration between metabolic disorders specialists and transplant specialists.

Pediatric cancer is a rare disease with an expected decrease in prevalence due to the declining birth rate. Thus, consolidating medical resources for high-quality medical care is essential. Conversely, discussing the equalization of care based on local medical conditions is equally critical. Several pediatric cancer patients have young parents and siblings, and receiving treatment in distant areas is challenging for economic or emotional reasons. Thus, treatment in the area where they live is strongly desired. Centralizing pediatric oncology care poses concerns of patients being overly concentrated in center hospitals and not being provided with high-level care that is typically offered only at center hospitals. This creates a widened disparity in care between patients due to fewer young doctors becoming specialists as there will be fewer opportunities for pediatric oncology care in the community. Hence, consolidating medical resources to strengthen cooperation between centers and partner hospitals is vital. Focusing medical resources on online information exchange, central pathology, diagnostic imaging, and long-term follow-up system establishment using telemedicine will protect regional hospitals. It will thereby holistically improve and maintain the level of pediatric oncology care in Japan.

The authors present a case of ependymoma, which is a rare surgical disease. To determine the significance of ependymoma surgery, we evaluated the frequency of repeat ependymoma surgeries proportionate to that of 235 neuroepithelial tumors/341 surgeries performed by the first author between 1997 and 2023. Repeat ependymoma surgeries accounted for 10/92 (11%) cases with WHO grades 2 and 3 (32 of 136 repeat surgeries [24%]). Ependymoma surgery to achieve local tumor control is of great significance. The treatment of pediatric/adolescent and young adult brain tumors aims to prolong the prognosis and reduce the treatment side effects. Therefore, neurosurgeons must maximize tumor resection while minimizing surgical morbidity, if surgery contributes to local tumor control.

Despite improving clinical outcomes of pediatric acute lymphoblastic leukemia (ALL), those of pediatric acute myeloid leukemia (AML) remain around 70%. This is partly due to a lack of understanding of the genetic background of pediatric AML, appropriate risk stratification, or molecule-targeted therapies. To fill the knowledge gap, we integrated transcriptional and genetic analyses of a large cohort of pediatric AML, identifying two pediatric AML-specific alterations, tandem duplications of UBTF (UBTF-TD) and GDXY insertions of CBFB (CBFB-GDXY), which were mutually exclusive with other class-defining alterations. UBTF-TDs are associated with FLT3-ITD and WT1 mutations, HOXB expression, and poor prognosis, while CBFB-GDXYs were associated with CBF-AML-like expression patterns. These data suggest that these alterations define new molecular subtypes of pediatric AML.

These alterations, as well as other pediatric-specific alterations such as CBFA2A3::GLIS2 or PICALM::MLLT10, are not covered by the current WHO classifications (WHO^5th), resulting in 30% of pediatric AML categorized as “acute myeloid leukemia with other defined genetic alterations” or “acute myeloid leukemia, myelodysplasia-related”. We then systematically categorized 889 pediatric AMLs into 23 molecular categories that are mutually distinct from one another, covering 91.4% of the cohort. These molecular categories were associated with clinical outcomes using two independent cohorts, establishing a prognostic framework based on molecular categories and minimal residual disease. Together, these studies provide the basis for future classification of pediatric AML and treatment strategies.

Recent advance in next-generation sequencing technologies has revolutionized the understanding of the genomic basis of leukemia. With whole genome and transcriptome sequencing, most acute lymphoblastic leukemia (ALL) can be defined by genomic subtypes based on the alterations in driver/disease-causing genes. However, most of these subtype-defining alterations are found in the coding regions, and our understanding of non-coding regions is still lacking. Nowadays, the increasing number of facts support the importance of non-coding alterations that may result in epigenomic changes, including putative enhancer generation and chromatin conformation changes. In this review, I will introduce recent development of genomics in leukemia focusing on 3D genomics with HiChIP technology from our recent publications on B-ALL and T/Myeloid Mixed phenotype acute leukemia (MPAL).

CDX2/UBTF B-ALL is the recently defined subtype characterized by unique expression profiles and two concurrent alterations, UBTF::ATXN7L3 fusion and deletion of FLT3 region resulting in deregulation of CDX2. H3K27ac HiChIP showed the mechanism to activate CDX2 by the deletion of FLT3 regions with the use of an adjacent enhancer.

BCL11B-driven leukemia is the subtype of immature leukemia that can transcend lineages, found in early T-cell precursor ALL, MPAL, and acute myeloid leukemia. Aberrant expression of BCL11B in the hematopoietic progenitors is caused by translocations of BCL11B region and active enhancers, or focal amplification to generate neo-enhancer, both of which showed abnormal loops by H3K27ac HiChIP.

The survival rate for pediatric cancer exceeds 80% in high-income countries, yet it drops to below 30% in low- and middle-income countries. Most pediatric cancers can be treated using generic medications, surgery, and radiation, all of which are accessible in these countries. The World Health Organization (WHO) aims to increase the global survival rate to over 60% by 2030. In 2018, Japan Heart, an international NGO, established a 40-bed pediatric medical center in Cambodia, offering free treatment for pediatric cancers, especially solid tumors. With the support of Japanese pediatric surgical teams and pathologists, local surgical techniques have been enhanced, leading to treatments based on more accurate diagnoses. Remote consultations with Japanese experts, initiated in 2020, have improved treatment planning and contributed to the development of local medical staff. There are ongoing efforts to collaborate with other pediatric cancer treatment facilities in Cambodia to improve national survival rates. In 2022, the center treated approximately 100 pediatric cancer patients annually, achieving a survival rate of over 50%. A new hospital is planned to open in 2025 in the suburbs of Phnom Penh to serve patients from Cambodia and neighboring countries such as Myanmar and Laos.

Participating in this NGO, which uses Japan’s expertise to bridge the pediatric cancer survival gap internationally, has brought immense personal satisfaction and joy. These efforts also facilitate the career development of physicians, including young doctors.

Among the therapeutic agents used in pediatric patients with hematologic malignancies, L-asparaginase and glucocorticoid are known to cause hypertriglyceridemia. Thrombosis and osteonecrosis are complications associated with hypertriglyceridemia during acute lymphoblastic leukemia (ALL) treatment. However, the risk factors for hypertriglyceridemia and their association with each complication remain unclear. This retrospective analysis investigated the risk factors for hypertriglyceridemia during ALL and lymphoma treatment at our hospital and its effects on patients during and after treatment.

Of the 138 eligible patients, 38 (27.5%) developed grade 4 hypertriglyceridemia during treatment according to the Common Terminology Criteria for Adverse Events version 5. Old age at diagnosis was a risk factor for hypertriglyceridemia. However, hypertriglyceridemia and the type of glucocorticoid or L-asparaginase dose were not associated. A median follow-up of 6 years and 2 months revealed that 14 patients had osteonecrosis, 10 had drug-induced diabetes, three had pancreatitis, and one had thrombosis. All patients experienced grade ≥3 hypertriglyceridemia during treatment. The median times to onset of complications after diagnosis of osteonecrosis, drug-induced diabetes, pancreatitis, and thrombosis were 28, 11, 1, and 6 months, respectively. Multivariate analysis revealed that peak triglyceride levels during hypertriglyceridemia was not correlated with pancreatitis and thrombosis but was a significant independent risk factor for osteonecrosis and drug-induced diabetes.

The results indicated that high triglyceride levels during treatment may contribute to the development of osteonecrosis and drug-induced diabetes. Therefore, close monitoring of patients with high triglyceride levels may aid in the early detection and treatment of these complications.

Hemostatic management is important in the perioperative period of patients with hemophilia A (HA). Herein, we report the case of a patient with HA who successfully underwent open-heart surgery for atrial septal defects under cardiopulmonary bypass (CPB) by monitoring the effects of heparin and factor VIII (FVIII) replacement therapy using rotational thromboelastometry (ROTEM^®) with the in vitro addition of heparinase. The patient was a 9-year-old boy with moderate HA who underwent open-heart surgery for atrial septal defects using CPB. Perioperative management included a preoperative bolus (52 U/kg) and continuous infusion (4.6 U/kg/hr) of rurioctocog alfa. Post-infusion, the patient’s FVIII activity was elevated to 101.8%, and clot time/clot formation time (CT/CFT) of ROTEM^® was 904/456 s. During the CPB management, anticoagulation with heparin was performed, and CT/CFT of heparinase-added ROTEM^® was 606/299 s and FVIII activity was 78.2%, indicating that FVIII replacement treatment sufficiently improved coagulation potential and adequately controlled perioperative hemostasis.

It is difficult to decide whether to perform surgery or observe patients with non-high-risk image‑defined risk factors (IDRF) after treatment. Case 1 is an 8-year-old boy with a neuroblastoma originating from the left adrenal gland. Case 2 is a 5-year-old girl with a ganglioneuroblastoma originating from the right retroperitoneum. There was no metastasis, N-MYC was not amplified, and IDRF remained positive after treatment in either case. The tumor grew, and surgery was performed. In case 1, the tumor was completely resected with the left kidney; however, the tumor was only partially resected because of hemorrhage in case 2, and the patient died of ventilation failure due to rapid tumor regrowth. In patients with non-high-risk IDRF after treatment, surgery aimed at total resection, allowing combined resection of other organs if the tumor regrows in cases in which the tumor shrinks after treatment, and should be performed as part of the initial treatment in cases in which the tumor does not shrink.

We report a case of Philadelphia chromosome-positive acute lymphocytic leukemia (Ph⁺ALL) wherein the BCR::ABL1 chimeric gene was also detected in peripheral blood neutrophils at initial presentation. The patient, a 9-year-old boy, was diagnosed with minor BCR::ABL1 chimeric gene-positive Ph⁺ALL. The peripheral blood neutrophil FISH test was also positive for BCR::ABL1. Treatment commenced with multi-agent chemotherapy involving dasatinib, resulting in molecular remission. However, a molecular relapse occurred following intensified therapy, prompting the consideration of hematopoietic stem cell transplantation. In recent studies, the BCR::ABL1 chimeric gene has been detected in cell populations beyond B lymphoblasts, and the concept of “CML-Like Ph⁺ALL” with a background of chronic myeloid leukemia (CML)-like disease has been proposed. The pathogenesis of this case was considered to be consistent with this disease concept. The pathogenesis and prognosis of CML-like Ph⁺ALL remain unclear, and further accumulation of evidence and analysis of similar cases is needed to establish optimal treatment.

Autoimmune hemolytic anemia (AIHA) in children is rare, and only a few cases have been reported regarding its long-term clinical course. Here, we present a case of AIHA that developed into prolactinoma 11 years after diagnosis in a 4-year-old girl with severe anemia. The hemoglobin level was dependent on the corticosteroid dosage, but partial improvement was achieved with rituximab treatment. Mild anemia persisted, but steroid treatment was completed 1.5 years after diagnosis. Blood tests revealed low complement levels and positive autoantibodies six years after diagnosis. The classification criteria for systemic lupus erythematosus was met 11 years after diagnosis, but had no clinical symptoms besides hemolytic anemia. Additionally, she had irregular menstruation and elevated serum prolactin levels, and a prolactinoma was diagnosed on magnetic resonance imaging. Currently, no case report has described prolactinoma in AIHA. Conversely, prolactinoma is observed in 20–30% of patients with systemic lupus erythematosus and associated with autoimmune diseases.

Tumor lysis syndrome (TLS) is recognized as an oncologic emergency because of its potential to cause electrolyte imbalance and multiple organ failure. Renal replacement therapy (RRT) is implemented in patients with advanced TLS that are resistant to medications. RRT is categorized as a renal indication for the direct treatment of AKI and non-renal indication for the removal of substances involved in the disease. We report the case of a 14-year-old boy with B-cell precursor acute lymphoblastic leukemia who developed rapid hyperphosphatemia and secondary hypocalcemia leading to arrhythmia and hypotension due to TLS, four days after initiating steroid therapy. By introducing RRT to correct electrocyte balance, leukemia treatment was continued safely. Hyperphosphatemia associated with TLS and secondary hypocalcemia can cause cardiac dysfunction; thus, RRT should be considered, even in the absence of renal dysfunction.