Forty years have passed since I began clinical research on childhood cancer as a pediatric surgeon. Through these years, I have met wonderful professors and participated in clinical research, academic activities, group study, and JCCG activities. I would like to look back on the path that I have taken and send messages to young doctors. I started clinically for childhood cancer at Osaka University in 1981 and met Dr. Keisei Kawa. Multidisciplinary treatment for solid tumors under Dr. Kawa’s leadership was started in 1985 and delayed local therapy for advanced neuroblastoma with Dr. Junichi Hara was started in 1993. I was in charge of the First Department of Surgery, Nihon University from 1998 and met Dr. Hideo Mugishima, who also promoted delayed local therapy. As vice president of the Japanese Society of Pediatric Cancer in 2002, and as president in 2004, I tried to integrate this society with the Japanese Society of Pediatric Hematology. From 2003 to 2015, I served as the chairman of the Japan Wilms Tumor Study (JWiTS) with the support of Dr. Tsugumichi Koshinaga, Dr. Junichi Hata, and Dr. Yasuhiko Kaneko. I served as vice chairman of the preparatory committee for JCCG (Chair Shuki Mizutani) in 2013 and as vice president and steering committee chairman of JCCG from 2014 to 2018. Finally, I would like to send two messages to young doctors. The first is “Taho Shoin” (Masahiro Yasuoka). If you are in contact with a good person, you will get good results without realizing it. The second is “Futoh” (Sanzo Genzyo). It is important to show the spirit of not returning the east if you do not reach India, and once you stand up, it is important to carry through to the end without bending your will.

Acute myeloid leukemia (AML) with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2), which accounts for 1–2% of AML cases, has a poor prognosis. A high expression level of EVI1 is known to be one of its feature, but the mechanism underlying this abnormal expression is as yet not known. Our group has established a transgenic mouse model (3q21q26-EVI1 mice) that recapitulates the inverted allele between 3q21 and 3q26 by linking two bacterial artificial chromosome (BAC) clones. By utilizing the 3q21q26-EVI1 mice, we found that the far upstream enhancer of GATA2 (G2DHE) activates EVI1 expression, leading to the development of leukemia. Furthermore, by comparing leukemogenesis in 3q21q26-EVI1 mice with that in mice with combined 3q21q26-EVI1 and GATA2 heterozygous deletion, we examined how a reduced GATA2 expression modulates EVI1-driven leukemogenesis. As a result, we demonstrated that in 3q21q26 leukemia in addition to the induction of EVI1 expression by the GATA2 enhancer, the mechanism of GATA2 haploinsufficiency is also important in leukemogenesis. The 3q21q26-EVI1 mice are the only mouse model that successfully recapitulates the increase in the number of megakaryocytes and platelets, which is a characteristic phenotype of human 3q21q26 leukemia. Mouse models established using BAC linking technology may also be a useful tool for elucidating the pathogenesis of other types of leukemia with chromosomal aberrations.

Acute myeloid leukemia (AML) is a clinically and biologically heterogeneous disease. Currently, genome analysis using next-generation sequencing has made remarkable progress with comprehensive and fusion gene analyses and expression analyses. However, there are still cases in which prognostic factors cannot be identified, and the identification of novel biomarkers in AML is urgently required. An association of DNA methylation patterns and molecular biological abnormalities with prognosis has been reported in adult AML. A few studies have also demonstrated this association in pediatric AML. We investigated the relationships among DNA methylation patterns and their clinical significance, molecular biological background, and prognosis in 64 pediatric patients with AML. Our findings suggest that DNA methylation levels at specific CpG sites indicate genetic alterations and gene expression patterns of pediatric patients with AML. In this paper, we reviewed the importance of DNA methylation analysis in AML, focusing on previous DNA methylation studies on AML and our research.

Cancer cells utilize different metabolic characteristics of normal cells to promote their growth with the production of energy and the synthesis of nucleic acids, amino acids, and lipids. Contrary to previous understanding that cancer cells uniformly prefer to utilize aerobic glycolysis, advances in analysis technology such as comprehensive metabolomic analysis and metabolic flux analysis have revealed that different cancer types, genetic mutations, and even cancer stem cells have different metabolic characteristics. The energy production mechanisms of leukemic cells for survival and proliferation are also being elucidated. Although the glycolytic system is essential for leukemogenesis, LSC survival reportedly depends on ATP production of OXPHOS in mitochondria, and chemotherapy resistance is correlated with OXPHOS activity. We are analyzing the energy metabolism of refractory leukemia with an extracellular flux analyzer and identifying novel therapeutic targets with the combination of metabolome and transcriptome analyses. The main mechanism of the combination of venetoclax and azacitidine is to suppress OXPHOS by decreasing glutathione levels in LSCs and inhibiting amino acid metabolism, and AML metabolism analysis can identify drug sensitivity and synergistic combination drugs. In the future, the integration of metabolic analysis with further analysis techniques such as single-cell metabolomics and lipidome analysis is promising for the development of novel therapeutic agents targeting leukemia energy metabolism.

The five-year survival rate for children with acute lymphoblastic leukemia (ALL) has improved to more than 90% in high-income countries. However, about 15% of the patients experience relapse, and relapsed ALL is resistant to commonly used multidrug chemotherapy. Although the prognosis of relapsed ALL patients with standard- and intermediate-risk features has been considerably improved, patients with high-risk features still have poor remission rates with all regimens applied so far. Thus, there is still potential for improvement of survival rates. The advent of novel immunotherapies, such as blinatumomab, inotuzumab, and chimeric antigen receptor-T cell therapies, has revolutionized the therapeutic landscape in the treatment of relapsed/refractory B-ALL, but the optimization of these treatments is needed. On the basis of our experience in relapsed ALL treatment, we discuss the future strategy of treatment and management of relapsed ALL in childhood.

Orbital rhabdomyosarcoma and retinoblastoma are representative tumors in ocular oncology. Rhabdomyosarcoma within the orbit is classified as stage 1, which has a favorable prognosis. Most cases are diagnosed by incisional biopsy, and systemic chemotherapy with radiotherapy is the standard treatment strategy instead of wide resection. The eyeball is preserved and practical visual acuity is expected in most cases. Retinoblastoma is the most common intraocular tumor in childhood. Eyes with small tumors are treated with local therapies such as laser therapy, cryotherapy, or plaque radiotherapy. Eye cancers in the advanced stage are treated with initial systemic chemotherapy, followed by selective ophthalmic arterial injection and local therapies. Eyes with refractory tumors or complications are removed. If histopathological risk factors are detected, such as optic nerve invasion or choroidal invasion, adjuvant chemotherapy will be necessary. Retinoblastoma is derived from the RB1 mutation, and other actionable mutations are rarely detected, so the merit of genetic panel testing is very limited.

The classification of intracranial ependymomas became segmented with the introduction of WHO2021 classification. The annual incidence of pediatric (age 15 years or younger) intracranial ependymomas in Japan is estimated to be about 60 cases. It is not easy to establish the best treatment strategy for this rare disease on the basis of WHO2021 classification. Only one peer-reviewed paper on the guideline for this disease was published by the European Association of Neuro-Oncology (EANO) in 2018. This guideline emphasized the importance of radiation therapy immediately after surgical resection in children older than 12 months. In Japan, the guideline was published on the web page of the Japan Society for Neuro-Oncology in September 2021. In this guideline, radiation therapy was not strongly recommended for patients under 3 years of age. At this point, two multicenter randomized clinical trials, which are primarily intended to determine the efficacy of chemotherapy for this disease, are in progress. In years to come, the following points should be resolved: (1) further improvement of treatment results after total resection of the tumor, (2) verification of efficacy of chemotherapy, (3) determination of the most suitable definitive age of initiation into radiation, and (4) selection of an appropriate treatment strategy depending on molecular classification.

The number of children with novel coronavirus infection (COVID-19) is small and their symptoms are milder than those of adults. Information on pediatric cancer patients with COVID-19 has remained limited. In this review, we summarize information on adult and pediatric cancer patients by focusing on overseas meta-analyses. The mortality rates of adult cancer patients with COVID-19 are reported to be 14–28% for solid tumors and 34% for hematological tumors, and advanced age, being male, and comorbidities are risk factors for severe COVID-19. In particular, the mortality rate has been reported to exceed 50% for patients under myelosuppression, and nosocomial infection should be carefully monitored. Although the prognosis of COVID-19 in children with cancer is better than that of adult cancer patients, treatment is often postponed or 4–10% of severe cases require ICU admission. Moreover, a mortality rate of 0–3% has been reported for patients under strong myelosuppression even in high-income countries. COVID-19 vaccines are widely used for adult cancer patients, but the seroconversion rates are lower in patients with hematological tumors (0.62) than in those with solid tumors (0.95) and in the general population. It is assumed that pediatric and young adult patients with cancers will become suitable candidates for active vaccination in the future. Health anxiety related to COVID-19 tends to be higher in childhood cancer survivors, especially with severe late effects, than in adult cancer survivors, so it is desirable to apply some distance-delivered care. At present, most of the clinical guidelines for childhood cancers are not based on sufficient evidence, but rather on the consensus recommendations of experts.

Radical surgery for malignant bone and soft-tissue tumors involves resection of the tumor as well as the adjacent bones, muscles, joints, and ligaments. In the case of tumor resection in which joint preservation is difficult, prosthesis is often used in reconstruction for function preservation and appearance. Late complications of reconstruction surgery include loosening of prosthesis and late infection. These complications occur frequently and are refractory to treatment. Considering the long treatment duration, the activities of daily living are substantially affected in children and young adults when late complications occur. Herein, we report two cases in which we treated refractory deep infection 10 or more years after tumor resection and prosthetic reconstruction for malignant bone and soft-tissue tumor and address issues related to such late complications.

The needs of home-based care for children with incurable cancer are expanding; however, there are problems owing to the rarity of the disease and the treatment progress, which makes it more difficult for children and their families to make decisions. From January to March 2018, we performed a survey among home-visit nursing stations in Kanagawa Prefecture to clarify the difficulties and needs of visiting nurses who take care of children with terminal-stage cancer and their families, and to consider the ideal medical collaboration to support better home-based care. Responses were obtained from 148 of the 395 stations. Twenty-four stations (16.2%) had experiences of visiting children with terminal-stage cancer. Regardless of their experiences, the visiting nurses reported having difficulty in assessing the symptoms of children at the end of life and in providing psychological care for these children and their families. They reported the necessity of a collaborative system with medical institutions and obtaining knowledge regarding childhood disease. Limited experiences in visiting children with cancer may be associated with their feeling of having difficulties in understanding children and their families, and in offering knowledge and skills specific for the child’s disease. To build a good relationship and support children and their families in a short period, the visiting nurses need to collaborate with medical institutions. To guarantee quality of life and a good home-based care for children and their families, a collaborative system and information sharing between the visiting nurses and medical institutions before and after patients’ transition to home-based care are necessary.

We report the case of a 5-year-old boy with an anaplastic large cell lymphoma (ALCL) associated with central nervous system infiltration, which entered remission after chemotherapy, intrathecal injection, and irradiation. At admission, the lymphadenopathy extended from his left neck to the supraclavicular fossa. MRI showed a tumor in the brain, and the cerebrospinal fluid cytology was positive for tumor cells. PET-CT images revealed many abnormal accumulations in the bone and in the subcutaneous and intracranial masses (in addition to the primary lesion). The bone marrow examination showed normal findings. The pathological findings of a cervical lymph node biopsy led to a diagnosis of ALK-positive ALCL, stage IV. The patient received chemotherapy with the ALCL99 protocol regimen and a regimen containing high doses of methotrexate and cytarabine. Ten intrathecal injections were administered; after the third injection, the cytology became negative. Craniospinal irradiation (18 Gy in 12 fractions) was also performed. He has remained in remission for 51 months after diagnosis and 31 months after the end of treatment.

To diagnose central nervous system (CNS) infiltration in leukemia, the presence of blasts in the cerebrospinal fluid must be confirmed. If the presence of blasts cannot be determined, it is difficult to diagnose CNS infiltration. A nine-month-old girl was diagnosed as having acute myeloid leukemia M5a with KMT2A (MLL) rearrangement. This cannot be detected by partner genes without CNS infiltration. She then received standard chemotherapy. She developed recurrent vomiting and convulsions and was suspected to have a relapse of CNS infiltration five months after discharge. However, it could not be diagnosed by cerebrospinal fluid cytopathology. We carried out KMT2A fluorescence in situ hybridization (FISH) and flow cytometry (FCM) analysis, which showed the proliferation of monoclonal monocytic cells with KMT2A split signals. On the basis of these findings, we were able to make a definitive diagnosis. Monocytic leukemia blasts are known to migrate into tissues, differentiate, and proliferate. FISH and/or FCM analysis may be useful when it is difficult to diagnose a relapse of CNS infiltration by cytopathology.

A 15-year-old girl was pointed out to have pancytopenia by a nearby doctor, and she was diagnosed as having refractory cytopenia of childhood (RCC) at the age of 5. She was independent from transfusion and had no severe infection or bleeding in her clinical course. She had neither facial abnormality nor deformity, although she was short of stature (–2.4 SD). Consecutive G-banding analysis of bone marrow cells suggested trisomy 21 in some proportion of analyzed cells. Therefore, at the age of 15, interphase FISH analysis of chromosome 21 in buccal smear cells was performed, and she was diagnosed as having mosaicism trisomy 21. The cases of mosaicism trisomy 21 do not necessarily have the typical phenotype of trisomy 21, although there has been no reported case of mosaicism trisomy 21 complicated by RCC. There is a possibility that mosaicism trisomy 21 is undiagnosed in some patients with RCC. Therefore, mosaicism trisomy 21 should be examined in RCC patients with short stature and possible karyotype.

Beta-blocker eye drops are used to treat ocular hypertension caused by steroids; however, little is known about the risk of hypoglycemia as a side effect. Here, we report the case of a one-year-old girl treated with carteolol hydrochloride ophthalmic solution for ocular hypertension resulting from long-term use of steroids to treat Langerhans cell histiocytosis (LCH). She developed severe hypoglycemia with impaired consciousness and convulsions when she suffered from infectious gastroenteritis. The blocking of the β-receptor by the carteolol hydrochloride ophthalmic solution was considered a major cause of her severe hypoglycemia. β-blockers have a high receptor-binding ability due to their pharmacological properties as receptor blockers. Moreover, their use may lead to side effects regardless of the plasma drug concentration. Therefore, caution is required when prescribing eye drops even at small quantities.

A three-year-old boy presented with abdominal pain. Computed tomography (CT) revealed a left renal tumor and bilateral lung metastases. Tumor biopsy revealed clear cell sarcoma of the kidney. Bone scans showed no abnormal radiotracer accumulation. The patient received preoperative chemotherapy according to the Japan Wilms Study Group protocol regimen. CT showed shrinkage of the primary lesion and lung metastases after the chemotherapy. Subsequently, a left nephrectomy was performed. Postoperatively, chemotherapy was continued in combination with radiotherapy, reducing the size and number of lung metastases. However, CT showed new osteosclerotic lesions in the vertebral body, ilium, and femur. Moreover, bone scans revealed abnormal radiotracer accumulation in the vertebral body. We initially suspected bone metastases; however, lung metastasis shrinkage suggested a flare phenomenon—an increased radiotracer accumulation despite a good response to the treatment. Therefore, the same chemotherapy was continued. A follow-up bone scan revealed a decreased intensity of vertebral body The flare phenomenon should be considered when there is an inconsistency between clinical and bone scan findings.

Although stage 4S neuroblastoma has a favorable prognosis in most patients, a few patients with massive hepatomegaly require critical management. Here we describe the case of a two-month-old girl with stage 4S neuroblastoma. She already had symptoms of lower leg edema, respiratory distress resulting from abdominal compartment syndrome, and coagulopathy at the initial visit. Abdominal radiotherapy that consisted of a fraction dose of 1.5 Gy for three days was initiated immediately after liver biopsy. On day 3 of radiotherapy, she developed respiratory failure, acute renal failure, and liver failure due to tumor lysis syndrome in addition to abdominal compartment syndrome. Hence, extracorporeal membrane oxygenation (ECMO) and continuous hemodiafiltration (CHDF) were initiated to stabilize her condition until the effect of radiation improved her abdominal compartment syndrome. Her respiratory status gradually improved and ECMO was successfully discontinued; CHDF was also discontinued after the recovery of kidney function. We conclude that radiotherapy is effective for abdominal compartment syndrome in stage 4S neuroblastoma patients, and ECMO can be an effective rescue choice in a patient with respiratory failure.