The third-term Basic Plan to Promote Cancer Control Programs, formulated in 2018 in Japan, includes cancer control measures for adolescents and young adults (AYAs). The annual number of new cancer cases among AYAs (aged 15–39 years) is approximately 20,000, which is higher than the number of childhood cancer cases (approximately 2,000), but accounts for only about 2% of the total (approximately 1 million cases) in Japan. The distribution of cancer types varies according to the age group of the AYAs, with a mix of childhood and adult cancers, including leukemia in those aged 15–19 years; ovarian, testicular, and thyroid cancers in those in their 20s; and breast, cervical, and digestive cancers in those in their 30s. In addition, AYA patients need support in various aspects, including not only cancer treatment but also oncofertility care, education, and employment. Despite the smaller number of AYA patients than of adult patients, the treatment and management of AYA patients are not well centralized, making it difficult for medical staff to accumulate experience in treatment and consultation support. Since the 2000s, cancer control measures for AYAs have been actively pursued in Europe and the USA. In Japan, research and support initiatives have started in recent years, but specific measures at the community and hospital levels are still required. In Osaka Prefecture, the Osaka Cancer Association established the Child/AYA subcommittee in 2011. This subcommittee conducts surveys on cancer in AYAs using data from the Osaka Cancer Registry, and it provides information on oncofertility care and support in school attendance of cancer patients. In this article, we review the current status of cancer care in AYAs in Japan and the efforts being made nationally and in Osaka Prefecture.

Medical care for patients with hemophilia has markedly advanced with the development of new therapeutic formulations. As an alternative to conventional plasma-derived coagulation factor concentrates, recombinant coagulation factor preparations, which emerged in the 1990s, became the mainstream, and in the 2000s, recombinant coagulation factor preparations with extended half-lives, in which chemical modifications or alterations were made to the recombinant coagulation factor, were developed one after another. Furthermore, in 2018, a novel antibody preparation administered subcutaneously became available for patients with hemophilia A. Today, treatment options for hemophilia patients are expanding. However, important issues such as the occurrence of inhibitors in hemophilia patients and intracranial hemorrhage during the neonatal period remain unresolved. In particular, the actual situation of hemophilia patients in Japan is still unclear. Therefore, from 2008 to 2020, we conducted a multicenter prospective follow-up study on inhibitor development in 417 newly diagnosed hemophilia patients (hemophilia A, 340, hemophilia B, 77) throughout Japan (Japan Hemophilia Inhibitor Study 2; J-HIS2). In this study, the background characteristics of patients, including genotype of Factor VIII (FVIII) or Factor IX (FIX) gene (F8 or F9), and information on treatment, infusion records, and bleeding status were investigated in detail, along with the occurrence of inhibitors. Regarding F8 variants in hemophilia A patients in Japan, which were revealed for the first time through this study, we found that null variants were a significant risk factor for inhibitor development, as similarly found in previous studies in other countries. On the basis of the final findings of J-HIS 2, which spanned more than 10 years, we report on the current issues in hemophilia care in Japan and discuss the prospects for pediatric hemophilia care in the next decade.

In recent years, hemophilia treatment has undergone a paradigm shift: nonfactor agents can prevent bleeding regardless of the presence of inhibitors, and clinical trials of gene therapy are underway. However, currently available nonfactor agents also require the concomitant use of coagulation factor agents for hemostatic management during breakthrough bleeds or in the perioperative period in patients with hemophilia A, and thrombosis sometimes occurs in some cases with the concomitant use of these agents. Moreover, inhibitors develop in patients with nonsevere hemophilia A, and even patients who do not require prophylaxis therapy suddenly experience difficulty in maintaining hemostasis. Thus, inhibitors remain an important issue in hemophilia care. Immune tolerance induction (ITI) therapy is the only treatment that aims for eradicating inhibitors, and the current status of this therapy in Japan (J-ITI Registry) has been reported. Factors related to the development of inhibitors had also been studied prospectively or retrospectively, mainly in Europe and U.S. In Japan, the J-HIS study has recently shown the relationship between F8 mutations and the risk of inhibitor development in patients with hemophilia A. Basic research on inhibitor development is also being conducted extensively. We hope that the information obtained from these studies will fully help establish a treatment strategy for eradicating inhibitors.

Hemophilia is an X-linked recessive bleeding disorder caused by mutations in the F8 (hemophilia A) or F9 (hemophilia B) gene. Bleeding in hemophiliacs can be treated with the administration of coagulation factor concentrates, whereas patients with severe bleeding require regular replacement therapy with coagulation factor products throughout their life to prevent joint bleeding. Gene therapy is being developed to cure hemophilia as a one-time treatment. The main strategy of gene therapy for hemophilia is the administration of an adeno-associated virus (AAV) vector carrying functional F8 or F9 cDNA. Several clinical trials using AAV vectors showed the maintenance of the plasma coagulation factor for several years following a one-time treatment. Although gene therapy is an extremely attractive treatment alternative for hemophilia, there are still issues to be resolved, including the treatment of the patients with anti-AAV neutralizing antibodies and liver dysfunction after the administration of a high dose of AAV vectors. Long-term observations on the maintenance of therapeutic efficacy and safety after treatment are also required. Gene therapy for hemophilia is expected to be approved in the next few years, but it is important to carefully discuss the efficacy and safety of gene therapy in clinical practice.

Pediatric malignancies are well indicated for proton beam therapy. In Japan, proton beam therapy for pediatric malignancies has been covered by the public health insurance since April 2016. The Kobe Proton Center was established in December 2017 as the first particle therapy center mainly dedicated to pediatric malignancies in Japan. Its strong points are as follows: (1) the building is connected by a bridge to Kobe Children’s Hospital, and concurrent chemotherapy is available, (2) a full-time anesthesiologist in charge of sedation is available, which is indispensable to the irradiation of young children, and (3) the clinic area is further divided into the children’s and adults’ areas to protect immune-compromised children. The Kobe Proton Center has treated the largest number of pediatric patients yearly in Japan since fiscal year 2018. Future issues of proton beam therapy for pediatric malignancies based on the experience of the Kobe Proton Center are as follows. Regarding patient acceptance, a nationwide collaboration system among proton beam therapy centers should be established and operational. Surgical bioabsorbable spacer placement is useful even in pediatric patients, but its safety has not been proved yet, and this method is currently not widely known. In some adolescents and young adults (AYA) patients, proton beam therapy is not covered by the public health insurance; therefore, the Hyogo prefectural government started the exemption system. For pediatric malignances, even patients with metastases can be completely cured, but proton beam therapy for such patients is currently not covered by the public health insurance. Continuous discussions should be warranted.

The Kyoto Prefectural University of Medicine (KPUM) began to provide proton beam therapy (PBT) for childhood cancer in April 2019. The compact proton therapy system that we installed here, manufactured by Hitachi, has some significant characteristics: (i) the system can provide spot-scanning proton beam delivery with a large field size, which can provide craniospinal irradiation adequately, and (ii) it can perform image-guided radiotherapy using kilovoltage X-ray images and cone-beam computed tomography. Our proton center has two separate rooms for treatments, one of which is decorated with beautifully painted pictures on the walls to create a relaxing atmosphere for children undergoing treatment. We also have cooperative work with pediatricians when conducting PBT under sedation, satisfying the requirements of PBT from other hospitals, and so on. From April 2019 to September 2021, the total number of children treated in the center was 34. Among these children, sedation for PBT was necessary on 21 children, and craniospinal irradiation was performed for 5 children. Thus far, we have performed PBT safely and effectively. However it is difficult to conduct more than 4 sessions of PBT with sedation on the same day in our center. Therefore, it is crucial that Japanese proton centers collaborate with each other to meet the various demands for PBT. Herein, I would like to report on the circumstances of the clinical practice and future issues in KPUM.

Although accurate diagnosis is an important aspect of treatment, the diagnosis of pediatric brain tumors is often difficult. The total number of patients with pediatric brain tumors is comparable to that of patients with pediatric leukemia; however, the numbers of patients by tumor types are small and the relevant experience of each institution is limited. Although molecular classification has become essential for the diagnosis and treatment of brain tumors, it is impossible to diagnose them within each institution. Therefore, centralized pathological diagnosis scheme is essential, through which diagnosis is made by several pathologists and molecular diagnosis of medulloblastoma or glioma is also performed. In addition, Comprehensive Genome Profiling, which has been covered by health insurance since 2019, provides meaningful information for patients with brain tumors. However, it is necessary to pay attention to when the examination should be performed, as it can be done only once under health insurance. To detect malignant transformation due to additional genetic abnormalities, it is recommended to test samples at the time of recurrence. However, specific patients including those with infantile glioma with the fusion gene NTRK should be examined at the time of onset of the disease. It has been known that there are cancer predisposition syndromes (e.g., Li-Fraumeni syndrome) among patients with pediatric brain tumors. In recent years, the number of cases identified as having cancer predisposition by cancer genome analysis has increased. Genetic counseling, tests among family members, and subsequent cancer screening plans for patients need to be closely coordinated in collaboration with clinical geneticists.

Safe maximal resection is desirable for pediatric brain tumors. Surgery should be performed with a proper understanding of the role of the extent of resection of the pediatric brain tumor. Medulloblastoma should be removed to the maximum extent with priority given to the preservation of neurological function. It should not be aggressively pursued at the cost of undue morbidity. There is no benefit of resection of residual tumors with sizes less than 1.5 cm². In atypical teratoid/rhabdoid tumors (AT/RTs), gross total resection is also a worthwhile goal and is associated with improved outcomes over those with significant residual disease. Neoadjuvant chemotherapy for AT/RTs might reduce both tumor size and vascularity, which enables maximal tumor resection. In pediatric low-grade gliomas, the goal is to achieve a complete cure by total resection, but priority may be given to the preservation of neurological function. Management based on genetic diagnosis is considered in pediatric low-grade gliomas. In pediatric brain tumor surgery, technological developments in various fields such as neuronavigation, tractography, functional magnetic resonance imaging (MRI) and intraoperative neuromonitoring enable safer and more maximal removal.

Hepatoblastoma is a representative pediatric liver tumor, but other tumors are encountered in daily clinical practice. Hepatoblastoma itself is rare in Japan with only 40–60 cases per year, but it is even rarer to encounter other tumors. In addition to hepatoblastoma and hepatocellular carcinoma, hepatocellular neoplasm, not other specified (HCN-NOS) have recently become hot topics in older children. Other liver malignant tumors include hepatic undifferentiated fetal sarcoma and malignant rhabdoid tumors. Benign tumors include FNH, mesenchymal hamartoma, and hemangioma. Among liver tumors, especially hepatoblastoma, surgical resection has been considered the most important. In recent years, the widespread adoption of liver transplantation has made it possible to completely resect the tumor even in cases that were previously considered inoperable. However, in liver transplantation, liver resection remains the first choice owing to problems such as the use of immunosuppressants and invasiveness to healthy donors. It may be possible to resect PRETEXT IV cases and tumors close to blood vessels with some ingenuity. In addition, the importance of total resection is the same for metastatic lesions. For the lung, which is a typical metastasis destination, it is possible to remove even minute metastatic lesions by the ICG fluorescence method.

With the development of medical care, the long-term survival rate of childhood cancer in Japan is estimated to have improved to 80%, which is equivalent to that in Western countries. However, a systematic long-term follow-up system for childhood cancer survivors (CCSs) does not yet exist. The reasons for this may include the lack of a nationwide data infrastructure and uniformity in clinical data to be collected. The absence of a systematic data set could be a barrier to the establishment of a systematic follow-up system; hence, the actual status of late complications among CCSs also remains unclear. It also makes setting up an effective support system difficult. Long-term follow-up for CCSs involves a wide variety of issues regarding late complications, transitions, and loss to follow-up. A nationwide system that administers follow-up care and an individualized support system based on data deduced from hypotheses about CCSs to be proven are needed to overcome these issues and ultimately return benefits to them. To address these issues, a nationwide long-term follow-up system is currently being established as part of the Comprehensive Research Project for the Promotion of Cancer Control. In this article, we describe the overall concept behind the research activities, the development of data infrastructure, and future prospects for international collaborations.

Patients’ quality of life (QOL) is a significant issue in routine pediatric cancer care; however, such care is often provided in a conventional manner per institutional practice. In this study, a survey of routine pediatric cancer care was conducted to ascertain the current situation in each institution and compare the differences in routine care between institutions. The survey questions were broadly classified into the following four topics: dietary restrictions, activity restrictions, supportive care, and physicians’ working conditions. The survey questionnaire was distributed to 96 institutions in Japan that provide pediatric cancer care, and responses were obtained from 60 institutions. Owing to the lack of adequate science-based evidence and guidelines for dietary restrictions, activity restrictions, and supportive care, many of the responses for these topics included conventional practice with a “rule of thumb” method per institution, with some questions having greatly varying responses between institutions. On the basis of the survey results, we plan to share approaches to high-quality supportive care and assist in reviewing dietary restrictions and living restrictions, which will become useful in improving pediatric cancer care and QOL of pediatric cancer patients.

Background: A nationwide survey was conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG: current JCCG) Supportive Care Committee to determine the current status of procedural sedation and analgesia for pediatric patients with cancer and to clarify issues encountered in such procedures.

Methods: A cross-sectional investigation at 155 institutions that are members of the JPLSG was conducted between October 2015 and March 2016 through a web survey (SurveyMonkey^®) to gather institutional information and details concerning procedural sedation and analgesia for pediatric patients with cancer.

Results: Valid responses were obtained from 89 (57%) institutions. Only 27% of the institutions had child life specialists (CLSs) and hospital play specialists (HPSs). Psychological preparation was routinely provided by 36% of the institutions prior to the procedures and treatments. The most common procedural sedation and analgesia medications used were oral triclofos for echocardiography and computed tomography, intravenous thiopental and thiamylal for magnetic resonance imaging and radiotherapy, intravenous midazolam and ketamine for lumbar puncture, bone marrow aspiration, and biopsy, and inhalational anesthetics in the operating room for central venous catheter (CVC) insertion. Sedation and pain management, except for CVC insertion, were performed by attending pediatricians in approximately 90% of cases.

Conclusions: Procedural sedation and analgesia were actively performed for pediatric cancer patients with the burden placed heavily on attending physicians. Therefore, inclusion of more CLSs and HPSs involved in pediatric cancer care is necessary to optimize procedural sedation and analgesia.

<Background> Coronavirus disease 2019 (COVID-19) can cause severe problems for pediatric patients with cancer. Moreover, clustering of medical staff members and patients in a hospital increases infection rates and induces medical system collapse. Therefore, strict infection control measures are needed. Here, we report our experience with COVID-19 infection control in a pediatric oncology ward.

<Results> In March 2021, a nurse from our ward developed COVID-19. All the other 39 staff members and 18 patients in the ward were negative for sudden acute respiratory syndrome coronavirus 2 as determined by the polymerase chain reaction test. We classified the exposure risk of the patients and staff members. All patients were divided according to their separation degree and restricted to their rooms. We introduced web-based visits and restricted family visits. All patients continued their therapy except for one, who postponed the therapy for one week; none of the patients required special treatment for their disease or psychological support. However, their families were quite anxious. Eight nurses stayed home. The remaining staff members were confused and tired from treating patients, attending to their families, and performing trivial duties. No secondary COVID-19 cases occurred. After two weeks, all restrictions were lifted.

<Conclusion> Our infection control protocol enabled the continuation of planned therapies, and no psychological effects of the restriction were detected among our patients. Conversely, the families were severely stressed, while the medical staff members were confused and tired. In such situations, it is important to continue family visits, announce restrictions in advance, and safeguard staff against disease exposure.

In this study, we aimed to clarify the content, target, and reasons for the provision of information to teachers and classmates at the time childhood cancer survivors return to school from the perspective of parents of the survivors. Parents were surveyed about the provision of information about their children upon returning to school. We analyzed all valid data obtained from 16 parents. As a result, we obtained the following findings. Because children can be open about their disease and so that children can obtain support from everyone involved, their parents informed their children’s classmates and teachers about their children’s disease and treatment, and their children being absent, late for school, and leaving early. Parents also told teachers and classmates about their children’s academic performance because their children were unable to do as well as their classmates and because they needed one-on-one educational guidance. Parents could easily inform teachers of their children’s difficulties in classes because of their good relationship with teachers. Parents also informed teachers and classmates of their children’s difficulties in school life in order to resolve their confusion about such difficulties. Because it was difficult for parents to consider their children’s career path, the parents did not tell anyone about it. The findings of this study may help healthcare staff and educational professionals support the process of determining the content of information provided to schools and its targets.

Graft failure is one of the most serious complications following hematopoietic cell transplantation (HCT). Rescue HCT is the only treatment option for graft failure. Recently, HLA-haploidentical HCT (Haplo-HCT) with post-transplant cyclophosphamide (PTCy) has shown promising results for hematologic malignancies, but its evidence for inborn errors of immunity (IEI) is limited. We report a successful salvage Haplo-HCT with PTCy following secondary graft failure in a patient with ectodermal dysplasia with immunodeficiency (EDA-ID) due to NEMO deficiency. The patient suffered from chronic diarrhea and Pneumocytis jirovecii pneumonia during his infancy. Following fludarabine and busulfan-based reduced intensity conditioning (RIC), he received HLA 7/8-matched unrelated bone marrow transplantation (BMT) at the age of one year. Engraftment was achieved on day 17. Ten months after BMT, he developed refractory pancytopenia. Haplo-BMT with PTCy from his father following RIC with fludarabine (150 mg/m²), melphalan (70 mg/m²), anti-thymocyte globulin (2.5 mg/kg), and 2 Gy of total body irradiation was conducted. Tacrolimus and mycophenolate mofetil were used for GVHD prophylaxis. Engraftment was achieved on day 12 without any comorbidities. Our result implicates the validity and safety of Haplo-HSCT with PTCy for patients with IEI.

The prognosis for patients with recurrent isolated central nervous system (CNS) acute lymphoblastic leukemia (ALL) is considered to be poor. It is considered that these patients should undergo hematopoietic stem cell transplantation, but there are many unanswered questions, such as whether autologous or allogeneic transplantation is better, and whether intrathecal injection (IT) should be performed. In this report, we describe the case of a six-year-old girl with B-cell precursor ALL. Eighteen months after the first relapse during maintenance therapy, the patient had an isolated CNS relapse. After achieving remission, the patient underwent cord blood transplantation after pretreatment, including 12 Gy of total body irradiation and 12 times of IT over 18 months. She has remained in remission for six years. In this patient, it is suggested that allogeneic transplantation and long-term IT can increase the possibility of cure in cases of second isolated CNS relapse after 18 Gy irradiation.

We report the case of a nine-year-old boy with localized Ewing sarcoma (EWS) of the right thorax. He was treated with standard chemotherapy but was inoperable because of his poor response to treatment. Subsequent high-dose chemotherapy with autologous peripheral blood stem cell transplantation, irradiation, and multiple additional chemotherapy regimens failed to show sufficient efficacy. He was then started on pazopanib, and the tumor shrank and remained stable for six months. However, the tumor regrew, and his respiratory status worsened. Therefore, he was started on cabozantinib, and his respiratory status improved. The use of these two oral multikinase inhibitors suppressed tumors in pediatric refractory EWS, eliminated the need for hospitalization and inpatient management, and allowed him to be cared for at home for nine months.

Herein, we report a case of Epstein–Barr virus (EBV) brainstem encephalitis after unrelated peripheral blood stem cell transplantation (uPBSCT), the distinctive radiological features of which enabled early diagnosis and intervention. A 13-year-old boy with FLT3-ITD-positive acute myeloid leukemia underwent HLA-DR1 antigen one locus mismatched uPBSCT with pretreatment including anti-thymocyte globulin (ATG). On post-transplant day 104, the patient had an altered consciousness. Cranial magnetic resonance imaging revealed bilateral hyperintensities in the thalamus, hypothalamus, internal capsule, parahippocampal gyrus, and midbrain to medulla oblongata, whereas peripheral blood examination revealed a high percentage of CD20-positive lymphocytes, suggesting EBV encephalitis. Accordingly, rituximab was initiated, which was effective. The patient was later found to be positive for EBV-DNA in blood and cerebrospinal fluid samples. The patient recovered without any neurological sequelae. Caution should be exercised in similar cases with an increase in ATG conditioning due to the diversification of donor sources.

Introduction: When high school patients with cancer are hospitalized for long durations, most of them either stay in school or drop out. The SHAIKEN, a volunteer group of medical students at Nara Medical University (NMU), has been providing learning support to such high school students.

Methods and Results: The impact of returning to school on four high school patients (two with hematologic malignancies and two with solid tumors) who were admitted to the NMU Hospital between May 2014 and March 2021 and who received learning support was examined retrospectively. Although two of the patients repeated a year owing to insufficient attendance, none of the four dropped out of school.

Conclusions: Findings suggest that medical students providing learning support to high school students can help them return to school. However, it also became clear that there are some problems with the student volunteers’ support, such as not being able to count the number of days of class participation.