Proton beam therapy (PBT) has a dosimetric advantage over X-ray radiation therapy, which allows for equivalent target volume coverage with reduced dose delivered to normal tissues and provides opportunities for acute and late morbidity risk reduction in pediatric cancer patients. PBT has been covered by the national health insurance for localized solid malignancies in patients under the age of 20 since April 2016 in Japan, and the number of patients subjected to PBT for pediatric cancer has been increasing at each institution. Reirradiation for patients with local or regional recurrences may retard tumor progression, palliate symptoms, and in some cases, even cure or provide long-term disease control, which can positively impact the overall health status and quality of life. Although data on the cumulative tolerance dose of critical organs and safety of reirradiation for pediatric patients are currently limited, there are some reports demonstrating the efficacy and safety of PBT for the reirradiation of recurrent central nervous system tumors. In the future, prospective clinical trials are required to evaluate the usefulness of proton beam reirradiation as a treatment option for pediatric cancer recurrence.

Radiotherapy is a major component of pediatric cancer treatment for both definitive and palliative purposes. Patients may develop recurrent lesions arising at the irradiated site. These recurrent lesions are sometimes inadequately controlled by other treatments and expected to be controlled further with additional radiotherapy. Recently, re-irradiation, i.e., repeated irradiation of recurrent lesions, has been a clinical issue in pediatric cancer. There are two concerns regarding re-irradiation for pediatric cancer. First, lesions recurring at the site subjected to standard radiotherapy are anticipated to be refractory to radiotherapy. Second, healthy tissue included in the target volume in first-line radiotherapy is anticipated to be affected adversely owing to the accumulated doses conferred by first-line radiotherapy and re-irradiation. Nevertheless, the number of reports of favorable outcomes of re-irradiation for pediatric cancer is increasing. In this report, the author summarizes the evidence for re-irradiation and knowledge of accumulated doses in irradiated healthy organs. Representative diseases and conditions for which re-irradiation is applied are discussed with a focus on re-irradiation efficiency and safety.

Reirradiation for pediatric cancer is considered in practice, but there are only a few reports on this treatment approach. In this study, we investigated the cases of patients who underwent reirradiation, including 33 patients (21%) who underwent more than one irradiation out of 158 patients treated with radiation therapy from 2013 to 2019. The results showed that brain tumors were the most frequent malignancies observed (10 patients.) Furthermore, cases of medulloblastoma patients who were reirradiated between 2015 and 2019 were examined in detail. There were three patients with relapsed medulloblastoma, all of whom were treated with 12 Gy/8 fractions of cranio-spinal irradiation, but they suffered a meningeal dissemination relapse after reirradiation. There were three patients with second cancer, glioblastoma, treated with reirradiation after treatment of medulloblastoma. These patients were irradiated with 40.05 Gy/15 fractions, but they developed early relapse and died. Reirradiation is considered to be one of the options because of reports of long-term survival, but its effectiveness needs to be investigated in the future.

The overall survival (OS) rate of pediatric patients with acute leukemia undergoing allogeneic hematopoietic cell transplantation (HCT) in the first or second complete remission (CR) is in the range of 60% to 70%. By contrast, the OS rates of patients undergoing allogeneic HCT in the third and subsequent CR or in non-CR remain unsatisfactory, suggesting the need to further decrease the risk of post-HCT relapse. On the other hand, long-term survivors of allogeneic HCT are at increased risk of developing late adverse effects, which are associated with high-dose total body irradiation (TBI) or high-dose chemotherapy used in myeloablative conditioning regimens, or with chronic graft-versus-host disease. Intensification of the conditioning regimen to reduce the risk of relapse after HCT increases transplant-related mortality, which cannot improve the transplantation outcomes. Instead, several therapeutic approaches are ongoing, aiming for the reduction of the pre-HCT tumor burden and the prevention or early intervention of post-HCT relapse. Non-TBI, non-busulfan reduced-toxicity conditioning will contribute to the improvement of long-term transplantation outcomes by reducing late adverse effects. Measurement of minimal residual disease by highly accurate assays is required to select these pre- and post-HCT treatments and assess their efficacies.

Mutations of the gene encoding fms-related tyrosine kinase 3 (FLT3), a type III receptor tyrosine kinase, are observed in approximately 30% of adults and 10% of children with acute myeloid leukemia (AML). There are two types of FLT3 mutation in AML, namely, FLT3 internal tandem duplication (FLT3-ITD) and tyrosine kinase domain mutation (FLT3-TKD); the former is the major type and strongly correlates with poor prognosis. The outcome of children with FLT3-ITD-positive AML is poor with a low rate of remission and a high rate of relapse. Currently in the Japanese pediatric AML studies, all the patients with FLT3-ITD are considered at a high risk of relapse and allocated to hematopoietic cell transplantation in the first remission. However, their prognoses have not improved. Recently, the development of tyrosine kinase inhibitors targeting FLT3 has been in progress, and two products have been approved to date for use in adults with relapsed or refractory FLT3-mutated AML: gilteritinib and quizartinib. There are no agents indicated for pediatric use, use for a combination therapy, or use for cases with the initial diagnosis of AML, but FLT3 inhibitors are becoming a promising treatment choice for relapsed or refractory cases. The current state of FLT3 inhibitors, development of novel therapeutics, and overview of FLT3-mutated AML therapy are discussed.

Nowadays, in internationally well-known institutes for fertility preservation (FP), pediatric cancer patients account for 12–18% of all FP patients undergoing ovarian tissue cryopreservation (OTC). OTC, which requires only 1–4 days, is useful for FP in pediatric patients with rapid progression of their cancer and for whom transvaginal egg retrieval is impossible. In Japan, there are 15 pediatric cancer hospitals, most of which do not have OTC facilities. As a solution to this, a centralized system similar to FertiPROTEKT and the Danish model, which have a long history of conducting top-level OTC, should be established. A centralized system requires open and frequent communications among the patient, family, pediatric surgeons, pediatricians, anesthesiologists, and assisted reproductive physicians. Building strong relationships is vital to smoothly perform shared decision making, general anesthesia, laparoscopic ovariectomy, cryopreservation, and postoperative management. For hospitals without OTC facilities, our Human Ovarian-tissue Preservation Enterprise (HOPE) can provide a transportation system to move the tissues from hospitals to HOPE and an OTC facility with experts who can handle the slow freezing method to cryopreserve tissues, the safety of which has been proven. Nowadays, about 2,500 pediatric cancer patients are reported annually with a five-year survival rate of 70–80%. Given the declining birth rate and aging population in Japan, FP for pediatric cancer patients is essential. By introducing the cases of transplantation of frozen-thawed ovarian tissues for induction of puberty and pregnancy, we discuss the benefits of FP for pediatric cancer patients and the challenges we faced to establish a centralized network system.

It has been reported that nearly 10% of children with cancer potentially have germline pathogenic variants of cancer predisposition genes. With the recent widespread use of multiple gene panels, the number of patients diagnosed as having such variants will increase. Clinical management strategies based on their diagnoses, such as molecular-targeted therapy and surveillance, are expected to improve their chances of survival. However, being diagnosed to have a predisposition to cancer can place a psychological burden on patients and their family members and negatively impact their life events. In addition, the cost of germline genetic testing and surveillance is not covered by health insurance in most cases here in Japan. In this paper, we review the current issues in medical care for pediatric patients with cancer predisposition, along with the results of a questionnaire survey about the medical condition of patients in hospitals accredited by the Japanese Society of Pediatric Hematology/Oncology. To provide better care for children with cancer predisposition in Japan, improvements to the medical system, including insurance coverage, counselling for patients and their families, establishment of a case registry, and clinical evidence for the efficacy of surveillance, are required.

Background: The COVID-19 pandemic, which began in 2020, has dragged on and changed people’s lifestyles. Pediatric cancer patients are receiving chemotherapy while taking adequate measures against COVID-19 infection.

Methods: At Kyushu-Okinawa area pediatric cancer hospitals, in June 2020 (after the first wave of COVID-19 infections in Japan) and September 2020 (after the second wave), we investigated the (1) experience with COVID-19, (2) its impact on medical care, and (3) its social and mental impact on patients and healthcare professionals. We discussed these issues at the monthly WEB conference.

Results: There were no cases of COVID-19 infection among pediatric cancer patients. The present situation had no effects on the outcomes of patients who were forced to change treatment for their underlying diseases. Visits and overnight stays of family caregivers, parent meetings, volunteer activities, nursery teachers/child life specialists, and playroom/in-hospital school management were restricted at all hospitals. Many patients and families suffered mental stress. The number of outpatients decreased. Telemedicine was provided at six facilities. Some restrictions were relaxed between the first and second waves, and the number of outpatients is now returning to normal.

Conclusion: COVID-19 rarely becomes severe in children. However, there are concerns about the effects of treatment changes and interruptions in care for hematological malignancies. These patients need not only adequate infection control but also mental care.

Children, adolescents, and young adults with cancer and their families have various needs in a wide range of life stages. We conducted a cross-sectional study using a structured questionnaire to understand the families’ needs for current pediatric oncology care in Osaka. Eligible participants were guardians of children or adolescents who were diagnosed as having cancer at ages under 20 years and undergoing cancer treatment at nine major pediatric oncology care hospitals in Osaka from 2015 to 2018. The questionnaire covered the following areas: (1) participants’ background, (2) information given before treatment, (3) supportive therapy, pain relief or reduction of emotional distress, (4) multidisciplinary team and consultation support, (5) treatment environment, (6) survivorship, and (7) overall reflections on cancer care. Two hundred out of 249 questionnaires (80%) were returned. The majority of participants reported being satisfied with the care they had received, whereas the proportion of respondents who received information on the late effects of treatment or potential risk of infertility varied among the hospitals. About half of respondents (95) reported that they had not been informed of the potential risk of infertility posed by their cancer treatment; 76 (80%) of them expressed a desire to be informed. Unmet needs were particularly high in terms of sibling support, hospital meals, bedside environment for accompanying family members, provision of information, and improvement in the application process for the medical expense subsidy. Sharing these identified needs with the medical staffs and local governments will help improve the pediatric oncology care delivery system.

Hemophilia treatments are continuously improving; however, hemophilia carriers still face various problems. Specifically, the carriers’ bleeding risk is a pressing concern and a recent focus of attention. We conducted a survey on the presence or absence of a tendency to bleed and conditions at delivery in mothers of patients with hemophilia who were treated at our hospital. We interviewed 14 confirmed and 9 suspected hemophilia carriers (23 in total). We evaluated coagulation factor activity in 17 participants. Among the 17 participants, eight showed a factor VIII or IX activity level of lower than 40%. More than half of the confirmed carriers reported difficulty in achieving hemostasis after tooth extraction and hypermenorrhea. No clear correlation was found between bleeding tendencies (y/n) and coagulation factor activity. Eight of the 14 confirmed carriers self-reported excessive bleeding during and after childbirth; four experienced massive bleeding of 1000 mL or more at delivery and two received blood transfusion. In the two participants who underwent blood transfusion, the activity levels of coagulation factors during the nonpregnant period were 40% or higher. Both participants were not informed of the possibility of being a hemophilia carrier even with hemophilia patients in their family members. It has been revealed that there are more-than-expected females who are troubled with bleeding symptoms among hemophilia carriers. It is still considered that commonly these carriers have not received sufficient explanation from medical providers. Therefore, it is important for medical professionals that are involved in treating hemophilia to support these carriers by providing sufficient explanation and support to them.

Hematopoietic stem cell transplantation (HSCT) increases the risk of cholelithiasis. Herein, we describe the case of an acute myelogenous leukemia (AML) patient presenting with hepatic dysfunction secondary to cholelithiasis during extensive chronic graft versus host disease (GVHD) following two courses of HSCT. Following a second relapse, haploidentical peripheral blood stem cell transplantation (PBSCT) induced complete remission. One year following PBSCT, the patient presented with abdominal pain and elevation of levels of serum transaminase and biliary enzymes. Although hepatic dysfunction was suspected to be due to extensive chronic GVHD, abdominal ultrasonography, however, revealed multiple gallstones, and she was diagnosed as having symptomatic cholelithiasis. Conservative therapy aided her recovery, and follow-up by regular abdominal ultrasonography was conducted. Risk factors for pediatric cholelithiasis following HSCT include multiple courses of HSCT, donor–recipient human leukocyte antigen mismatch, and GVHD. For patients who have undergone HSCT and have multiple risk factors for cholelithiasis, it is necessary to consider aggressive abdominal ultrasonography because of its convenience and non-invasiveness.

We report a case for which phenytoin (PHT) was effective in decreasing tacrolimus (Tac) concentration in a 9-year-old girl diagnosed with acute myeloid leukemia. The patient received chemotherapy, but no remission could be achieved. Therefore, allogeneic hematopoietic stem cell transplantation was performed with myeloablative conditioning. Engraftment was achieved on day 20. She complained of right hypochondralgia, and a mild elevation of hepatobiliary enzymes was observed on day 33, which led to the diagnosis of hepatic sinusoidal obstruction syndrome. Despite withholding Tac administration on day 38, its concentration increased to 34.6 ng/mL on day 40. Since Tac could not be removed by dialysis, PHT was administered with the hope of decreasing the Tac concentration via its interaction with PHT. The Tac concentration was 18.4 ng/mL on the day after PHT administration was initiated, and it decreased steadily thereafter. PHT may be an effective option for elevated Tac levels.

A 2-year-old female presented with acute heart failure and renal failure, and she was started on Extra-corporeal membrane oxygenation (ECMO) and continuous hemodiafiltration (CHDF). ECMO led to improvement in her heart function; however, she developed high blood pressure following ECMO withdrawal. Computed tomography revealed a left adrenal tumor and double renal arteries that were narrowed at their origin. Urinary vanillylmandelic acid and homovanillic acid, as well as serum neuron-specific enolase levels were increased, and I¹²³-metaiodobenzylguanidine (I¹²³-MIBG) scintigraphy revealed I¹²³-MIBG accumulation in the tumor. Blood tests showed high plasma renin and aldosterone levels. Bone marrow aspiration revealed abnormal cells, and she was diagnosed as having neuroblastoma and renovascular hypertension. We concluded that a neuroblastoma concomitant with renovascular hypertension precipitated hypertensive cardiac shock and severe renal failure. Chemotherapy improved hypertension and renal failure. Chemotherapy with ECMO and CHDF are effective rescue strategies in patients with neuroblastoma complicated by severe heart and renal failure.

Here, we describe the case of a 14-month-old boy with a left retroperitoneal tumor that was diagnosed as stage 3 neuroblastoma (image-defined risk-factor-positive, MYCN amplified). He underwent five courses of induction chemotherapy and high-dose chemotherapy comprising busulfan+melphalan, followed by autologous bone marrow transplantation. On day 72 after transplantation, he underwent partial resection, and a histopathological analysis showed surviving viable tumor cells. On day 77, computed tomography (CT) scan showed progression of the primary tumor. Although salvage therapy was performed, CT scan on day 100 showed multiple pleural metastases. Local irradiation of the primary tumor (30.6 Gy/17 fractions) and whole lungs (15 Gy/10 fractions) was also performed. Peritoneal dissemination occurred and he died on day 207. Post-autopsy analysis showed high expression levels of ALK in the primary tumor and autopsy specimens. Neuroblastoma with MYCN amplification and high expression levels of ALK can result in rapid exacerbation, and the introduction of new agents such as ALK inhibitors is warranted.

Purpose: To provide guidance regarding dietary and nutritional management practices in pediatric cancer in Japan, a nationwide survey was conducted to understand the current situation.

Method: From April to July 2017, the Supportive Care Committee of the Japan Children’s Cancer Group (JCCG) surveyed 153 institutions regarding dietary and nutritional management protocols, using the Survey Monkey^® Web survey system.

Results: Of the 153 institutions contacted, 110 institutions (72%) and 112 clinical departments (106 internal medicine departments and 6 surgical departments) returned valid responses. Dietary restrictions during chemotherapy were performed in 47% and 46% of departments “at the start of chemotherapy” and “at the time when neutrophils <500/μL”, respectively. Nonhospital food was conditionally allowed by 90% of all departments. Most departments restricted nonheated foods, but whether the physicians permitted the consumption of milk, fermented beverages, sealed side dishes, lunch boxes, and home cooking varied among departments. Approximately 40% of all departments reported that all patients received nutritional support from dietitians or a nutritional support team.

Discussion: This survey revealed that dietary and nutritional management protocols for patients with childhood cancer were inconsistent among various health institutions in Japan. In the future, we would like to provide guidance that can be shared among all participating JCCG facilities.