In recent years, the treatment results for childhood cancer have significantly improved and the five-year survival rate has reached 80% or higher. However, cancer remains the leading cause of death, and complications may threaten life and degrade the quality of life for a long time after treatment. By the development of biomarkers useful for treatment stratification and therapeutic agents based on genomic information, immune cell therapy, and functional repair and treatment with regenerative medicine, safer and more effective treatments are expected. On the other hand, a long-term cohort study based on the childhood cancer registry is desired. Establishing standard treatment for the adolescent and young adult (AYA) generation, that has a poor prognosis for many childhood cancers, is also an issue which should be solved in collaboration with adult clinical trial groups. Regarding the research system, Japan Children’s Cancer Group has established data centers, a series of centralized diagnostic system for immunological data, genetic profiles, pathological data, and imaging data, and a sample storage system. Regarding the medical system, a regional cooperation system centered on childhood cancer core hospitals is being developed, but it is also necessary in the near future to review the medical system in response to the steadily declining birthrate. The goal of medical care is not only to cure the disease but also to support the healthy growth and development and independence of AYA patients. Sharing decision making with patients and their families is important, and it is desirable to promote the participation of patients and people involved in research and development.

The Fukushima Daiichi Nuclear Power Plant Accident that followed the Great East Japan Earthquake raised concerns about pediatric thyroid cancers, which occurred after the Chernobyl Accident. Therefore, the Fukushima Prefectural Health Survey “Thyroid Ultrasound Examination” (TUE) was started about seven months after the earthquake. TUE consisted of a primary examination with thyroid ultrasonography and a confirmatory examination for those who were found to have thyroid nodules of 5.1 mm or larger or cysts of 20.1 mm or larger. The “Preliminary Baseline Survey”, which was the first-round survey, was conducted during the period considered to be the latent period for the development of thyroid cancer after radiation exposure, and the “Full-Scale Survey”, which is conducted every two years, started in FY2014. Evaluations up to the second-round survey showed that thyroid cancer that developed during these rounds of survey was not considered to be the effects of radiation. Currently, the fifth-round survey, which started in FY2020, is being conducted. The risk of thyroid cancer is often very low, and thyroid cancer in children and young adults is generally considered to have a good prognosis. However, knowledge about the natural history of thyroid cancer is lesser in children than in adults, and a more careful management is required depending on the risk level. In this study, thyroid nodules were examined according to the guidelines of relevant Japanese medical societies, and 260 cases were diagnosed as malignant or suspicious for malignancy on the basis of cytological diagnostic findings as of the end of FY2020. In this article, we report the progress and current issues of TUE and review findings on pediatric thyroid cancers found in Fukushima.

Chromosomal translocations are one of the most common types of genetic rearrangement induced by agents that damage DNA. Chromosomal translocations involving 11q23 are the most frequent chromosomal aberrations in secondary leukemia. The molecular mechanisms of chromosomal translocations, however, remain largely unknown. We found that a defect of ATM kinase, a DNA damage signaling regulator, increases the incidence of 11q23 chromosomal translocation in etoposide-treated cells. We also observed that the phosphorylation of ARP8, a subunit of the INO80 chromatin remodeling complex, after etoposide treatment is regulated by ATM and attenuates ARP8 interaction with INO80. The ATM-regulated phosphorylation of ARP8 reduces the excessive loading of your INO80 and RAD51, a recombinase involved in DNA repair, onto the breakpoint cluster region. These findings suggest that the phosphorylation of ARP8 regulated by ATM plays an important role in maintaining the accuracy of DNA repair to prevent etoposide-induced 11q23 abnormalities. We also examined the changes of higher-order nuclear structures around breakpoints of 11q23 translocations. Studies of mechanisms of chromosomal translocations will contribute to the prevention of late effects of cancer treatment in childhood.

Integrated genomic and transcriptome analyses have been carried out to identify molecular diversity in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Despite refined risk classification, patients classified as at a low risk at diagnosis still account for most cases with relapses. Therefore, novel strategies are needed to identify patients with high risk for relapse. MicroRNAs (miRNAs) are non-coding RNAs that bind to mRNAs and regulate the expression levels of their gene products. Although an increasing number of studies have identified miRNAs as potential biomarkers and therapeutic targets in several cancers, there are only a few studies on integrated analysis of miRNA profiling in pediatric BCP-ALL. To comprehensively investigate miRNA and mRNA profiling in pediatric BCP-ALL, we analyzed 140 high-risk patients. Consensus clustering of miRNA expression data identified a distinct profile characterized by global downregulation of miRNAs (miR-low cluster; MLC), and the profile was not associated with any known genetic subgroups. Patients clustered in MLC had worse prognosis, even in hyperdiploid cases. Moreover, a subset of non-MLC samples at diagnosis acquired an MLC-like miRNA profile at relapse. Integrative miRNA:mRNA analysis findings suggest that the downregulation of miRNAs in MLC led to the upregulation of genes of oncogenic signaling pathways. These findings underscore the importance of integrative analysis of miRNA and mRNA and suggest that miRNA-based classification would be helpful for better risk stratification and may improve the outcome in pediatric BCP-ALL.

Although treatment outcomes for pediatric malignant solid tumors have improved, the prognosis of patients with metastases is often poor. Although we are surgically removing lung metastases, surgery alone is often insufficient, and the development of new treatments is highly desired. Therefore, to develop a research platform close to actual clinical settings and to develop a treatment method using such a platform, we constructed a patient-derived xenograft (PDX) model by transplanting the resected lung metastases into immunodeficient mice. A study using this lung metastasis model has begun. Fourteen lung metastatic specimens (including pleural dissemination) were subcutaneously transplanted into NSG mice, and 12 were successfully established. The types of tumor (number of tumor specimens successfully established/number of transplants) were osteosarcoma (6/6), hepatoblastoma (1/2), Ewing’s sarcoma (1/1), malignant myoepithelial tumor (1/1), malignant rhabdoid tumor (1/1), hepatocellular carcinoma (1/2), and yolk sac tumor (1/1). The engraftment rate of PDX is generally not high, but the use of lung metastatic specimens may contribute to our high success rate of establishment. For osteosarcoma and Ewing’s sarcoma, we succeeded in generating a lung metastasis model by dispersing subcutaneous PDX in a protease cocktail and injecting it into the tail vein of mice. Taking advantage of the PDX characteristics that the tumor cells are from humans and the interstitial cells are from mice, the mouse and human transcriptomes can be evaluated separately for each PDX. We are proceeding with gene expression analysis with the aim of developing new therapeutic methods specialized for lung metastasis from the viewpoint of tumor microenvironment.

Background: As a new treatment strategy for neuroblastoma, adoptive transfer of natural killer (NK) cells has been conducted in several clinical trials. However, methods of preparing highly activated and high-dose NK cells have not yet been developed. Now, we have developed a cutting-edge, off-the-shelf, and feeder-free method to generate highly activated and expanded human NK-like cells from peripheral blood.

Methods: Highly activated NK-like cells (GAIA-102) were generated as previously described (Saito S. et al. Hum Gene Ther 2013, AdoptCell-NK Kit: Cat. no. 16030400). Briefly, CD3-depleted PBMCs were prepared by adhesion culture for 14 days. Spheroids of IMR32 (neuroblastoma cell line) were cocultured with fluorescence-labeled GAIA-102, and invasion of effector cells into the spheroids was observed. Spheroids were then manually disrupted, and the number of viable tumor cells was counted by flow cytometry.

Results: In 3D cytotoxicity assay, GAIA-102 efficiently killed IMR32 spheroids as compared with primary NK cells, anti-GD2 antibody or the combination of both. Live imaging demonstrated that GAIA-102 actively migrated, infiltrated and altered spheroid morphology, and subsequently mediated tumor cell killing in IMR32 spheroids. In contrast, primary NK cells could not invade into the spheroids.

Conclusion: GAIA-102 exhibits high cytotoxicity and invasion activity against neuroblastoma spheroids. GAIA-102 is highly promising for the treatment of solid, bulky lesions of advanced neuroblastoma. Now, we are preparing for a clinical trial of GAIA-102 for recurrent or refractory neuroblastoma.

Although the number of pediatric and adolescent and young adult (AYA) patients with cancer is much smaller than that of adult cancer patients, malignant disease is one of the significant causes of death among pediatric and AYA patients. In particular, patients with relapse or metastatic disease still have a dismal prognosis, and effective standard therapies have not been established for these patients with intractable cancers. On the other hand, recent advances in genome-wide approaches provide specific gene-mutation-based therapies for patients with intractable pediatric and AYA cancers. However, gene targets, novel molecular targeted drugs, and clinical trials for patients with pediatric and AYA cancers are currently limited in Japan. In addition, since the gene mutation spectrum in pediatric and AYA patients differs from that of adult patients, development of specific cancer multigene panels in pediatric and AYA cancers is necessary. Thus, further improvement of genomic medicine for pediatric and AYA cancers is necessary.

Cancer genome profiling testing (multigene testing) methods have been clinically applied to detecting alterations of numerous cancer-associated genes, and these new methods are widely used in pediatric cancer. In pediatric cancer, these comprehensive methods play an important role not only in identifying a biomarker for therapeutic targets, but also in definitive diagnosis and prognosis prediction. The precision medicine approach is expected to contribute to minimizing complication without compromising relapse risk. It should also be noted that a certain fraction of children with cancer have pathogenic variants in cancer predisposition genes. Thus, genetic counseling and surveillance system should be established. To utilize complex results of genetic analysis, medical interpretation should be reviewed by an “expert panel”. Considering the uniqueness of pediatric cancer, an exceptional process of consultation is permitted. As a future perspective of pediatric cancer genomic medicine, expansion of drug availability, development of optimal multigene testing, and education are issues to be solved.

The 2016 revision of the WHO classification of tumors of hematopoietic and lymphoid tissues proposed a section on myeloid tumors with a germline predisposition. In inherited bone marrow failure syndrome, the differentiation and proliferation of hematopoietic cells are impaired by a genetic predisposition, resulting in single-line cytopenia and pancytopenia. Its clinical diagnosis has been made on the basis of the characteristic physical findings. Prototype diseases include the following. Fanconi anemia is a disorder of genomic instability in DNA cross-linking. Dyskeratosis congenita is a disorder of poor telomere maintenance. Diamond-Blackfan anemia and Shwachman-Diamond syndrome are disorders of ribosome dysfunction. In recent years, owing to advances in genetic analysis, novel inherited bone marrow failure syndromes have been established, whose causative genes are SAMD9, SAMD9L, MECOM, and ERCC6L2. Biallelic mutation in ADH5 combined with polymorphism in ALDH2 has also been identified. Environmental factors in the presence of genetic predisposition modify disease courses, and DNA damage causes additional abnormalities in hematopoietic stem cells, resulting in oncogenesis. On the other hand, reversion mutation is occasionally acquired and the condition is improved in such cases. Hematopoietic cell transplantation is an important treatment for the cure of inherited bone marrow failure syndrome; however, there remain many issues such as its indication and timing, selection of donors, preconditioning, post-transplant complications, and secondary cancer. Appropriate medical care should be provided on the basis of the characteristics of each type of inherited bone marrow failure syndrome.

I am a musculoskeletal tumor surgeon who has worked at a cancer center, and I would like to share my thoughts and experiences in treating AYA patients. In the case of patients between 15 and 19 years of age, cancer treatment often causes interruption of schoolwork, and thus academic support is essential. If the patient is under 18 years of age, they should apply for the Pediatric Chronic Specified Diseases, and if the patient has undergone an artificial joint replacement due to osteosarcoma, they should apply for a physical disability certificate. In general, people between 20 and 39 years of age are undergoing dramatic changes in their lives, such as employment, love, marriage, and childbirth, and it is necessary to take measures according to their stage of life. In addition to applying for the physical disability certificate, I sometimes explain the “employment quota for the disabled” to those who are thinking of finding a job. Patients with artificial joint replacements in their limbs are often considered to have a physical handicap, but by being open about their disability, they can receive employment opportunities and a comfortable working environment. Although treatment begins at the initial consultation room (i.e., with only the patient and doctor), good treatment is not created by the doctor and patient alone. I believe that the support of a multidisciplinary team (MDT) is important for the well-being of patients.

With the improvement of treatment results, the need for long-term follow-up, which is a part of total care, is increasing for childhood cancer patients. In addition, the necessity of the system is shown in the national cancer control. Given these factors, the “long-term-follow-up (LTFU) system development project for children and AYA (Adolescent and young adult) cancer patients” was started in 2017, which is aimed for medical professionals in charge of LTFU of childhood cancer patients to acquire the knowledge of LTFU and transitional medical care for childhood cancer and also to know how to operate the LTFU clinic. About 40% of the participants so far are nurses, and the background of the participants has changed. Result of the questionnaire survey of the training participants suggest that the nurses acquired knowledge that they previously did not sufficiently have, and they have also become more aware that childhood cancer patients who are undergoing growth and development need long-term involvement after diagnosis. Thus, participation in the training was evaluated to have a positive effect. On the other hand, the operation of LTFU clinics in clinical settings faces issues such as lack of manpower, and medical fees related to the establishment of an organizational structure. We have to consider future tasks so that the needs of those who have experienced childhood cancer can be better met.

Recently, over 98% of junior high school graduates in Japan have gone on to pursue higher education. However, there is no guarantee that in-hospital higher education may be realized by all students. Although the Japanese Ministry of Education issued a notice in 2015 regarding concessions for students who could not attend school due to hospitalization, many schools are yet to respond, which has halted the education of hospitalized students.

In Osaka, prefectural high school students can avail of a learning support system. Since 2012, when it was implemented, there have been 23 students who required long-term hospitalization and considered seeking learning support at our facility. Eleven prefectural high school students hospitalized by 2020 continued learning through individual support plans that combined in-person classes, online classes, and/or educational videos. They completed their school grade or graduated along with their classmates. On the other hand, eight private/other prefectural high school students were unable to avail of learning support. Half of them had to either repeat their school grade or drop out on reaching the attendance limit. Furthermore, owing to the impact of Covid-19 restrictions, four students hospitalized in 2021 have not been offered any classes.

Prefectural high school students can continue to learn throughout the duration of their hospitalization and be promoted or graduate. However, the same cannot be said of private/other prefectural high school students who spend their time in the hospital and are anxious about their future. At present, various modes of communication and support must be implemented so that such disparities among students are eliminated.

Recent developments in risk stratification and supportive care in pediatric cancer treatment have greatly improved the survival rate of childhood cancer. On the other hand, childhood cancer survivors remain at risk for late complications even after the disease is cured. The importance of long-term follow-up of childhood cancer survivors to promote and maintain a healthy lifestyle is undisputed, but not all of them receive adequate follow-up examination and care. Owing to the wide spectrum of late complications that can occur in childhood cancer survivors, the care that needs to be provided can be complex, sometimes creating barriers to transitional support or interruptions in follow-up. The patient’s own knowledge of comorbidities and long-term follow-up is also a major factor in follow-up continuity. Education of patients for them to acquire health literacy is an important factor to enhance long-term follow-up of childhood cancer survivors. In the ever-changing field of pediatric cancer care, it is desirable to enhance follow-up tools and systems.

Invasive fungal infection in pediatric patients with leukemia or malignant tumors is intractable and has a poor prognosis in many cases. Delayed diagnosis and treatment may also affect the prognosis. However, an early definite diagnosis is difficult in many patients; thus, it is important to make an early diagnosis using appropriate auxiliary methods. It is also important to prevent infection during treatment of acute leukemia or after hematopoietic stem cell transplantation, in which the risk of infection is high. In the treatment and prophylaxis of infection, an appropriate antifungal drug needs to be selected depending on the type of fungus. Since pediatric patients have more rapid hepatic metabolism than adult patients, the optimum dosage of a triazole antifungal agent per kg body weight is higher in children. When using these agents, careful attention should be paid to possible drug interactions related to cytochrome P450 (CYP) metabolism. In particular, triazole antifungal agents may inhibit the metabolism of cyclosporine and tacrolimus and thus increase the concentrations of these drugs in blood. The adverse effects of antineoplastic drugs, such as vincristine, cyclophosphamide, and gemtuzumab ozogamicin, may also be increased owing to the inhibition of their metabolism. Thus, if the administration of an antifungal agent is started or terminated, the effects on other drugs should be considered. Since voriconazole is affected by a genetic polymorphism in CYP2C19, which is related to its metabolism, monitoring is required by measuring its trough concentrations in blood.

Research on late neurocognitive sequelae in long-term survivors of childhood cancer remains limited in Japan due to the lack of neurocognitive assessment tools. The objective of this study was to cross-culturally adapt and validate the Childhood Cancer Survivor Study Neurocognitive Questionnaire (CCSS-NCQ) to fill the research gap. The CCSS-NCQ, which is a standardized self-reported measure of neurocognitive function, is comprised of four domains: Task Efficiency, Emotional Regulation, Organization, and Memory. The Japanese translated version of CCSS-NCQ was distributed to 34 childhood cancer survivors, and its construct validity was evaluated by confirmatory factor analysis. A four-factor model identified in the original CCSS-NCQ was not confirmed. As opposed to the four-factor model identified in the original CCSS-NCQ, the three-factor model in which Memory and Efficiency converged to one factor, was observed. Since the majority of participants were brain tumor survivors, the results from this study may provide insights on the vulnerability of this group to treatment-related neurocognitive impairment. Further studies with a larger sample size are warranted to firmly evaluate the construct validity of the Japanese CCSS-NCQ.

High-dose intravenous methotrexate (HD-MTX) and intrathecal MTX can cause long-term neurotoxicity that adversely affects intellectual function. We report the final results of a three-year longitudinal study of cognitive function of patients from 23 institutions. Data were collected from children diagnosed as having standard-risk acute lymphoblastic leukemia (ALL) between 2011 and 2016. A total of 57 patients aged three to nine years at the time of diagnosis were consecutively enrolled and the results of 43 were statistically analyzed. We used the Wechsler Intelligence Scale for Children-4^th Edition (WISC-IV) to obtain the scores for full-scale IQ (FSIQ), verbal comprehension index (VCI), perceptual reasoning index (PRI), working memory index (WMI), and processing speed index (PSI). The cognitive function of participants was tested using WISC-IV before and three times after the completion of HD-MTX therapy over three years. The four indices (VCI, PRI, WMI, and PSI) were statistically compared across four time points using ANOVA. Mean FSIQ scores were 99.09 (SD=14.72), 99.26 (SD=15.01), 102.30 (SD=11.08), and 101.12 (SD=11.69) at the four time points, respectively. Scores of Verbal Comprehension at TIME 1 were the lowest, whereas those of Working Memory were the lowest after TIME 2. These results should be verified with respect to daily life problems encountered by the patients.

Fertility preservation is a challenge to overcome in order to improve survivorship of adolescent and young adult (AYA) cancer patients. The St. Jude medulloblastoma-96 protocol, which involves radiotherapy followed by chemotherapy with high-dose alkylating agents and autologous peripheral blood stem cell transplantation, is widely used to treat medulloblastoma. Despite the high overall survival rate, loss of fertility is inevitable. We report the case of a 16-year-old girl with cerebellar medulloblastoma. After gross resection of the tumor, peripheral blood stem cell collection was started 14 days after surgery, and radiotherapy consisting of 23.4 Gy craniospinal irradiation and 32.4 Gy tumor bed boost irradiation was started 24 days after surgery. After radiotherapy, the anti-Müllerian hormone level decreased to 1.84 ng/mL. Random-start controlled ovarian stimulation was performed by administering an FSH analog for nine consecutive days followed by hCG injection for the final stage of oocyte maturation. Four oocytes were successfully cryopreserved without any adverse events or a delay in high-dose chemotherapy. Random-start controlled ovarian stimulation is a promising technique to preserve fertility in AYA patients, which does not delay treatment of medulloblastoma.

A 9-year-old boy initially diagnosed as having acute lymphoblastic leukemia experienced a relapse during the first-line treatment. Consequently, bone marrow transplantation with myeloablative conditioning from a human leukocyte antigen-matched sibling donor was performed to treat relapsed leukemia. Elevated BNP levels along with cardiac enlargement and dysfunction were detected five months after the last dosage of anthracyclines and three months after bone marrow transplantation. At diagnosis of treatment-related cardiac dysfunction caused by several factors, including anthracycline, cyclophosphamide, and total-body irradiation, he was treated with candesartan and carvedilol for heart failure. Eight months later, the left ventricular ejection fraction recovered from 20.9% to 56.7%. Reportedly, anthracycline-related cardiotoxicity in adult patients typically develops within 1 year of its final administration, and early intervention could possibly recover cardiac function. We recommend regular monitoring of serum BNP levels and echocardiograms to detect cardiac dysfunction at the subclinical stage, especially for patients with multiple risk factors.

A 6-year-old boy with mixed-phenotype acute leukemia in his first remission with chemotherapy developed pancytopenia with progressive anemia and fever during his maintenance therapy. The maintenance therapy was discontinued, and he was admitted to our hospital for further investigation. The bone marrow aspirate smears revealed erythroid hypoplasia with a few giant pre-erythroblasts and no obvious leukemic cells. Antibiotics, immunoglobulin, and red blood cell transfusion were administered. His pyrexia resolved in 3 days and the pancytopenia gradually improved. Laboratory tests showed elevated levels of human parvovirus (HPV) B19-IgM in serum and positivity for HPVB19 DNA in the bone marrow, leading to the diagnosis of HPVB19-induced pancytopenia. When pancytopenia accompanying progressive anemia develops in patients with leukemia during maintenance therapy, HPVB19 infection should be considered, in addition to recurrence of the primary disease.

A 5-year-old girl with FUS-ERG-positive acute myeloid leukemia failed to achieve remission despite chemotherapy, resulting in prolonged agranulocytosis for two months. She developed cough, fever and back pain, and was diagnosed as having invasive pulmonary aspergillosis (IPA) on the basis of chest CT images showing abscess in the left lung and her positivity for the serum galactomannan antigen. Her symptoms gradually improved with the combination of voriconazole (VRCZ) and micafungin (MCFG); however, massive hemoptysis occurred on the 16th day of the antifungal therapy. Contrast-enhanced CT revealed a pseudoaneurysm on the left intercostal artery adjacent to the IPA lesion. Urgent arterial embolization successfully prevented hemoptysis, followed by the left upper pulmonary segmentectomy. Two months after, she received allogeneic hematopoietic cell transplantation (HCT) concurrently with VRCZ. The IPA did not recur for 12 months after HCT. Multidisciplinary management consisting of arterial embolization and surgery was effective for IPA with massive hemoptysis.

The treatment regimen for classical Hodgkin lymphoma (cHL) has been established. However, once cHL in some cases becomes refractory to chemotherapy or has relapsed, it becomes difficult to manage the disease with conventional cytotoxic chemotherapy, and the prognosis is extremely poor in such cases. We report the case of a pediatric patient with refractory cHL that relapsed after brentuximab vedotin treatment and high-dose chemotherapy with autologous stem cell transplantation. Four courses of nivolumab (anti-PD-1 antibody) resulted in complete remission, and the patient has since been in remission for four years.

Trametinib, a MEK inhibitor, is expected to have efficacy for low-grade glioma with BRAF fusion. However, there are limited data on its safety and efficacy, especially in Japanese children. Here, we report a case of KIAA1549-BRAF fusion pediatric refractory optic pathway glioma (OPG) treated with trametinib. An 8-year-old girl was diagnosed with OPG at 7 months of age. She received five types of chemotherapy and underwent four surgeries. However, the tumor size continued increasing, resulting in hydrocephalus and progressive consciousness disturbance. Ventriculoperitoneal shunting was not performed because of the extremely high cerebrospinal fluid (CSF) protein concentration. Since KIAA1549-BRAF fusion was detected by cancer multi-gene panel testing, she received trametinib monotherapy for 2 months, during which the tumor size remained stable and CSF protein concentration decreased. No grade 3 or higher adverse events per the Common Terminology Criteria for Adverse Events occurred. Trametinib was safe and effective in our case, and further evaluation in a large cohort should be conducted for confirmation.