Central nervous system (CNS) involvement is an important complication of acute lymphoblastic leukemia (ALL). Although intrathecal chemotherapy and high-dose systemic chemotherapy are administered to prevent the CNS involvement in ALL, CNS involvement occurs in some patients with ALL during and after chemotherapy. In addition, the meninges are a primary site of CNS involvement in ALL, but the reason why ALL cells involve the meninges is as yet unclear. It is necessary to elucidate the mechanism of the CNS involvement in ALL and to establish a new prophylaxis on the basis of this mechanism. We found that ALL cells migrate into the CNS along vessels that pass directly between the vertebral or calvarial bone marrow (BM) and the subarachnoid space. Moreover, the basement membrane of these bridging vessels is enriched with laminin, which is known to coordinate neuronal progenitor cell pathfinding in the CNS. Integrin α6, a subunit of two cell surface laminin receptors, is expressed in the majority of ALL cases. We showed that PI3Kδ inhibitors suppressed the migration of ALL cells to the CNS in ALL mouse models because integrin α6 expression is regulated by PI3Kδ. Our data suggest that ALL cells have alternative routes that are involved in the CNS, and PI3Kδ inhibitors have the potential to prevent of the CNS involvement in ALL.

Central nervous system (CNS) involvement in acute lymphoblastic leukemia (ALL) has been considered as a feature of high-risk disease. Although this risk is mitigated by current intended CNS-directed treatments based on risk stratification strategies, currently 10% or more of children will die from relapsing or unresponsive ALL. CNS-directed treatments are effective; however, they do not specifically target CNS leukemic cells and are associated with both serious short-term toxicities and debilitating long-term morbidities. Understanding the biology of ALL cells that lodge in the CNS may lead to the development of drugs that specifically target them, and this could further improve outcomes with fewer complications. Using patient samples and patient-derived xenograft (PDX) models, we found that CNS-derived leukemic cells had transcriptional signatures indicative of physiological adaptation to hypoxic microenvironments, and VEGFA is one of the most up-regulated genes in CNS-derived leukemic cells. An in vivo preclinical assay showed that VEGFA could be targeted to treat patients with ALL and who have CNS involvement. We are now focusing on a therapeutic strategy against CNS leukemia using CART cells. These observations may be useful for not only further mechanistic research, but also future clinical trials.

[Introduction] Challenges are associated with treating acute leukemia that relapsed in the central nervous system (CNS) after conventional modalities have been administered. [Case] A 10-year-old girl was diagnosed with mixed-phenotype acute leukemia with BCR-ABL1. The disease was resistant to induction chemotherapy, and re-emerged after a short success with dasatinib. She underwent bone marrow transplantation (BMT) from her father. The disease relapsed in the CNS when she was 12 years old. The CNS overt relapse was successfully treated by cerebrospinal irradiation, and minimal residual disease in the bone marrow went into molecular remission following the intravenous infusion of peripheral blood lymphocytes from her mother (a non-BMT donor). When she was 13 years old, the disease relapsed in the CNS again. Intrathecal infusion of maternal lymphocytes was initiated. Maternally derived cells in the cerebrospinal fluid (CSF) were replaced with paternal-type lymphocytes, BCR-ABL1-positive leukemic cells were no longer detected 1 week after the first trial, and symptoms disappeared. These effects lasted for 2 months. [Discussion] Paternal-type lymphocytes in the CSF were activated and presumably recruited from the peripheral blood of the patient. This intrathecal cell therapy exerts similar effects to cytokine therapy and may overcome the anergy of BMT-donor-derived lymphocytes against leukemic cells. [Conclusions] The current treatment was safe and effective. It also provides insights into the mechanisms underlying the significance of cell-immune therapy.

Oncogenic fusion genes, including ALK, ROS1, NTRK1, NTRK2, and NTRK3, have been detected in various subtypes of tumor. These genes encode human receptor tyrosine kinases, and promising, molecular-targeted agents have been developed for these fusion genes. Recent studies have revealed these fusion genes in pediatric brain tumors, especially infantile glioma and some very rare histological subtypes. In 2019, NTRK inhibitors were clinically approved for NTRK fusion-positive refractory or relapsed pediatric solid tumors. In this paper, we review the current knowledge of pediatric brain tumors and these targetable fusion genes. To develop better treatment strategies and to further expand the clinical application of molecular-targeted agents, various matters must be assessed, including the clinical and pathological features of cases harboring fusion genes, the appropriate timing and duration of the administration of inhibitors, and the mechanisms of resistance to the inhibitors.

It is difficult to perform clinical studies on children with rare renal tumors, such as clear cell sarcoma, rhabdoid tumor, or recurrent tumor, because the number of cases is too small in Japan. For these tumors, international collaboration is necessary. The Japan Wilms Tumor Study (JWiTS) Group has performed clinical trials according to the study protocol established by the National Wilms Tumor Study (NWTS) Group in the USA. The studies of the NWTS Group were succeeded by those of the Children’s Oncology Group (COG) in the USA. The new studies of COG consisted of several parts of protocols, and biological analysis is necessary for risk classification. Therefore, it is difficult for us to collaborate with COG. The renal tumor committee of the International Symposium of Paediatric Oncology (SIOP) started a new clinical study protocol called “Umbrella”, which covers all the pediatric renal tumors. It is easy to join this study from all over the world, and we will be able to compare the biological differences of Wilms tumor between Japanese and European populations. Therefore, the JWiTS Group is now preparing to join the SIOP-Umbrella protocol.

International collaboration is an effective way of studying rare diseases such as childhood solid tumors. Currently, the solid tumor division of the Japan Children’s Cancer Group is working on three international collaborative clinical studies of liver tumors, extracranial germ cell tumors, and renal tumors. Data from these studies are managed by the data center of the National Center for Child Health and Development. However, some problems due to the differences in the contents of protocol between Japan and other countries, such as those in research implementation system, clinical data collection, and adverse event reporting, have been found. In particular, management of the qualification of participating institutions and researchers affiliated with the institution is strictly required in collaboration with the United States. Furthermore, some other problems exist, such as ensuring the expected patient number, collaborating with medical facilities for adults especially in cancers occurring in young adults, collection and provision of information in collaboration with overseas institutions, and difficulties due to the disparity between foreign rules and the Japanese Clinical Trials Act. There are still many challenges in supporting international collaborative studies including data management; therefore, we have to gain further experience and resolve problems found in the collaboration.

With the introduction of integrated diagnosis in the revision of the 2016 World Health Organization (WHO) classification, the clinical management of pediatric brain tumors has undergone significant changes. Pediatric gliomas frequently harbor targetable genetic alterations, such as BRAF V600E and NTRK fusions, and rarely have adult-type genetic alterations such as IDH mutations. The use of immune-checkpoint inhibitors is a promising strategy for a small genetic subgroup of pediatric gliomas. Treatment strategies based on genetic alterations determined by multigene testing are now required. In contrast, medulloblastomas (MBs) have a few directly targetable abnormalities; however, precise risk stratification has become possible through detailed genetic analysis. Radiotherapy, including high-dose craniospinal irradiation (CSI), is still the main treatment strategy. A recently published study from the Japan Pediatric Brain Tumor Consortium (JPBTC) revealed promising results with high-dose chemotherapy (HDC). High-risk MB patients treated with HDC added to the main treatment strategy achieved more favorable outcomes than standard-risk MB patients treated without HDC. Treatment optimization based on genetic subgroups is necessary. After the identification of specific genetic alterations in an atypical teratoid rhabdoid tumor (ATRT), an increased number of patients with ATRT have been reported. Although the efficacies of radiation therapy and intrathecal chemotherapy are well known, the clinical benefits of treatment strategies including CSI are unknown. The standard treatment of ATRT is still under development.

Internal tandem duplication (ITD) mutations in FLT3 are common in acute myeloid leukemia (AML) and are associated with poor prognoses. Here, we report the case of a pediatric patient with FLT3-ITD-positive refractory AML treated with gilteritinib, a FLT3 inhibitor. A 13-year-old boy diagnosed as having FLT3-ITD-positive AML de novo was initially treated with cytarabine, mitoxantrone hydrochloride, and etoposide. At the end of this induction therapy, a bone marrow evaluation revealed no response (90% blasts). The patient was treated with a second phase of standard induction chemotherapy followed by oral administration (80 mg/day) of gilteritinib, a tyrosine kinase inhibitor. He showed an excellent response to this therapy and achieved complete remission as shown by bone marrow evaluation. He then completed the second and third courses of chemotherapy with gilteritinib. He displayed sepsis and herpes zoster, which were considered grade 3–4 adverse events regardless of the treatment. He also exhibited treatment-related adverse events: elevated aspartate aminotransferase and alanine aminotransferase levels. He was in complete remission when he underwent a human leukocyte antigen (HLA) -mismatched (mismatch at the HLA-DR locus) unrelated donor allogeneic transplant. His one-month bone marrow aspiration demonstrated 99% donor chimerism and FLT3-ITD-negative remission. This case highlights the finding that the use of gilteritinib in combination with chemotherapy is well tolerated and effective, even in patients with FLT3-ITD-positive refractory AML. This treatment offers hope to some individuals with similar cases.

Hepatoblastoma (HB), the most common pediatric liver cancer, has the highest association with the mutational activation of β-catenin. However, the underlying mechanism by which Wnt/β-catenin signaling induces HB tumor formation is unknown. Here, we identify growth regulation by estrogen in breast cancer 1 (GREB1) as a previously unknown target gene of Wnt/β-catenin signaling. GREB1 promoted the proliferation and suppressed the differentiation of HB cells. GREB1 bound Smad2/3 and competed with histone acetyl transferase p300 in the nucleus, resulting in the inhibition of TGFβ-dependent cytostasis. GREB1 was overexpressed in tumor lesions of 10/11 HB cases (90.9%) and in a public dataset of patients with HB. The region-specific expression pattern of GREB1 in HB tissues tended to be positively correlated with the accumulation of β-catenin. Forced expressions of β-catenin, YAP, and c-Met (BYM) induced HB-like liver tumor in mice, with increases in the expression levels of GREB1 and HB marker genes; GREB1 knockdown suppressed the expression of HB marker genes and tumor formation in BYM mice. Furthermore, we synthesized amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides (ASOs) that target human GREB1. GREB1 depletion by ASO injection suppressed HepG2-derived liver tumor formation in mice. These findings uncover a previously unrecognized involvement of the Wnt/β-catenin-GREB1-Smads axis in HB pathogenesis, suggesting that GREB1 represents a potential therapeutic target for β-catenin-driven HB.

The specific cytogenetic abnormality in about 60% of patients with alveolar rhabdomyosarcoma (RMS) is the fusion gene PAX3-FOXO1 (P3F), and the prognosis of P3F-positive RMS is much worse than those of P3F-negative RMS. Thus, novel therapeutics for the treatment of P3F-positive RMS are desperately needed. Myogenic differentiation 1 (MyoD) and myogenin (MYOG) play important roles in skeletal muscle differentiation. Both MyoD and P3F are upstream regulators of MYOG. Interestingly, it was reported that when the MEF2 binding site in the MYOG promoter (pMYOG) was mutated (mMEF2), MyoD transactivation was abolished, but the P3F transactivation was not affected. Two RMS cell lines, Rh30 (P3F-positive) and RD (P3F-negative), and normal skeletal muscle cells (SkMC) were used in the following experiment. We prepared pMYOG-controlled OAd (M-OAd) with and without mMEF2 (M-OAd-WT and M-OAd-m, respectively) and evaluated their characteristics. In the comparison of the cytolytic effect of M-OAd on RMS cells, both M-OAds were found to kill Rh30 cells under a low titer condition that can be used clinically, whereas M-OAd-m showed a one order of magnitude lower cytolysis in RD than M-OAd without mMEF2. Neither M-OAds replicated nor killed SkMC. In an in vivo study, both M-OAds strongly suppressed tumor growth derived from Rh30 regardless of the presence or absence of mMEF2, and they could spread intratumorally as much as the multitargeted positive control virus. Our findings indicated the applicability of the MYOG promoter to the design of the oncolytic adenovirus for RMS. Additionally, M-OAd might be useful for enhancing its specificity and safety with mutation in the MEF2 binding site.

Both prednisolone and dexamethasone play crucial roles in the treatment of acute lymphoblastic leukemia (ALL); however, they are associated with various complications. We compared the adverse events associated with two steroid-containing protocols (prednisolone, 40 mg/m²/day for 2 weeks and dexamethasone, 10 mg/m²/day for 2 weeks) used in the re-induction phase of the treatment of newly diagnosed B-cell precursor ALL in 56 consecutive children treated at our institution between 2009 and 2017. The first 26 patients (ALL02 group) diagnosed before 2012 received 26 courses of chemotherapy, including prednisolone in the re-induction phase, and the remaining 30 patients (B12 group) diagnosed from 2012 to 2017 received 56 courses of chemotherapy, including dexamethasone in the re-induction phase. The symptoms and laboratory findings during the re-induction phase were compared between these patient groups on the basis of their medical records. Liver dysfunction, hypercholesterolemia, hypoproteinemia, obesity, febrile neutropenia, and glucose intolerance were more frequent in the B12 group than in the ALL02 group. Fibrates for hypercholesterolemia were frequently used in the B12 group; furthermore, abnormal glucose tolerance requiring insulin administration occurred only in the B12 group. Active prevention and early treatment should be considered for patients treated with dexamethasone in the re-induction phase of ALL therapy as dexamethasone use was found to be associated with a higher incidence of steroid-associated adverse events than prednisolone use.

The intravenous form (IV) of busulfan (Bu) can be stably administered, but there are few large-scale studies on its safety and efficacy in children. We performed a retrospective analysis of 83 pediatric patients who received IV Bu before undergoing stem cell transplantation at our center from January 2007 to September 2017. In these 83 patients (44 with solid tumors, 13 with acute myeloid leukemia, 12 with acute lymphocytic leukemia, 6 with myelodysplastic syndrome, 2 with malignant lymphoma, 2 with hematopoietic disorder, 2 with immunodeficiency, and 2 with others), stem cell transplantation was performed 90 times, including 77 instances of myeloablative conditioning. The median age was 5 years (range, 5 months–16 years), and the male:female ratio was 50:33. We performed autologous hematopoietic stem cell transplantation in 50 patients and allogeneic hematopoietic stem cell transplantation in 40 patients. The three-year overall survival (54.0% vs 59.1%, p=0.34), 1-year nonrelapse mortality (18.7% vs 21.4%, p=0.39), and engraftment rates (88.2% vs 96.7%, p=0.65) did not significantly differ between the IV-BU- and oral-BU-treated groups. Twenty-seven (30%) patients received Bu once daily. Three patients showed interstitial pneumonia (3.3%), 13 showed hepatic sinus occlusion syndrome (14.4%), 4 showed central nervous complications (4.4%), and 6 showed bronchiolitis obliterans (6.7%), but there were no significant differences between the IV-BU-treated and oral-BU-treated groups. The survival rates and adverse effects were similar in both the once-daily and four-times-daily IV-BU-treated groups. In conclusion, the efficacy and safety of IV Bu in pediatric patients are equivalent to those of oral Bu. Bu administration once daily exhibited similar safety and efficacy.

To elucidate the needs of childhood cancer survivors (CCSs) and to determine the support they require, we conducted a retrospective analysis of CCSs who visited the dedicated outpatient department for long-term follow-up (LTFU) at our institution. Details about consultations between July 2014 and March 2017 were collected from the medical records of 216 consecutive patients. Qualitative and inductive analyses of the collected data were conducted. The collected information included 454 patient concerns, which were divided into the following five main categories: (i) concerns about physical symptoms associated with past treatments, (ii) current psychosocial problems, (iii) anxiety about possible future symptoms and events, (iv) requests for required information and support, and (v) difficulties not associated with childhood cancer. Most of the consultations were related to physical symptoms that affected daily life such as pain and fatigue. Regarding psychosocial aspects, there were numerous consultations about emotional instability and disease notification. The following five principal needs for LTFU were identified: (i) appropriate therapeutic intervention for physical symptoms, (ii) longitudinal support for psychosocial problems by co-medical staff, (iii) reduction of anxiety about the future, (iv) predictive support according to developmental stages and life events, and (v) role of a general pediatrician. Our study indicates the importance of screening for CCSs with predictable problems and requiring longitudinal support, as patient needs vary depending on the underlying disease, treatments, age, and social backgrounds.

The purpose of this study was to understand the difficulties faced by children who have recovered from cancer and their psychosocial support during their growth and development after school re-entry. The subjects were 14 child cancer survivors aged 18 to 26 years, who had completed their treatment three or more years before. A qualitative descriptive analysis was conducted on the basis of the results of semistructured interviews. From 37 subcategories of 94 codes, 15 categories including 6 major categories of difficulties were extracted. Factors of difficulty were associated with school life and work. It was found that childhood cancer survivors had difficulties in school life, such as “absenteeism from classroom because of decreased physical fitness after chemotherapy.” As for difficulties in relationships and communication with friends, they felt “frustrated from being incapable of interacting in a group owing to decreased physical fitness or on-going treatment,” and faced confusion and conflict about changes observed in oneself after admission to school, such as “an awareness of identity differences before and after returning to school, and lowered motivation.” Furthermore, they suffered from study delays and a disadvantage in further education owing to hospitalization and outpatient therapy. Physiological and psychological late effects of cancer affected their career and postemployment. These findings suggest that the construction of a system in which teachers and care providers discuss psychosocial problems and provide continuous support is important for childhood cancer survivors to redefine their self-concept and establish their new roles throughout their school life.

A 6-year-old boy presented with cough and dyspnea. Computed tomography revealed a mediastinal mass and left-side plural effusion. T-lymphoblastic lymphoma was diagnosed on the basis of cytologic findings of the pleural fluid. Following induction therapy, radiological examination confirmed complete remission. However, after five chemotherapy courses, positron emission tomography showed abnormally high uptake in the anterior mediastinum. The mass was biopsied; examination revealed a relapse and a t(9;17)(q34;q23) chromosome abnormality. He showed poor response to the ifosfamide, carboplatin, and etoposide (ICE) regimen and nelarabine, and bone marrow involvement was observed following the chemotherapy. He underwent cord blood transplantation (CBT), with a myeloablative regimen comprising 180 mg/m² melphalan and 12 Gy of total body irradiation at nonremission status; however, a bone marrow relapse was detected on day 21. He died of disease progression on day 70 after CBT. Considering the adverse prognostic features related to this chromosomal abnormality, identification of the fusion gene and novel strategies, including molecular targeting therapy, are warranted.

An 11-year-old girl developed intermittent numbness and pain in the soles of both feet. After a month, she experienced numbness in both arms and diarrhea. Abdominal computed tomography (CT) revealed extensive tumors in the retroperitoneal cavity and obstructed ureters. Because of elevated levels of serum potassium (8.8 mEq/L) and creatinine (16.8 mg/dL), we performed hemodialysis on admission and bilateral ureteral stenting the next day for acute renal failure. CT/MRI demonstrated tumor invasion into the spinal canal from L4 to S1. We diagnosed the patient as having mature B cell lymphoma on the basis of retroperitoneal biopsy findings. Treatment in accordance with the guidelines of JPLSG B-NHL-14 was commenced, and a week later, the patient’s neurological symptoms disappeared. After nine months, the patient was in complete remission. Her serum creatinine level became normal. Previous reports showed that most patients with pediatric malignant lymphoma/leukemia of the retroperitoneum or kidney with acute renal failure recovered their renal function and had a favorable prognosis after appropriate treatment in the acute phase. These suggest that it is important to perform prompt initial treatments.

A previously healthy 1-year-old boy presented with persistent fever, cough, and tachypnea at a local hospital. Chest X-ray suggested diaphragmatic hernia; thus, he was referred to our hospital. Laboratory examinations and imaging studies indicated congenital pulmonary airway malformation accompanied by pulmonary infection. Although the patient’s symptoms improved after antibiotic administration, they later recurred. A partial lung excision was performed, and a histopathological examination revealed pleuropulmonary blastoma. Homozygous mutations in DICER1 were detected in the tumor cells, but not in the germline. He received the ifosfamide, vincristine, dactinomycin, and doxorubicin (IVADo) regimen after surgery, after which he remained in remission for over 9 months. Pleuropulmonary blastoma is a rare malignant tumor with poor prognosis, and some patients have germline DICER1 mutations associated with various malignancies. Pleuropulmonary blastoma should be considered as a cystic lung disease. Moreover, long-term follow-up is required to detect relapse and distant metastasis.

Here, we report the cases of two patients who presented with immune thrombocytopenia (ITP) after receiving intravenous immunoglobulins (IVIGs) for the treatment of their Kawasaki disease (KD). In addition to IVIGs, they were also administered oral aspirin. Although their KD symptoms were promptly ameliorated, the platelet counts of the first and second patients decreased 13 and 21 days after the diagnosis of KD, respectively. The complication was diagnosed as ITP, and they received further IVIG therapy using another type of immunoglobulin, after which the patients’ platelet counts increased. There have been few reports on KD complicated by ITP, and none of the reported cases involved IVIG therapy. Our patients received another type of IVIG for their ITP in addition to IVIGs administered for their KD, and their platelet counts promptly increased. Our cases suggest that IVIG therapy is a treatment option for ITP that arises after the administration of IVIGs for KD. However, IVIGs should be used carefully because of the risk of IVIG thrombosis.

Background: Pharmacological pain management issues in pediatric cancer patients in Japan have not been identified.

Methods: A cross-sectional investigation at 155 institutions belonging to the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) was conducted between October 2015 and March 2016 by web survey, addressing pharmacological pain management issues in each institutional policy.

Results: The eligible responses were obtained from 81 institutions (response rate, 52%). Among these institutions, 98% provided pain management by pediatric oncologists, and 37% were aware of and implemented the World Health Organization (WHO) guidelines published in 2012. The first choice of analgesics for mild pain was oral acetaminophen. For more-than-moderate pain, low-dose strong opioids or pentazocine were used at some institutions. Immediate-release oral morphine and transdermal fentanyl were the first choices among strong opioids in cases without blood access in 48% and 47% of institutions, respectively. On the other hand, intravenous morphine and intravenous fentanyl were the first choices in cases with blood access in 80% and 68% of institutions, respectively. Pregabalin was administered for neuropathic pain. Steroid was administered for bone pain. Radiation therapy and nerve block were also performed at 36% and 7% institutions, respectively.

Conclusions: Pediatric oncologists were the main providers of pharmacological pain management. Although some off-label analgesics and adjuvants, as well as radiation therapy and nerve block are not mentioned in the guidelines, they were actually used in some hospitals. These should be carefully investigated for indications, proper use, efficacy, and safety.