The International Neuroblastoma Pathology Classification, which is used to distinguish the Favorable Histology (FH) and Unfavorable Histology (UH) Groups among peripheral neuroblastic tumors, has been incorporated into the Children’s Oncology Group (COG) neuroblastoma clinical trials and plays a significant role in patient stratification and protocol assignment. Since the survival rate of patients in the UH Group is still very low, we have been continuously investigating biologically relevant relationships between molecular alterations leading to a poor prognosis of the patients and their histological/cytological manifestations. First, we established a new concept of MYC-driven neuroblastoma and demonstrated that either n-MYC or c-MYC oncoprotein overexpression has a more direct prognostic impact than genomic amplification. In this subgroup of UH neuroblastomas, nucleolar hypertrophy is found to be the sign for sustaining higher levels of n-MYC/c-MYC oncoprotein expression. In addition to MYC-driven neuroblastomas, we are proposing to include telomere-related gene alterations, such as telomere reverse transcriptase (TERT) overexpression and alternative lengthening of telomere (ALT) phenotype activated by the loss of the alpha-thalassemia/mental retardation syndrome X-linked (ATRX) protein, for identifying new subgroups in the UH neuroblastomas. Classifying/stratifying the patients in the UH neuroblastomas into four subgroups, namely, MYC, TERT, ALT and Null, on the basis of immunohistochemically identifiable and actionable/druggable targets could lead to future precision pathway-targeting therapies.

In the past, liver surgery relied heavily on the experience of surgeons, and it took many years to understand the anatomy of the liver and develop various techniques. However, owing to recent advances in image analysis systems and the spread of dye fluorescence methods, preoperative simulations and intraoperative navigations have become indispensable for performing safe and accurate hepatectomy. In this paper, we highlight the progress of simulation and navigation in the field of liver surgery and also details our efforts during this process. The main preoperative simulations used in liver surgery include a method of displaying a contrast-enhanced CT image in 3D on the screen and rendering it as an actual 3D model. The purpose of intraoperative navigation is to accurately identify the excision area, the position of the tumor, and the vessel to be ligated. The course of intrahepatic vessels varies greatly from case to case, and they cannot be visualized easily as they are covered by the thick hepatic parenchyma. Correct hepatectomy is possible by accurately aligning the understanding of the preoperative simulation with the actual liver through intraoperative navigation by various methods.

Chimeric antigen receptor (CAR)-T cell therapy is a cell-based cancer immunotherapy that utilizes autologous T-lymphocytes genetically modified with the chimeric antigen receptor (CAR) gene. CD19-targeted CAR-T cell therapy (tisagenlecleucel) has shown dramatic treatment results in patients with relapsed and refractory acute lymphoblastic leukemia, and was approved in the US in 2017 as well as in Japan in 2019. In this article, I review the history of CAR development, from the initial developmental stage to clinical success. In addition, I describe differences in the results of CAR-T cell therapy using different costimulatory signals and a brief history of CAR-NK cell therapy.

Epidemiology is “the study of the distribution and determinants of health-related states or events in specified populations, and the application of this study to the prevention and control of health problems”. A population-based cancer registry (PBCR) represents the gold standard for the provision of information on cancer incidence or survival in a defined population. PBCRs can serve to identify the possible causes of cancer in a community and to assess the impact of cancer control activities. In Japan, PBCRs were initially conducted at the prefectural level before being expanded to the national level in 2016 in accordance with the Promotion of Cancer Registries Act of 2013. According to a recent report from the national cancer registry, in 2017, the annual number of new cancer cases in children aged 0–14 was 2,223 (only malignant cases, excluding cancer in situ), and the age-standardized incidence rate was 148.6 per million. In 2018, the World Health Organization (WHO) launched the Global Initiative for Childhood Cancer with the aim of reaching at least a 60% survival probability for children with cancer by 2030. To monitor the incidence or survival probability of childhood cancer among the entire child population, PBCRs are essential. This paper provides an introduction to the basic principles, methods or study examples of descriptive epidemiology of childhood cancer.

Introduction: Desmoid tumor (DT) is a very rare mesenchymal tumor and has local aggressive behavior with no distant disease. Although the wait-and-see strategy and tumor resection are first-line therapies, complete surgery is often challenging because of the invasion of the muscle and the fascia and a high tendency of local recurrence. To avoid cosmetic or functional sequelae, chemotherapy is selected as a treatment option.

Method: Five cases of pediatric desmoid tumors treated with chemotherapy at the National Cancer Center Hospital were analyzed retrospectively.

Result: The median patient age at diagnosis was 12.0 y (7.3–14.6 y), and the tumor involved the upper limb in three patients, the lower limb in one patient, and an intra-abdominal site in one patient. Methotrexate (MTX)+vinblastine (VBL) was given to four patients, pazopanib to three patient, and doxorubicin to one patient. One patient achieved partial response (PR), and in one patient, the disease was maintained stable over one year with MTX+VBL. A 14-year-old-girl with femoral DT was successfully treated with pazopanib for six months; after achieving good PR, tumor resection was performed, and her contracture improved considerably after treatment. A 12-year-old boy with a family history of Gardner syndrome had multiple intra-abdominal DTs, and his DT was resistant to MTX+VBL or pazopanib; he experienced repeated abscess formation or intra-abdominal rupture because of rapid tumor growth. He achieved PR with doxorubicin monotherapy.

Discussion: In our experience, disease control was generally possible with chemotherapy in pediatric cases of DT. DT with Gardner syndrome showed resistance to chemotherapy, similar to previous reports.

Various tumor-profiling multiplex gene panels are being developed, some of which are covered by National Health Insurance in June 2019. Some patients cannot receive targeted therapy even when actionable alterations are detected, because agents for targeted therapy of their disease are not approved. The first option for such patients is to participate in a registration-directed trial for drug approval; however, it is impossible for them to join when they do not fit the eligibility criteria. Therefore, a new trial called “BELIEVE”, which aims to improve drug access, has been planned. The BELIEVE trial is designed as a basket/umbrella trial and conforms to patient-proposed healthcare services—a system within the mixed billing system to apply a combination of treatments covered and not covered by the public health insurance. Patients aged 16 or older with solid tumors showing actionable alterations detected by multiplex gene panel tests are eligible. Patients are assigned to receive treatment on the basis of genetic changes found in their tumors. Treatment is administered in accordance with the directions in the package insert. In each drug cohort, the primary endpoint is response rate. Some collaborating pharmaceutical companies provide drugs for free to reduce the costs borne by the patients. The BELIEVE trial is a multi-institutional study organized by the National Cancer Center Hospital and started in October 2019. This is a novel approach for improving drug access. With the knowledge and experience gained from the BELIEVE trial, we wish to further discuss the use of a similar platform for pediatric patients.

Proton beam therapy for pediatric malignant solid tumors has recently been covered by the national health insurance in Japan, and opportunities for surgical spacer placement have increased, facilitating more effective radiotherapy. We performed spacer placement using an expanded polytetrafluoroethylene (ePTFE) sheet as a spacer material for four children with malignant pelvic tumors. The tumor surface was covered with five 2-mm-thick patches to secure a 10-mm margin, which reduced the exposure of the intestine and prevented dose reduction at the tumor edge. In all these patients, no postoperative complications were observed, and proton beam irradiation was performed as planned. Since the safety of the ePTFE sheet remaining in the body has not been established, we removed the spacer after irradiation in three of these patients. Recently, a bio-absorbable spacer has been developed; thus, ePTFE sheets are expected to fall out of use as spacers in the future. However, it is possible to apply spacer placement techniques to absorbent spacers as well. We herein summarize and report our experiences in treating these four patients.

Paroxysmal nocturnal hemoglobinuria (PNH) is rare in children. Most childhood PNH involves progression from aplastic anemia (AA). A 15-year-old girl presented with pancytopenia and severe hypoplastic bone marrow. PNH-type blood cell-positive AA was diagnosed from findings that 1.9% of red blood cells (RBCs) and 50.6% of granulocytes were PNH-type blood cells (CD55^–/59^–). She received immunosuppressive therapy (IST) and achieved complete remission six months later, but her disease then became chronic. At 23 years of age, she showed thrombocytopenia and hemolytic anemia. Bone marrow findings showed erythroid hyperplasia, and percentages of PNH RBCs and PNH granulocytes were 24.4% and 84.6%, respectively. AA-PNH syndrome was diagnosed. About 4–9% of cases of AA in adulthood progresses to PNH. Cases of childhood AA in remission after IST require long-term follow-up into adulthood for hemolytic anemia and PNH-type blood cells.

Here, we report the case of a 14-year-old female, who presented with a headache and severe hypereosinophilia (269×10³/μL). Fluorescence in situ hybridization analysis showed she was negative for the FIPIL1-PDGFRα fusion gene, FDGFRβ, and FGFR1. Molecular testing of the patient’s bone marrow showed no evidence of T-cell receptor rearrangement. Therefore, she was diagnosed as having hypereosinophilic syndrome. Although she was initially treated with prednisolone (PSL), hydroxyurea (HU) was added as a second-line treatment, as her condition was unchanged. Upon the initiation of HU, the patient’s eosinophil count improved markedly. HU was discontinued after four months of treatment. The patient’s eosinophil count remained normal for 1 year since the end of the therapy. Our patient exhibited an immediate marked response to HU and did not suffer organ failure. However, there are no guidelines about the tapering and cessation of HU, and it is considered that careful observation and the accumulation of cases are necessary.

We describe the case of a patient with ovarian relapse of B-lymphoblastic leukemia (B-ALL) 4 years after primary diagnosis, who has been in remission following second-line chemotherapy, bilateral salpingo-oophorectomy, and unrelated cord blood transplantation (UR-CBT). A four-year-old girl was diagnosed as having ETV6/RUNX1-positive B-ALL. She achieved complete remission (CR) after treatment in accordance with a BFM-based protocol. Two years after completing chemotherapy, laboratory examination revealed elevated creatinine, BUN, and LDH levels. CT showed bilateral hydronephrosis and ovarian tumors. Ovarian relapse of ALL was confirmed by laparoscopic biopsy. Although she remained in bone marrow remission, FDG-PET-CT demonstrated multiple lesions in the retroperitoneum, mediastinal lymph node, and liver. She achieved a second CR after BFM-oriented chemotherapy for recurrent ALL, followed by bilateral salpingo-oophorectomy and UR-CBT. She has remained in CR for 20 months since UR-CBT. Unlike testicular relapse, ovarian relapse in ALL is rare. This case may provide insight into the management of ovarian relapse in ALL.

Emicizumab is a bispecific antibody used for hemostasis by binding with activated coagulation factor (F) IX and FX rather than activated FVIII. We report on the case of a 6-year-old boy with inhibitor-positive hemophilia A who has been treated with emicizumab. When he was 9 months old, the patient was found to have severe hemophilia A, for which recombinant (r) FVIII was administered as a replacement therapy. When he was 1 year and 7 months old, he had a severe hematoma due to buttocks bruising, and an FVIII inhibitor was detected. The patient received activated prothrombin complex concentrates as a bypass hemostasis therapy and an rFVIII replacement for immune tolerance induction (ITI). Because the FVIII inhibitor has not disappeared, emicizumab has been administered every two weeks since the patient was 5 years and 4 months old. Emicizumab has had excellent prophylactic effects against bleeding, has reduced injection stress, and has improved the quality of life of patients with ITI failure.

An 11-year-old girl presented with hematuria and disturbance of consciousness, and was later diagnosed with bladder tumor. Trans-urethral resection of the bladder tumor showed that it was covered with rough-surfaced reddened mucosa and active bleeding was observed from the top of the mass. Inflammatory myofibroblastic tumor (IMT) was diagnosed postoperatively. Partial cystectomy was additionally carried out because of the possibility of IMT recurrence. IMT should be differentiated from rhabdomyosarcoma, although bladder tumor in childhood is very rare. The primary treatment for IMT is resection of the tumor and careful monitoring for recurrence must be undertaken.