In 1971, “Wilms” tumor was intensively discussed at the Pediatric Oncology Meeting hosted by The Japan Pediatric Society and The Japanese Society of Pediatric Surgery, with the support of the Children’s Cancer Association of Japan. This Meeting was taken over by the Japanese Study Group for Pediatric Cancer in 1985 and by the Japanese Society for Pediatric Cancer in 1991. The Japan Wilms Tumor Study (JWiTS) was founded in 1996 by Haruo Ohkawa. This project aimed to:

1. Introduce a nationwide unified protocol (NWTS protocol).

2. Introduce a central pathological diagnosis system.

3. Establish a database.

4. Promote molecular biology research.

In 2003, the JWiTS was extensively developed by Masahiro Fukuzawa and was taken over by the Japan Children’s Cancer Research Group Renal Tumor Committee (JCCG-RTC). As the results of the JWiTS-1 (1996–2005) have shown, the concordance rate between the facility and central pathology was poor (81.7%). The JWiTS-2 (2006–2014) requesting to submit the specimens to the central pathology, Wilms tumors at stages I to III had a relapse-free survival (RFS) and overall survival (OS) of 90% or higher. However, in stage IV, RFS was 66.2%, and OS was 84.6%, which demands improvement. The subtypes of Wilms tumor—anaplastic Wilms tumor, blastemal predominant Wilms tumor, and bilateral Wilms tumor—are noteworthy. Clear cell sarcoma of the kidney has an RFS of 33.3%, and the rhabdoid tumor of the kidney has a poor prognosis with an OS of 25% and RFS of 18.8%. In 2014, the JCCG-RTC decided to participate in the Umbrella Protocol of the International Society of Pediatric Oncology (SIOP) Renal Tumor Study Group.

The development of inhibitors is one of the most serious complications in patients with hemophilia (PwH). International studies have reported that certain genetic and treatment-related factors are associated with inhibitor development in PwH. However, the genotype distribution of the factor (F) VIII(IX) gene (F8 or F9) and its impact on inhibitor development in Japanese PwH remain unknown. In 2007, the Japan Hemophilia Inhibitor Study 2 (J-HIS2) was organized to establish a nationwide registry system for PwH and to elucidate the risk factors for inhibitor development; it was designed as a prospective investigation following a retrospective study, J-HIS1. Patients newly diagnosed after January 2007 were enrolled in the J-HIS2 and followed up for inhibitor development and clinical environments from 2008 to 2020. Of the 417 patients (340 PwHA and 77 PwHB) from the 46 facilities enrolled in the study, 83 (76 PwHA and 7 PwHB) were recorded with inhibitors. Inhibitors were observed in 31.0% of severe PwHA cases, 8.0% of moderate PwHB cases, 1.6% of mild PwHB cases, and 17.1% of severe PwHB cases. Most inhibitors (89.7% in severe PwHA and 71.4% in severe PwHB) were detected within 25 days of exposure. Genotyping of these patients revealed an association between inhibitor development and null variants of F8 (p<0.01) or F9 (p<0.05). Based on the final results of J-HIS2 and detailed information on the F8 genotype identified in PwHA enrolled in the J-HIS studies, the prospects of treatment in consideration of inhibitor development are discussed in this section.

von Willebrand disease (VWD) is a congenital bleeding disorder that is caused by quantitative and qualitative abnormalities in the von Willebrand factor (VWF); moreover, VWD is associated with an extremely diverse pathophysiology. VWD is classified into the following subtypes: quantitative defects (Type 1), qualitative defects (Type 2), and near-complete absence of plasma VWF (Type 3). Further, type 2 VWD is subcategorized into types 2A, 2B, 2M, and 2N. The most common symptom of VWD is mucocutaneous bleeding due to impaired primary hemostasis, typically menorrhagia in women with VWD. Hemarthrosis and intramuscular hematoma due to impaired secondary hemostasis occur in Type 3 and 2N, wherein the level of coagulation factor VIII is markedly decreased. Distinguishing between patients with VWD and healthy individuals based exclusively on their bleeding symptoms is challenging, since mucocutaneous bleeding and menorrhagia occur even in healthy individuals. Patients with VWF levels <30% are diagnosed with VWD; however, accurate diagnosis is difficult in some cases because numerous factors affect the plasma VWF levels. Consequently, VWF levels vary across a wide range (50–200%), even in healthy individuals. Desmopressin and VWF concentrate are used for the treatment of VWD. In addition to plasma-derived VWF/FVIII products, recombinant VWF is also available for clinical use. A clear understanding and knowledge regarding the characteristics of VWF and the diverse pathophysiology of VWD is important for the accurate diagnosis and treatment of VWD, based on the new clinical practice guideline established by the Japanese Society on Thrombosis and Hemostasis.

In the context of particle therapy for malignant abdominal tumors, the significant challenge of radiation-induced damage to the gastro­intestinal tract in close proximity to the tumor hinders the effective delivery of a curative dose. To address this limitation, a spacer implantation technique was developed at Kobe University. This technique involves inserting an ePTFE sheet between the tumor and the gastrointestinal tract during laparotomy as preparation for particle irradiation. It has successfully treated over 200 patients with malignant abdominal tumors between August 2006 and March 2022. Furthermore, our research efforts led to the development of a non-woven absorbable spacer, resulting in the launch of NESKEEP®. From June 2019 to March 2022, more than 50 cases have been performed utilizing NESKEEP®. The NESKEEP® offers advantages due to its enhanced flexibility compared to ePTFE sheets, facilitating easy disassembly, connection, and shaping to fit the tumor, securing it between the tumor and organ. The absorbable nature of the material also expands the use of NESKEEP®, potentially aiding in complicated resections of the gastrointestinal tract and infections. This presentation aims to provide an overview of the surgical techniques employed in NESKEEP® implantation and discuss future issues in absorbable spacer implantation, including its application to pediatric patients.

[Background & Purpose] With recent improvements in the treatment outcomes of childhood cancer, surgical supportive care for pre­serving gonadal function and fertility have become increasingly vital. Herein, we reviewed space-making particle therapy using an absorbable spacer, and reported our surgical experiences of transpositioning and preserving the gonadal glands to avoid irradiation with subsequent pelvic radiotherapy for radiation reduction in children.

[Gonadal Transposition] Three patients with high-risk rhabdomyosarcoma underwent gonadal transposition prior to radiotherapy. One case underwent transposition of the bilateral ovaries laparoscopically, and the other underwent unilateral transposition. In the another case of a male, testicular transposition was relatively easy to perform.

[Ovarian Preservation] Three girls underwent laparoscopic unilateral oophorectomy for ovarian tissue cryopreservation prior to chemotherapy including alkylating agents. All of them had brain tumors and were prepubescent.

[CONCLUSION] An absorbable spacer, gonadal transposition, and ovarian tissue cryopreservation as radiation reduction surgery is feasible and should be considered if applicable. Long-term follow-up is needed to verify the contribution of these surgical procedures towards preserving fertility.

In recent years, along with the overall spread of fertility-sparing therapy, fertility-sparing therapy has also been applied to pediatric patients. Oocyte and ovarian tissue cryopreservation are indicated in girls. Oocyte cryopreservation is a well-established medical technique; however, it cannot be applied to urgent care patients because the controlled ovarian stimulation necessary for oocyte pick-up takes about two weeks. In addition, other conditions are necessary for its implementation, such as having a menstrual cycle and being able to undergo vaginal egg retrieval. In addition, the pregnancy rate from oocyte cryopreservation is fairly low. In contrast, ovarian tissue cryopreservation can be performed even in pre-menarche patients, and the number of days required for preservation is low. However, with diseases that tend to have minimal residual presence in the ovary, such as leukemia, tumor cells may be mixed in with the preserved ovarian tissue, and in some cases the original disease can recur through their transplantation. Our institution has already performed ovarian tissue and oocyte cryopreservation for 78 and 4 children, respectively, and its feasibility has been demonstrated. Reliable registration in a registry system and long-term follow-up are also important for establishing evidence in Japan.

The discovery of sarcoma-specific fusion genes in the 1980s was a major breakthrough in sarcoma research. To date, a variety of sarcoma-specific fusion genes have been identified, which have greatly improved the accuracy of pathological diagnoses. However, the absence of blood-based biomarkers has been a major hindrance to monitor tumor burden. In recent years, attempts have been made to develop liquid biopsies using circulating molecules such as nucleic acids and extracellular vesicles. cf-miRNA was first detected in sarcoma patients by Miyachi et al. Although ctDNA-based methods have recently been approved, these problems include poor sensitivity, high cost, and relatively long turnaround time. Recent advancements in treatment include approvals for the use of targeted agents such as pazopanib, eribulin, and trabectedin for advanced soft-tissue sarcomas. For advanced osteosarcoma and Ewing’s sarcoma, molecular target drugs, including cabozantinib, have been shown to be effective in Western countries but have not yet been approved in Japan. Cancer gene profile testing has brought attention to a wider indication for treatments based on specific genetic abnormalities in sarcomas. Although immune checkpoint inhibitors against sarcomas have not been satisfactory, efforts are being made to develop treatments targeting other immune cells in the sarcoma microenvironment. This article provides an overview of current topics in sarcoma research.

The prognosis remains poor for high-risk patients with neuroblastoma (NB) (older age at disease onset, distant metastases, MYCN amplification, telomere abnormalities, and recurrent cases), and only anti-GD2 antibodies have been recently introduced into clinical practice for the treatment of NB since the 1980s. The development of new therapies such as molecular targeted therapies, immunotherapy, and radiation therapy for high-risk groups with NB is still eagerly awaited. In this review, I will update the status of identifying poor prog­nostic biomarker molecules for NB and the development of targeted therapies against these molecules. The biomarkers of poor prognosis in NB and the development of new therapies targeting them include: 1. telomere abnormalities: TERT and ATRX mutations (ATM inhibitors); 2. epigenome abnormalities (EZH1/2 and DNMT inhibitors); 3. MYCN amplification (Aurora-A, CDK7, BRD, and BET inhibitors); 4. cell cycle pathway abnormalities (CDK4/6 and WEE1 inhibitors); 5. RAS/RAF/MAPK pathway abnormalities (MEK inhibitors); and 6. the ATM/ATR/ARF/MDM2/p53 pathway (CHK1 and MDM2 inhibitors). The molecular mechanisms and current status of drug development and clinical trials will be reviewed.

The treatment outcomes for pediatric acute myeloid leukemia (AML) have been significantly enhanced based on risk-based therapy guided by genomic analysis and treatment response. Recently, progress in genomic analysis has led to genomic abnormalities identification that can be beneficial for prognostic predictions. For instance, in RUNX1::RUNX1T1-positive AML, the presence of KIT exon 17 mutations has been identified as a poor prognostic marker. Pediatric AML cases with KMT2A gene rearrangements have demonstrated varying prognoses, depending on the fusion partner. Furthermore, the analysis of acute megakaryocytic leukemia, a representative pediatric AML subtype, has revealed various genomic abnormalities, including CBFA2T3::GLIS2, NUP98::KDM5A, and KMT2A rearrangements, demonstrating their close association with prognosis. Recently, RNA-seq expression analysis has led to the development of prognostic models, such as the LSC17 and pLSC6 scores based on the gene expression levels of 17 and 6 genes, respectively, which are associated with leukemia stem cells. Single-cell analysis has been attempted, offering insights into cellular hierarchies and potential treatment strategies based on specific cellular fractions. In the future, integration of newly identified genomic abnormalities and prognostic models with treatment responses will result in novel risk stratification development, enabling more precise prognostic predictions and therapeutic development.

In recent years, intensity-modulated radiation therapy and proton beam therapy have been increasingly applied to cranio-spinal irradiation, necessitating precise target considerations. Therefore, we conducted a questionnaire survey on cranio-spinal irradiation to clarify the current treatment landscape at each facility.

We invited 100 facilities affiliated to the Brain Tumor Committee to participate in the survey via e-mail, and received responses from 54 facilities (54%). Of these, 46 utilized photon beam therapy, while 8 employed proton beam therapy. Over a 3-year period, photon beam therapy facilities treated varying number of cases: less than 3 at 24 facilities (52%), 9 at 10 (22%), 18 at 7 (13%), and more than 18 at 2 (4%). In contrast, proton beam therapy facilities treated 1 (13%), 2 (25%), 5 (63%), and 1 (13%) cases, respectively. Eight of the photon beam therapy facilities treated patients with intensity-modulated radiation therapy, and six of these facilities applied tomotherapy. An inquiry into the clinical target volume of cranio-spinal irradiation in proton beam therapy facilities revealed that a few included the cranial nerves, including the optic nerve.

The survey suggests a potential trend towards the increased adoption of high-precision treatments such as intensity-modulated radiation therapy and proton beam therapy. This rising trend necessitates a more detailed definition of the target volume.

In recent years, several measures have been implemented to promote the development of pediatric drugs, generating increasing momentum and expectations. However, pharmaceutical companies still face numerous challenges; continuing collaborations with government agencies, academia, and patient groups is deemed necessary to develop solutions. Current data reveal that over 70% of pediatric drugs approved overseas remain unapproved and approximately half of the domestically unapproved drugs are yet to begin development in Japan. In the initial stages of new drug development (from the creation of new drug seeds to the establishment of Proof-of-Concept in early clinical development), emerging companies in the West have led many cases; the concept of national borders in new drug development is gradually disappearing, with domestically completed cases becoming rare.

In the field of pediatric cancer drug development, this trend is more pronounced. To consider measures to promote pediatric cancer drug development, implementing policies that encourage even emerging overseas companies to show enthusiasm for development in Japan is necessary, without being bound by the concept of “Japanese companies/Japan-originated new drug development.”

In particular, a transparent development scheme for pediatric drugs, a regulatory design that enables rapid marketing, and a guarantee of returns commensurate with investment and business continuity are necessary. For this, the issuance of guidance, regulatory systems not bound by existing mechanisms, and financial assistance (reduction of development costs, drug price allowances, tax incentives, etc.) are anticipated.

In this paper, we share several ideas discussed by the members of the National Council on Pediatric Cancer Measures, which includes Japanese and overseas pharmaceutical companies. We aim to contribute to enhancing access to pediatric cancer drugs in Japan and encourage all stakeholders to continue to cooperate and take action.

Insufficient investment in evidence-based cancer control strategies in Japan is attributed to the rarity and diversity of childhood and AYA (Adolescent and Young Adult) cancers, as well as the lack of understanding of these diseases and patient needs. This paper provides an overview of my epidemiological research, using population-based cancer registry data or clinical research datasets. Moreover, it presents assessments of pediatric cancer care needs for families with children diagnosed with cancer. The paper encompasses the background of these studies and offers insights into my experiences conducting studies abroad.

Since 2013, I have been joined with the Cancer Control Center, Osaka International Cancer Institute, undertaking a survey on the treatment of leukemia and lymphoma among AYA patients in Osaka, etc. In 2015, I studied at the University College London, conducting a comparative study of childhood cancer incidence and survival in Japan and the UK, and a comparative study of Wilms tumor in Japan and the UK. In July 2018, I conducted a brief study at the International Agency for Research on Cancer on international comparisons of childhood renal tumor incidence. Furthermore, in 2020, I analyzed data from the Osaka Cancer Registry to summarize long-term trends in leukemia survival in children and AYAs. From 2018 to 2021, with the cooperation of nine hospitals in Osaka Prefecture, I conducted a survey to assess the needs of families with children diagnosed with cancer, focusing on pediatric cancer care. The scope of this survey is currently being expanded to encompass the Kinki area. I look forward to the results being beneficial for young doctors interested in pursuing research opportunities in the future.

[Background] Nearly 3 years ago, comprehensive genomic profiling (CGP) of patients with advanced solid tumors was provided by national health insurance. Center for Cancer Genomics and Advanced Therapeutics (C-CAT) has been aggregating cancer genome data from CGP testing to establish a database optimized to serve the Japanese populace. We summarized here the challenges of accessing molecular-targeted agents for pediatric patients with solid tumors. [Methods] Using the “C-CAT Data Utilization Portal”, we extracted data from 0–15-year-old patients who underwent CGP testing between June 1, 2019, and April 4, 2022, and subsequently received targeted therapy. Using this data, we evaluated the access of this cohort to targeted agents. [Results] Data were obtained from 687 patients (288 patients with CNS tumors and 399 patients with non-CNS tumors), including 352 patients who received at least one molecular-targeted agent option in the C-CAT report. Following CGP testing, 40 (5.8%) patients gained access to a targeted agent due to a genetic alteration, four received an approved drug, eight participated in clinical trials, two received agents through patient-proposed healthcare services, and 26 were treated by off-label use of agents. [Discussion] Only a small portion of pediatric patients receive targeted therapy and off-label use was the major means of access. These results emphasize the importance of facilitating access to targeted agents and establishing evidence for pediatric safety and efficacy.

Background: The Center for Cancer Genomics and Advanced Therapeutics (C-CAT) has been aggregating cancer genome data from comprehensive genome profiling (CGP) testing since June 2019. This optimized database provides evidence-based variant interpretations and options for targeted therapies directed to the Japanese populace. Herein, we summarize the molecular alterations in pediatric patients with solid tumors. Methods: Using the C-CAT data utilization portal site, we extracted variant information from patients aged 0–15 years, who underwent CGP testing from June 1, 2019, to April 4, 2022. Results: The data from 687 patients (288 patients with CNS tumors and 399 patients with non-CNS tumors) were available, including 467 (68%) patients with at least one germline or somatic aberrations with level F and above evidence in the C-CAT report. The most frequent genomic alterations included single nucleotide variants and insertions/deletions (in TP53, BRAF, H3F3A, PIK3CA, CTNNB1, and NF1), amplifications (in MYCN, MYC, ERBB2, CDK4, and PDGFRA), and partial or whole gene loss (in CDKN2A, CDKN2B, SMARCB1, ATRX, RB1, and PTEN). In all, 68 (10%) patients harbored a fusion gene involving EWSR1, BRAF, ALK, CIC, NTRK1, NTRK3, FGFR3, and so on. Five patients had high tumor mutation burden (≥10 mutations/Mb). Discussion: These results represent the heterogeneous mutational landscape in pediatric cancers and illustrate the importance of identifying and generating evidence for applying genomic results to the clinical care of patients.

To elucidate the current status and challenges of information sharing and healthcare education for childhood cancer survivors (CCSs), we conducted an interview survey targeting representative physicians in charge of long-term follow-up (LTFU) clinics for CCSs at 11 childhood cancer centers. A qualitative descriptive analysis was adopted. The analysis extracted six categories of information sharing at LTFU: “insufficient patient education to keep them informed of the correct information from the early stages of the disease”, “an explanation of the disease along the psychosocial situation of CCSs”, “motivation to keep themselves interested in their health and continue to receive medical care”, “sharing the fact of their illnesses with supporters”, “multi-professional collaboration” and “difficulty in building relationships with other medical departments”. In the topic of patient education, three categories, “providing opportunities to lead a healthy lifestyle”, “support for regular follow-ups”, and “education to obtain the right knowledge to improve health management awareness”, were extracted. Two categories, “sympathetic approach to CCSs” and “policy on patient care”, were identified regarding the physician’s perception. In this study, the physicians recognized that proper appreciation and autonomous actions were essential to enhance CCSs’ health awareness. They also perceived the importance of encouraging regular follow-ups, active utilization of educational tools, and transition to adult departments and primary health clinics.

The incidence of acute appendicitis during chemotherapy for pediatric cancer is low (0.3–1.5%) and there is no consensus on the criteria for selecting between operative and nonoperative treatment for its initial management. We retrospectively reviewed the stage of appendicitis, its treatment, and treatment outcomes in six cases in which acute appendicitis had developed during chemotherapy in our department. Five patients underwent nonoperative treatment and one underwent laparoscopic appendectomy as the initial treatment. There was a trend toward longer chemotherapy delays in the nonoperative treatment group. Two patients with nonoperatively treated phlegmonous appendicitis relapsed and underwent appendectomy. Chemotherapy delays of 27 and 37 days, respectively, were required in these two cases. One patient who underwent laparoscopic appendectomy as the initial treatment had a wound infection and pancreatitis, a possible complication of chemotherapy. However, the chemotherapy delay was only 5 days. These findings suggest that nonoperative treatment might not be an effective initial management in patients with phlegmonous appendicitis. Further studies with a large number of patients are needed to confirm these findings.

A solid pseudopapillary neoplasm (SPN) of the pancreas is a low-grade malignancy that usually occurs in young women, and surgical excision remains the first-choice treatment. We describe a boy who was incidentally diagnosed with a pancreatic tumor with a high index of clinical suspicion for a pancreatic SPN, during follow-up after congenital biliary dilatation. However, considering that the patient was asymptomatic and that this tumor is rare in male children, he underwent follow-up without further evaluation. The tumor showed enlargement, and enucleation was performed, 2 years later. Intraoperatively, we observed no invasion or metastasis to other organs; however, we should reflect on that. Contrast-enhanced ultrasonography was useful for differentiation of this lesion from other pancreatic tumors.

A 7-year-old boy was diagnosed with neuroblastoma of the right adrenal gland with opsoclonus and myoclonus at 3 years and 6 months of age. He had ganglioneuroblastoma nodular, International Neuroblastoma Risk Group (INRG) clinical stage L2, no MYCN amplification, and was classified as an intermediate risk group. Two years after chemotherapy and operation, recurrence of three longitudinal lymph nodes occurred in the retroperitoneum, and these were resected by laparotomy. The caudal mass located between the abdominal aorta and inferior vena cava was excised. The right lobe of the liver was dislocated, the inferior vena cava to the left side of the caudate lobe of the liver were confirmed, the right diaphragmatic peduncle was longitudinally incised, and two residual tumors were found in the right retrocrural space, which were successfully resected. Postoperative radiation therapy and GD2 antibody infusion were performed, and no residual disease was observed. Therefore, the transabdominal-transdiaphragmatic approach from laparotomy view is effective for posterior mediastinal tumors.