Integrated diagnosis based on the WHO 2016 update is important for the treatment of pediatric brain tumors. This integrated diagnosis is based on the pathological specimen obtained by surgery. Accurate preoperative diagnosis is clinically essential for deciding the strategy of surgical intervention. Some recent imaging characteristics have shown the possibility of preoperative speculation of integrated diagnosis. We introduce our imaging diagnostic approach for posterior fossa pediatric brain tumors. Diffusion-weighted imaging (DWI) has been reported to be a biomarker of tumors because the apparent diffusion coefficient (ADC) obtained from DWI is well inversely associated with tumor cellularity. A high-cellularity tumor such as medulloblastoma showed a low ADC value, whereas the posterior fossa ependymoma (PF-EPN) showed an intermediate ADC value, and pilocytic astrocytoma showed a high ADC value. The WNT medulloblastoma developed at the CP angle and lateral recess of the fourth ventricle, and the SHH medulloblastoma developed in the hemisphere. Groups 3 and 4 medulloblastoma developed midline in the fourth ventricle. Good enhancement was a characteristic of group 3, whereas minimal or no enhancement was a characteristic of group 4 medulloblastoma. PF-EPN-A and PF-EPN-B could be differentiated by their enhancement pattern, that is, poor and good enhancement, respectively. These surrogate imaging markers would be useful for the preoperative diagnosis of pediatric brain tumors. We introduce an imaging diagnostic algorithm for the differentiation of pediatric posterior fossa brain tumors.

Germ cell tumors are diverse, ranging from benign tumors such as mature teratomas to extremely aggressive tumors, with the developmental origins thereof also divided into the gonadal and extragonadal areas. Therefore, histopathological classification is complicated and the grades of malignancy vary. Furthermore, there are biological differences depending on age, with differences in prognosis depending on the primary site. In addition, there are differences in approaches and treatment strategies, particularly for gonad germ cell tumors in children and adults. Therefore, it was considered necessary to establish a unified staging system and a new risk classification, which lead to the establishment of an international consortium for malignant germ cell tumors (MaGIC) centered around the Children’s Oncology Group (COG). Challenges such as over-treatment for low-risk cases, reduction of treatment complications, and the establishment of standard treatment for high-risk cases were pointed out as issues to be reviewed by an international collaborative clinical study. Currently, an international collaborative clinical study (AGCT1531) is underway, under the leadership of COG, wherein the following two tests are being conducted: (1) for the standard-risk group, a randomized study with BEP therapy is being conducted on a protocol change to carboplatin for the purpose of avoiding late toxicity of cisplatin in conventional BEP therapy; (2) for the low-risk group, not only for the testes, which had a good prognosis in the past, but also for stage 1 cases of all primary lesions, surgical monotherapy is being conducted and monitored in order to verify the non-inferiority thereof to conventional chemotherapeutic combination therapy. The JCCG Germ Cell Tumor Committee in Japan is also playing a central role in this international collaborative clinical study, which is limited to 16 major domestic facilities, with case registrations currently initiated.

Hemophilia is a bleeding disorder characterized by frequent spontaneous joint and muscle bleeding and superficial bleeding occurring from infancy. Induction of prophylactic replacement of Factor VIII and IX products at a young age resulted in decreased bleeding frequency, leading to improved quality of life (QOL). However, patients and their families have suffered from frequent venipuncture for prophylaxis, especially during childhood. In Japan, extended half-life (EHL) products have been available since 2014. We report the efficacy of these products in nine and seven patients with hemophilia A and B, respectively, who used them for >1 year. The administration of EHL products resulted in reduced intravenous injection frequency and annual bleeding rate in patients with hemophilia A and B. Furthermore, increased Factor VIII or IX trough levels were observed in patients and higher factor levels were obtained with EHL products than with standard half-life (SHL) products using the same frequency of administration in patients actively performing sports. Our data showed that 70% of patients with hemophilia A and all patients with hemophilia B used EHL products as a prophylactic replacement for SHL products. Patients’ satisfaction and QOL were further improved. The development of a nonfactor product, emicizumab, will lead to more choices for personalized prophylaxis according to the lifestyle of each patient.

Hemophilia is an X-linked inherited bleeding disorder resulting from defects in the gene F8 (hemophilia A) or F9 (hemophilia B). Prophylaxis administration of coagulation factor concentrates is necessary to prevent joint bleeding in severe cases. Hemophilia is an attractive target for gene therapy owing to the monogenic nature and the easy evaluation of therapeutic coagulation factors in the blood. Currently, several clinical trials for hemophilia gene therapy have been conducted. Most of them are using the adeno-associated viral (AAV) vectors to transduce the genes of coagulation factors into the liver. A single administration of AAV vectors maintains the therapeutic levels of the coagulation factors over a long period, improving the bleeding rate, consumption of factor concentrates, and quality of life (QOL). On the other hand, the application of gene therapy using AAV vectors is limited to adult patients because their therapeutic effect is diminished by cell division. Therefore, the genome editing approach has attracted much attention because it can provide a permanent therapeutic effect from childhood. Indeed, a clinical trial that uses the AAV vector to deliver a genome-editing tool to the liver has been conducted. To apply gene therapy as a general medical care in the future, long-term observations of efficacy and safety, as well as discussion about its high medical costs, are essential.

Congenital thrombocytopenia (CT) is a heterogeneous group of bleeding disorders caused by inherited defects in platelet production. Recent studies have elucidated several causative genes for the disorders; however, the major causes remain unknown. Although CT has been considered rare, about 10% of cases of chronic/intractable immune thrombocytopenia (ITP) should be diagnosed as CT. Platelet transfusion is contraindicated for ITP, but remains a key option for CT. Once ITP is diagnosed, patients with CT are often treated with glucocorticoids and by splenectomy. In addition, patients with MYH9 disorders often develop nephritis and deafness. Cases with defects in transcription factors may be associated with hematological malignancy. There is a pressing need for the development of an operational system for the differential diagnosis of CT. To solve this issue, we developed a new system, based on an AMED grant that aims to (1) establish a centralized diagnosis system using conventional immunofluorescence staining, flow cytometry, and next-generation sequencing panel analysis using 56 known pathogenic genes, (2) perform whole-exome sequencing analysis in families without any known pathogenic variants in the panel analysis, (3) archive samples at the National Center for Child Health and Development (NCCHD), and (4) establish a nationwide registry for CT at the NCCHD. We have registered 137 cases and analyzed 120 cases, which led to the identification of pathogenic variants of MYH9, WAS, VWF, ITGA2B, ITGB3, ETV6, RUNX1, ANKRD26, ACTN1, CDC42, and FLNA. The novel system will contribute to the investigational and clinical development of CT in Japan.

Radiation therapy plays an important role in cancer treatment, as is the treatment of pediatric cancer. However, the number of patients is on the increase, and more time is required as radiation therapy becomes more precise. Under such circumstances, it has become difficult to treat pediatric cancer with sufficient time. It is also an important issue how to treat pediatric cancer, coordinate with medical staff, and build an optimal radiation therapy team. This time, anesthesiologists, medical radiologists, nurses, and child life specialists gave lectures from their respective perspectives and discussed how to address the above problems. Treatment and care for pediatric and adolescent and young adult (AYA) cancer is not complete within the radiation therapy team, but it is necessary to provide a comprehensive team-based medical treatment across multiple departments and multiple occupations depending on the patient’s situation. It was confirmed that a multidisciplinary medical team was required to collect expertise and provide the best treatment and care for a common goal as one team.

Acute myeloid leukemia (AML) accounts for approximately 25% of pediatric leukemia cases, with approximately 180 patients newly diagnosed each year in Japan. In general, AML is classified into three groups [acute promyelocytic leukemia (APL), myeloid leukemia associated with Down syndrome (ML-DS), and others] and is treated with different treatment strategies. Retinoic acid with conventional chemotherapy leads to a safe and promising outcome in patients with APL. Recently, arsenic trioxide and gemtuzumab ozogamicin have been expected to reduce late complications and further improve treatment outcomes. Reduced-intensity chemotherapy is effective for patients with ML-DS; however, the prognoses of relapsed and refractory patients are dismal. Optimization of the classification of patients with ML-DS into several groups is desired; thus, the measurement of minimal residual disease by flow cytometry and the detection of GATA1 mutations is expected. For patients with other types of AML, they may be further classified into three groups on the basis of risk stratification according to chromosome and genetic analyses and chemosensitivity to induction therapy. However, the prognosis of patients with a refractory or relapsed disease remains a serious problem that should be solved. A novel therapeutic approach that includes the use of FLT3 inhibitors, which has recently been approved in Japan for adult patients with relapsed and refractory AML bearing FLT3-ITD, will be necessary to improve their prognosis.

Until the 1990s, anticancer drugs were handled similarly to nonhazardous drugs, i.e., without the use of special protective tools. However, many reports have shown the harmful effects of exposure to anticancer drugs on medical staff who handle them. This led to the establishment of guidelines for the safe handling of these drugs. In this review, we comprehensively discuss the occupational exposure to anticancer drugs and the guidelines to be followed to minimize or avoid this exposure. Exposure to anticancer drugs causes various toxicities in the human body. They are classified into acute toxicities, which include dermatitis and headache, and chronic toxicities, which include carcinogenesis and teratogenicity. The exposure routes are transdermal, inhalation, oral, and direct exposure into the tissue by accidental needle pricks. There is a risk of exposure during all procedures involved in anticancer drugs, such as during preparation, dispensing, transportation, administration, post-administration, and treatment. Therefore, both the medical staff who directly handle anticancer drugs and nonmedical personnel such as cleaners, caregivers, and families are at risk of exposure. Measures to prevent exposure generally involve the introduction of closed connection devices, utilization of a safety cabinet, management of working hours, and wearing gowns, masks, goggles, and gloves. Additionally, a spill kit, which is composed of cleaning equipment, is used when environmental exposure occurs. It is also important to establish an operation procedure in advance and disseminate this information to all staff members. The risk of exposure to anticancer drugs can be reduced by accurate knowledge of their exposure routes and toxicities, and the implementation of safe handling measures.

Primary immunodeficiency (PID) is a group of diseases caused by the disruption of immune regulation mechanisms such as infection susceptibility, autoimmunity, and auto-inflammation due to abnormalities in genes involved in immune regulation. More than 400 diseases and their responsible genes have been identified. Some of the PIDs are frequently complicated by malignant tumors, especially in lymphoid organs. Some of the genes responsible for PID are also found as somatic mutations in hematological tumors. Therefore, understanding the mechanisms of PID development is important in considering hematological tumorigenesis.

The antimicrobial stewardship program (ASP) is an effective strategy for controlling antimicrobial resistance. ASP is important among immunocompromised patients, including cancer patients and hematopoietic cell transplantation (HCT) recipients, because of their high likelihood of receiving broad-spectrum antibiotics. However, the optimal method of ASP for such patients has not been well established, especially for children. We retrospectively reviewed days of therapy (DOTs) of broad-spectrum antibiotics and DOTs/1,000 patient-days in each year from 2012 to 2016 and compared them. The total patient-days and the number of hospitalized patients and HCT recipients tended to increase. The DOTs/1,000 patient-days of carbapenem significantly decreased and remained low (76 to 40). Although the number of prescriptions of antipseudomonal antibiotics and glycopeptide antibiotics increased along with the increase in the total number of cancer patients and HCT recipients, the DOTs/1,000 patient-days significantly decreased and remained low. The cost of broad-spectrum antibiotics was reduced by approximately five million yen annually. The overall mortality and infection-associated mortality did not change. Our ASP strategies applied in collaboration with a pediatric hematology–oncology physician and the ASP team safely minimized the use of broad-spectrum antibiotics.

Solid pseudopapillary neoplasm (SPN) of the pancreas is a low-grade malignancy that is rare in children. It often occurs in young women, and patients undergoing complete surgical resection show a favorable prognosis. In this study, we investigated treatment outcomes of SPN in our department. We retrospectively reviewed the medical records of six patients with SPN treated in our department between 1990 and 2019. Demographic characteristics, tumor localization, rendered treatment, and outcomes were assessed. All six patients were girls. Their ages at the time of surgery were 6–14 years (median 10.5 years). The tumor localization was the pancreatic body in two patients and the tail in four patients. Four patients underwent distal pancreatectomy with splenectomy and two patients underwent enucleation. Postoperatively, one patient required transfusion because of intraoperative bleeding, and two patients developed grade B postoperative pancreatic fistula (POPF). The postoperative course was uneventful in the other patients. Postoperative hospital stay was 8–28 days (median 14.5 days), and the follow-up period was 1–122 months (median 50.0 months). All six patients were alive without recurrence. Surgical outcomes of SPN were favorable in our case series. Although splenic preservation was difficult in patients with SPN affecting the splenic hilum, laparoscopic mobilization of the spleen was useful during tumor resection in these patients.

Recently, the number of home-visit nursing stations for children has been increasing, and it has become possible to provide home-based end-of-life care for pediatric cancer patients. In this study, we aimed to identify the problems of end-of-life care in our department. We conducted a retrospective review of end-of-life care of 16 pediatric cancer patients in our department from November 2011 to October 2019. Furthermore, we administered a questionnaire to 89 home-visit nursing stations to examine the status and issues of home-visit nursing for end-of-life pediatric care. The median end-of-life period at home before 2016 was 16 days, but after 2016, it increased to 149 days because of home-visit nursing interventions. In the questionnaire survey, 60% of home-visit nursing stations indicated that they would conditionally accept pediatric cancer patients requiring end-of-life care. Lack of knowledge regarding pediatric nursing, difficulties in communicating with patients and their families, and difficulties in understanding the patient’s medical conditions were identified as problems. Visiting nurses answered that cooperation with hospitals was important for them to be able to accept more pediatric cancer patients. It is expected that the home-stay period will be extended because home medical care staff can provide some medical procedures. In the future, we will strengthen cooperation with community healthcare professionals through activities such as holding educational workshops and we will develop specific cooperation methods.

Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) is a high-risk subtype characterized by a gene expression signature similar to that of Ph-positive ALL (Ph⁺ALL). The outcome for patients with Ph-like ALL may be improved by treatment with tyrosine kinase inhibitors; however, it is difficult to identify Ph-like ALL by conventional cytogenetic and molecular analyses. Here, we present the case of a female adolescent with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) having a NUP214-ABL1 fusion, which was identified from the results of array comparative genomic hybridization (aCGH). She experienced extramedullary relapse after allogeneic HSCT, but achieved complete remission after receiving dasatinib. This suggests that tyrosine kinase inhibitors might be effective for Ph-like ALL with a NUP214-ABL1 fusion.

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph⁺ALL) with tyrosine kinase domain mutations is highly resistant to therapy. Ph⁺ALL harboring T315I mutation shows a particularly poor prognosis. An 8-year-old boy diagnosed as having Ph⁺ALL at a previous hospital was transferred to our hospital after induction therapy. Because imatinib intolerance and hepatic dysfunction caused by dasatinib necessitated frequent discontinuation of tyrosine kinase inhibitors, he experienced recurrence. As T315I mutation was confirmed by genetic analysis, he underwent bone marrow transplantation (BMT) in the nonremission status from an HLA-identical sibling with a chemotherapy containing cytarabine, mitoxantrone, and prednisolone, followed by a myeloablative conditioning regimen containing melphalan and 12 Gy total body irradiation. Engraftment was obtained on day 17, and he is alive in complete remission without any complications for more than 7 years after BMT. It is necessary to investigate the efficacy of BMT in large numbers of patients with Ph⁺ALL harboring T315I mutation.

We present a case of duodenal perforation during induction therapy for acute lymphoblastic leukemia (ALL) recovered by conservative treatment without surgery. A 3-year-old boy with repeated infection and leucopenia was diagnosed with precursor B-cell ALL. On day 26 he had severe abdominal pain and fever. We suspended chemotherapy and started to administer antibiotics and H₂ receptor antagonist. The abdominal CT scan on day 28 showed free gas and perforation in the duodenal bulb, so we diagnosed duodenal perforation. As we observed no worsening of symptoms nor any progression of peritonitis, we continued conservative treatment such as nothing per os, intravenous drip, nasogastric tube detainment, proton pump inhibitor and antibiotics. His symptoms were alleviated. No surgical treatment was performed. After that, complete remission was maintained without recurrence of ulcer and perforation. Gastrointestinal perforation during chemotherapy is a severely adverse event, so prophylactic supportive therapy should be considered if abdominal symptoms persist.

Vertebral body compression fracture rarely occurs in acute lymphoblastic leukemia (ALL) at the time of diagnosis. A 4-year-old girl presented with back pain. Magnetic resonance imaging revealed a compression fracture of the 10th thoracic vertebra and a tumor beside the vertebral body. We diagnosed her as having B precursor ALL on the basis of findings of bone marrow examination and started chemotherapy. Following treatment, she remained in complete remission. Before chemotherapy, the bone mineral density of the 1st to 4th lumbar vertebra decreased to −4.5 SD. Although the height of most vertebral bodies temporarily decreased, compression fracture did not recur during chemotherapy. Clinical features of ALL with vertebral compression fracture as a presenting symptom are still unclear. The presence of a vertebral compression fracture at the time of diagnosis of ALL may increase the risk of refracture and failure of vertebral body repair. Early bone mineral density-promoting interventions should, therefore, be considered for this condition.

We present a case of stage 4 neuroblastoma of the left adrenal gland with MYCN amplification in a 2.5-year-old boy. At the time of diagnosis, the tumor had a component that was partially negative for ¹²³I-metaiodobenzylguanidine (MIBG) with MYCN amplification. Treatment was completed in accordance with the high-risk protocol, and complete remission was achieved. However, 14 months after treatment completion (at 4.5 years of age), the patient developed a facial nerve palsy. Cancer recurrence was observed in the left cerebellopontine angle, left orbital bone, and bone marrow. The recurrent lesion was weakly positive/negative for MIBG, the urinary catecholamine level was not elevated, and the bone marrow metastatic cells were negative for tyrosine hydroxylase. MIBG-non-avid neuroblastoma has a better prognosis than MIBG-avid neuroblastoma. However, among MIBG-non-avid tumors, non-catecholamine-secreting neuroblastomas have an increased likelihood of containing more undifferentiated and aggressive components and require caution for early relapse.

Adrenal cortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis in children. A 14-year-old girl presented with bilateral leg edema, signs of Cushing’s syndrome and virilization. She underwent surgery with complete resection of a right adrenal tumor. Findings of endocrinological laboratory tests and histopathological analysis of the tumor confirmed the diagnosis of functional ACC. She was treated with a combination of oral mitotane and intravenous cytotoxic drugs. She required right pulmonary metastasectomies on two occasions at 47 and 104 months after the initial ACC diagnosis. ¹⁸F-FDG-PET/CT was valuable for detecting recurrence in the follow-up of this patient with silent clinical signs.

A 9-month-old boy presented with persistent and recurring fever, left axillary lymphadenopathy, and systemic pustular eruption. His clinical features including an osteolytic lesion in the skull (forehead), skin lesions, lymphadenopathy, and elevated levels of soluble interleukin-2 receptor in the serum mimicked those found in patients with multiorgan Langerhans cell histiocytosis. BCG was identified in a lymph node biopsy specimen, which confirmed the diagnosis of BCG-itis. His symptoms quickly improved with the antituberculosis drugs isoniazid and rifampicin. Mendelian susceptibility to mycobacterial disease (MSMD) was suspected as an underlying pathology. On the basis of mutation search findings, he was diagnosed as having partial IFN-γR1 deficiency with a previously known de novo heterozygous mutation in IFNGR1. We should pay attention to the resemblance in the clinical features of Langerhans cell histiocytosis and BCG-itis.

IgA and haptoglobin (HP) deficiencies are rare diseases. Their first sign in patients is often anaphylaxis when they receive blood transfusions. Here, we describe the case of a 2-year-old Japanese girl with neuroblastoma who showed anaphylactic shock. She was referred to us for the treatment of neuroblastoma. As a result of receiving intensive chemotherapy, she presented with pancytopenia. Immediately after the second transfusion, she developed dyspnea, hypotension, and bradycardia, and stopped breathing. She was diagnosed as having anaphylactic shock and rescued by cardiopulmonary resuscitation. Subsequently, we used washed PC and RBC. As a result, there was no recurrence of the anaphylaxis. Serological tests showed that Hp was absent and anti-Hp antibodies were detected. In addition, molecular analyses demonstrated congenital Hp deficiency in this patient. The anaphylactic shock was induced by the marked interaction between the transfused Hp and the anti-Hp antibodies. The relationship between congenital Hp deficiency and neuroblastoma warrants investigation.

Introduction: Past clinical studies by the Japan Wilms Tumor Study Group (JWiTSG) revealed that treatments for bilateral Wilms’ tumors (BLWT) started with primary surgery (nephron-sparing tumor resection or nephrectomy). However, results of the JWiTS-1 studies revealed the problem of preserving renal function. Therefore, a new protocol study for BLWT (RTBL) was started in 2014. Here, we report the results of the RTBL14 clinical study.

Methods: In this study, initial chemotherapy using actinomycin-D, vincristine and doxorubicin was started without tumor biopsy. Reduction in tumor size was evaluated by a central radiological review, and nephron-sparing surgery was performed to preserve as much of the renal parenchyma as possible. The primary endpoint of the RTBL study was the success rate of bilateral renal preservation one year after treatments.

Results: Only 23 institutions joined the study, and only three patients were enrolled within four years. It was difficult to collect enough cases within the study period, so the study was abandoned in March 2019. Among the three patients, two completed the study protocol; however, the protocol was stopped because of intratumoral hemorrhage in one patient. The bilateral renal parenchyma was successfully preserved in only one patient.

A questionnaire survey was conducted to identify the reasons why institutions did not join the RTBL14 study. The most common reasons were the rarity of BLWT and the difficulty of the ethical review.

Conclusions: It is difficult to perform a clinical study of rare conditions such as BLWT. International collaboration is necessary to perform clinical studies of extremely rare tumors.