The Paediatric Hepatic International Tumour Trial (PHITT) is a collaborative trial involving three major clinical groups running pediatric liver tumor trials. The aim of the PHITT is to build on the cooperative experience of different consortia to undertake four randomized comparisons of groups of patients with tumors (hepatoblastoma (HB) and hepatocellular carcinoma (HCC)). Decision guidelines for surgical intervention are based on the PRETEXT system and established to evaluate whether reducing treatment doses for low-risk patients maintains their excellent EFS and decreases acute and long-term toxicity. Intensification of therapy with the use of novel agents will be evaluated in a high-risk group. A real-time consultation system will be established to help a local team refer their patients with advanced HB/HCC to a transplant team for further treatment. Selection of the appropriate patients for consideration for up-front surgery requires good imaging during diagnosis and a careful radiological review, anticipating clear resection margins especially in areas adjacent to vascular structures (≧1 cm to the middle hepatic vein). Histological confirmation of HB is required except in emergency situations where the patient is too ill to safely undergo a biopsy. Within the trial, a surgical review study will be included to evaluate the surgical treatment of POST-TEXT III and IV HB. Data obtained from this study will be the basis for assessing the optimal surgical approach for these complex tumors. It is expected that the trial will improve the outcomes in patients with advanced HB/HCC.

In the treatment of patients with Wilms tumor, the National Wilms Tumor Study Group (NWTS) in the USA follows the upfront surgery principle, whereas the SIOP in Europe follows the upfront chemotherapy principle in all stages of the disease. In Japan, the Wilms Tumor Study Group (JWiTS) follows the upfront surgery principle. The advantage of upfront surgery is that accurate surgical and pathological diagnoses enable the risk classification and help in choosing the suitable postoperative treatments. On the other hand, the advantage of upfront chemotherapy is that the reduction in tumor size will reduce the surgical risk, and the downgrading of the stage of the disease may result in the omission of doxorubicin and radiotherapy. Upfront chemotherapy also enables the effects of chemotherapy to be confirmed. In the NETS staging system, the patients who underwent tumor biopsy (open or needle) became stage III, whereas in the SIOP staging system, the patients who underwent needle biopsy did not become stage III. In the JWiTS-2 study, tumor spillage was responsible for most of the stage III cases. Therefore, if they were treated with the upfront chemotherapy principle, the reduction in tumor size might have reduced the surgical risk and the tumor had been resected without spillage.

With the spread of cancer genomic medicine, an increase in the number of patients found to have cancer predispositions is expected. However, medical systems such as cancer surveillance programs for patients with cancer predispositions, especially Li-Fraumeni syndrome (LFS), which is predicted to be diagnosed most frequently in pediatric cancer patients, have not yet been established. I will discuss the feasibility of LFS cancer surveillance in Japan by reviewing six published articles about ongoing surveillance programs and an article on the meta-analysis of whole-body MRI (WBMRI), which is frequently used in cancer surveillance. Overseas, the progress reports of the ‘Toronto protocol’ conducted under the Toronto/Utah/CHLA LFS study are positively accepted, and on the basis of this protocol, 12 cancer surveillance programs are in progress in six countries. The number of patients with positive results as determined by WBMRI is high and the cancer detection rate is sufficiently high at 7%. Early detection and treatment of cancer may improve the overall survival of LFS patients. It is desirable to advance cancer surveillance research for LFS patients in Japan.

Pathologists and clinicians often have difficulty in diagnosing and choosing a therapeutic strategy for pediatric soft tissue tumors because of their rarity. Therefore, it is necessary to have a good understanding of the concept of histopathological diagnosis and its molecular biological background. The widely used World Health Organization (WHO) classification of pediatric soft tissue tumors is based on cell differentiation determined by histopathological analysis, and the tumors are classified into 12 categories and three biological potentials. In addition, the development of molecular biological analysis technology has revealed various genetic backgrounds, which are reflected in the WHO classification. However, genetic alterations and histological types do not always match, because tumor-specific genetic alterations are occasionally found in other tumor groups. In molecular biological analysis, errors in sample collection and analysis may occur at a constant rate. Therefore, the results of histopathological analysis are presently prioritized over those of molecular biological analysis. For prompt treatment, clinicians need to determine how extensive histopathological, molecular, and biological studies should be performed at their own institutions.

Rhabdomyosarcoma is the most common soft tissue sarcoma in children and adolescents. It is classified into embryonal, botryoid, spindle cell and alveolar subtypes in the International Classification of Rhabdomyosarcoma (ICR), but the spindle cell/sclerosing rhabdomyosarcoma is listed as an independent category in the WHO classification (4^th edition) published in 2013. Most alveolar rhabdomyosarcomas harbor fusion genes involving either PAX3 or PAX7 and FOXO1. Recent studies showed that the fusion-positive alveolar rhabdomyosarcoma has the poorest prognosis. In tumors of spindle cell rhabdomyosarcoma of infants, fusion genes involving VGLL2, TEAD and SRF were reported, and these tumors showed favorable outcomes. In a subset of spindle cell/sclerosing rhabdomyosarcoma, tumors with a hot-spot mutation of MYOD1 were reported, and the same type of mutation was observed in a small number of cases with the embryonal type. These tumors with the MYOD1 mutation were reportedly aggressive. In this paper, the pathological classification and molecular genetic alterations of rhabdomyosarcoma are reviewed and their clinical implications are discussed.

Multimodality treatment is crucial for pediatric cancers. Improvement in therapies leads to increased cure rates among patients, while it is also of immediate importance to reduce complications in survivors. Radiation therapies present risks of several complications. In 2016, proton beam therapy was approved for insurance coverage in Japan. Recent research has revealed that particle therapy can significantly reduce the unnecessary irradiation of surrounding tissues such as the intestines or ovaries. However, it is preferable to perform X-ray irradiation over a broad area such as the entire abdomen in cases of fast-expanding tumors, which do not afford enough time to plan for proton beam therapy, or in cases of palliative care. Intensity-modulated radiation therapy (IMRT) is preferable in cases with more than two irradiation target areas or in cases requiring a decreased dose in the central area. Discussions with radiologists and pediatricians are needed to determine the timing or other aspects of radiation therapies. This article is an overview of radiation therapies for pediatric tumors.

The assessment of the quality of published medical articles using a peer review system was first established in the 16th century in England. The major difference between Japanese and English papers is that the latter have much more readers worldwide. In this article, I will show in detail how to write a paper in English. I will also describe a recent concept of misconduct including plagiarism, fabrication, and falsification, which often occur in writing a paper. In addition, I will explain how to review papers.

Chromosomal rearrangements between 3q21 and 3q26 give rise to acute myeloid leukemia (AML) with poor prognosis. The rearrangements induce inappropriate EVI1 expression by recruiting a GATA2-distal hematopoietic enhancer (G2DHE) to the proximity of EVI1, which is the major cause of leukemogenesis. The acquisition of G2DHE by EVI1 reciprocally deprives this enhancer of one of the two GATA2 alleles, resulting in reduced GATA2 expression. As GATA2 deficiency is strongly associated with AML, we examined whether reduced GATA2 expression also contributes to leukemogenesis by using the 3q21q26 transgenic mouse model that recapitulates the G2DHE-driven EVI1 misexpression. To analyze the contribution of reduced GATA2 expression, we crossed 3q21q26 mice with Gata2 heterozygous knockout mice. Of note, 3q21q26::Gata2+/− mice developed leukemia faster than 3q21q26 mice, indicating that Gata2 heterozygous deletion promotes the EVI1-provoked leukemic transformation. In the leukemic 3q21q26 mice, B220+ and Gr1+ cells occupied their bone marrows. Transplantation analysis showed that the B220+ population contained leukemia-initiating cells and differentiated into Gr1+ leukemia cells. In the 3q21q26::Gata2+/− mice, the differentiation of the B220+ cells was suppressed and the cells showed enhanced proliferation. In conclusion, GATA2 haploinsufficiency accelerates leukemogenesis associated with 3q rearrangement.

The aim of this study was to assess the clinical outcomes and problems in fetuses and neonates with germ cell tumors arising around the upper airway. A retrospective study was carried out for ten patients with germ cell tumors arising around the upper airways in the fetal and neonatal periods, who received treatment at our institution between 1989 and 2018. The diagnoses were epignathus in seven patients and cervical teratoma in three patients. The pathological diagnoses were mature teratoma in five patients and immature teratoma in five patients. Giant neck masses were prenatally diagnosed in six patients with epignathus or cervical teratoma. The ex utero intrapartum treatment (EXIT) procedure was performed in four patients with evidence of tracheal compression by the tumors, but not in two patients because of intrauterine fetal death or death due to respiratory failure after birth. Although airway management under the EXIT procedure was successful in three patients, it failed in one patient. All patients with mature teratoma survived to discharge, whereas four of the five patients with immature teratoma did not survive to discharge. Only the patients whose tumors were resected after birth survived to discharge. We concluded that the EXIT procedure was effective for the airway management of fetuses prenatally diagnosed with neck masses arising around the airway. In patients with giant neck masses, not only the airway management at delivery, but also the treatment strategy for the tumor itself should be considered.

Aim: Chemotherapy is generally recommended as an initial treatment of malignant non-Hodgkin lymphoma. According to the Japanese guideline, local treatment including surgery is not the first choice. However, intestinal Burkitt lymphoma (BL) presenting with intussusception sometimes requires emergent operation. The purpose of the study of this case series was to evaluate the characteristics and outcome of BL in children presenting with intussusception.

Methods: We retrospectively reviewed the medical records of 5 BL patients presenting with intussusception as the initial symptom and treated between 2001 and 2015 at our hospital.

Results: The median age at diagnosis was 13 years (range, 2–21 years). There were two stage II and two stage III patients, and one stage IV patient. Two patients were preoperatively diagnosed with lymphoma. As the initial treatment, intestinal resection was performed in three patients [resection group (RG)], and chemotherapy was administered in two patients [chemotherapy group (CG)]. The median period from the initial surgery to chemotherapy was 48 days (18–50 days) in the RG and 5 days (1–9 days) in the CG. The total treatment period was 3 months (2–7 months) in the RG and 6.5 months (6, 7 months) in the CG. One patient in the CG required ileocecal resection of a residual tumor and adjuvant chemotherapy. The median follow-up period was 31 months (0–173 months) except for one deceased patient, and four patients are alive without any disease.

Conclusions: Primary surgery for BL with intussusception may contribute to the shortening of the treatment period.

The appropriate dosage and most suitable administration method for metronidazole (MNZ) in children have not yet been established. Furthermore, the safety and efficacy of MNZ injection in children have not been determined. In this study, we sought to provide data regarding the administration method and the effect, safety, and so forth of MNZ injection. Therefore, children under the age of 15 years who received anticancer agent therapy and underwent stem cell transplantation treated with MNZ injection in the two years from 1 July 2014 to 30 June 2016 at our institute were examined retrospectively. The patients’ characteristics, method of drug administration, drug administration period, dosage, efficacy, side effects, and antimicrobial agents used before were analyzed. Four patients between the ages of 2 and 10 years (median: 8 years 5 months) with six episodes were included. All the patients with episodes received a 20-min infusion of 10 mg of MNZ injection per kg body weight every 8 h. The underlying diseases were acute lymphocytic leukemia in two patients, chronic granulomatous disease in one, and nephroblastoma in the other. The administration period was between 3 and 15 days (median: 9 days), and the total number of MNZ injections was between 6 and 43 (median: 23.5). The total dose was between 900 and 17,200 mg (median: 4,750 mg). Treatment was successful for all the patients with episodes. Side effects (elevation of blood tacrolimus levels) were noted in only one patient; that patient had been receiving oral tacrolimus therapy. Although a small number of episodes were examined, MNZ injection was found to be relatively safe and effective by considering concomitant medication.

Although countermeasures against adolescent and young adult (AYA) cancers are currently being promoted in Japan, domestic reports of treatment and especially psychosocial problems encountered by patients are limited. We retrospectively reviewed AYA cases in our pediatric hematology/oncology department on the basis of medical records. The subjects were 64 patients aged 15 years or older at the time of admission to our department from January 2005 to December 2015. The median age was 17 years (15 to 41 years). The numbers of cases of hematopoietic tumors, brain tumors and solid tumors were 27, 21 and 16, respectively. Outcome data were available for 62 patients; 35 survived and 27 died. In 10% of patients, lack of prompt consultation with experts and delay of appropriate diagnosis were considered to lead to their poor prognosis. As for school attendance, 23.6% of the patients attending high school and all four patients attending college were forced to quit school or be on holdover status. Psychosocial problems considerably varied among AYA patients, including those arising from post-treatment chronic complications, difficulty in returning to daily life and friendship recovery in the premorbid state, and difficulty in finding employment; one patient committed suicide. There were patients, however, who showed a positive personal sense of growth with cancer experience. On the basis of their characteristics, AYA patients should each be carefully assessed, and it is important to find out what they really think. Knowledge gained from such assessments should be shared and reflected in medical practices in the future.

Pediatric brain tumors comprise the second most common pediatric malignant tumors and affect key aspects of development such as learning and gaining experience in society. School re-entry during or after treatment is one of the most important problems that affect pediatric patients. There are some research studies of cognitive problems and maladjustment among patients with pediatric brain tumors, but such research is limited, especially in Japan. We therefore investigated the cognitive function, quality of life (QOL), and adaptive behavior of pediatric patients with brain tumors after school re-entry, and from the viewpoint of occupational therapy, we considered how to support these children. The participants in this study were 10 pediatric patients with brain tumors, aged 6–16 years. Cognitive function was assessed using the Wechsler Intelligence Scale for Children-Fourth Edition, and QOL was assessed using the Japanese version of the Pediatric Quality of Life Inventory version 4.0 core scale and brain tumor module. The Asahide-shiki Social Adaptability skill test was used to assess adaptive behavior. The mean IQ score was 92.9±10.3 and we found that many children had normal scores in cognitive function. In addition, many patients and parents had a relatively good QOL. In contrast, 40.0–90.0% of the children exhibited large interindividual differences in their abilities. Over half of the children exhibited decreased social adaptation skills, especially those in life and personal relationships. We expect that occupational therapy is important to improve social adaptation skills in pediatric patients with brain tumors. Studies with larger cohorts are needed to determine the appropriate support with occupational therapy.

The purpose of this study was to qualitatively explore the factors affecting illness disclosure in first-job-seeking survivors of childhood, adolescent, or young-adult cancer and reactions from people in human resources to the disclosure. Sixteen survivors participated in semistructured, face-to-face interviews, and 12 transcripts that clearly identified situations of illness disclosure in first-job seeking were analysed using thematic analysis. Factors that contributed to the decision to disclose were ‘perceived health problems after treatment and self-identity as cancer survivors’, ‘advice about illness disclosure from surrounding people’, ‘impact of illness disclosure on obtaining the job’, ‘emotional burden of withholding illness disclosure’, and ‘anticipated difficulty after employment due to withholding of illness disclosure’. Survivors who did not perceive health problems after treatment as an issue in their daily life tended not to disclose. However, survivors who were concerned about increased emotional burden from withholding disclosure and those who judged that they would need accommodations after employment tended to disclose. Reactions from human resource professionals were ‘matter-of-fact attitudes’, ‘comparisons with other employees’, and ‘inquiries about the current state of illness’. Reactions were not always positive, with variation observed depending on whether the corporation in question employed individuals with cancer or similar disabilities, or if the professional had personal knowledge about cancer. These findings suggest that support may be necessary for first-job-seeking survivors. Specifically, it may be necessary to provide information about both pros and cons of illness disclosure, as well as strategic support regarding when and how illness should be disclosed.

A 10-year-old girl was admitted to the hospital because of fever and headache. A blood examination revealed leukocytosis with blasts. Bone marrow examination confirmed the diagnosis of acute myeloid leukemia (FAB-M2). She harbored an FLT3 internal tandem duplication mutation, so she required hematopoietic stem cell transplantation. After 4 courses of chemotherapy, she underwent cord blood transplantation and achieved complete remission (CR). The conditioning regimen consisted of cyclophosphamide (120 mg/kg body weight) and total body irradiation (12 Gy), and the prophylaxis for graft-versus-host disease consisted of tacrolimus and short-term methotrexate. Engraftment was performed on day 32. Bone marrow examination on day 35 revealed CR, but peripheral Wilms’ tumor 1 (WT1) mRNA was detected on day 34. She received sorafenib (oral FLT3 inhibitor, 200 mg/kg body weight) daily from day 40 as maintenance therapy. Subsequently, she remained on CR and was negative for WT1 mRNA for 2 years under daily sorafenib maintenance therapy. In this patient, sorafenib maintenance therapy appeared safe and effective.

Pediatric non-Hodgkin lymphoma (NHL) with epidural involvement is rare, and to the best of our knowledge, no cases of NHL with sacrum involvement have been reported. We report a case of clavicular NHL with sacral epidural involvement. An 8-year-old boy was admitted with a mass extending from the right precordium to the shoulder. Fluorodeoxyglucose positron emission computed tomography revealed a mass in the right shoulder and sacral epidural involvement, and magnetic resonance imaging showed an enhanced mass in the sacrum. The patient was diagnosed as having clavicular precursor B-cell lymphoblastic lymphoma with sacral epidural involvement on the basis of a biopsy from the mass in the shoulder. He was treated according to the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) ALB-NHL03 protocol. Primary lymphoma of the bone is rare, and no cases of pediatric lymphoma with epidural involvement have been reported. He has been doing well without relapse 8 months after therapy completion.

A 4-year-old boy with poor oral intake lost weight during maintenance therapy for infantile acute lymphocytic leukemia. Immediately before completion of the maintenance therapy, he contracted norovirus enteritis and experienced progressive weight loss resulting in hospitalization. Tube feedings and continuous administration of replacement fluids were started. Folic acid deficiency caused megaloblastic anemia, requiring folic acid supplementation. Later, vitamin K deficiency caused a subdural hematoma necessitating vitamin K supplementation and emergency removal of the hematoma. Additionally, parenteral nutrition was started, the patient gained weight, and his oral intake improved. The patient developed megaloblastic anemia and hemorrhagic disease due to vitamin K deficiency in the presence of various coexisting factors including primary disease treatment, the condition of his home environment, and the occurrence of norovirus enteritis. Such complications rarely develop during the treatment of leukemia, and our report emphasizes the importance of nutritional assessment.

A 1-year-and-9-month-old boy was referred to us for swelling of the left forearm. Magnetic resonance imaging revealed a solid tumor in the forearm about 6 cm in size. There was no metastatic lesion, and he underwent biopsy. Clinically, he was suspected of having infantile fibrosarcoma on the basis of the results of histopathological analysis and his clinical course. However, a central pathological review disclosed a suspicious myofibroma. Chemotherapy consisting of vincristine, actinomycin, and ifosfamide was carried out but the tumor size remained unchanged. Chemotherapy was discontinued 2 months after initiation. However, the tumor size increased 3 months after the discontinuation of chemotherapy; hence, he underwent marginal resection 4 months after the discontinuation of chemotherapy. The pathological diagnosis was unclassified spindle cell sarcoma. Local irradiation and 3 cycles of chemotherapy with vincristine, ifosfamide, and doxorubicin were carried out, and the treatment was completed. We recommend collecting another biopsy sample for histopathological examination if the pathological diagnosis is incompatible with the clinical course.

The patient was an 8-year-old girl in whom stage IV infantile neuroblastoma developed 8 months after birth. Remission was achieved after combination chemotherapy, high-dose chemotherapy with autologous stem cell transplantation, and primary tumor resection. On periodic examination 7 years after treatment completion, a 2 cm tumor was detected by abdominal ultrasonography in the pancreatic body. Since the patient was negative for various tumor markers, pancreatic solid pseudopapillary neoplasm (SPN) was suspected. Distal pancreatectomy was immediately performed and histopathological analysis of the tumor showed it to be pancreatic SPN. One year and 10 months after the surgery, no recurrence has occurred. SPN is a low-malignancy tumor, but it may invade surrounding tissue, metastasize, and recur. Thus, careful time-course observation is necessary. In our patient, the age at onset differed from that of typical SPN, suggesting the possibility of secondary cancer after treatment of neuroblastoma or metachronous double cancer. This emphasizes that long-term follow-up examinations, including imaging, is important after pediatric cancer treatment.

Systemic autoimmunity may develop in association with severe Wiskott-Aldrich syndrome (WAS). Here, we present a patient with WAS complicated by steroid-resistant systemic autoimmunity, which was successfully treated with rituximab. A Japanese boy suffered from recurrent infections and eczema, and was genetically diagnosed as having WAS at one month of age. When the patient was 11 months old, he started to develop systemic autoimmune symptoms including dermatitis, vasculitis and arthritis. Rituximab was markedly effective for these symptoms, whereas prednisolone and cyclosporine A were not. After remission of his autoimmunity, he underwent allogeneic umbilical cord blood transplantation as the curative therapy for WAS. As growing attention has been paid recently to humoral immunity in association with the autoimmunity of WAS, rituximab might be one of the key drugs for treating such autoimmunity.

Baker’s cyst is rare in children with hemophilia. A five-year-old boy with moderate hemophilia B received prophylactic Eftrenonacog alfa therapy. His left knee swelled after hitting a chair. Despite treatment with Eftrenonacog alfa, the swelling did not subside. Computed tomography showed the possibility of Baker’s cyst. However, it was diagnosed as obsolete hematoma by ultrasonography and he was treated with Nonacog alfa. Although the size of the hematoma was not reduced, the swelling was improved and he was discharged. However, the size gradually increased. Thus, we hypothesized new bleeding and he was treated with Albutrepenonacog alfa. The mass was suspected as Baker’s cyst on the basis of magnetic resonance imaging (MRI) findings. We punctured it as therapeutic diagnosis and saw hemorrhagic mucous fluid. We diagnosed bleeding in Baker’s cyst. It is likely that ultrasonography has higher sensitivity in detecting bleeding. In atypical cases of knee swelling, we should assess it by ultrasonography and MRI.

Here, we report five Japanese cases of hemoglobinopathy. These are the first Japanese cases of Hb Sabine and Hb Hazebrouck. Patient 1 had severe hemolytic anemia from infancy. Splenectomy was performed because of repeated aplastic crises. Genetic analysis showed Hb Sabine [β91(F7)Leu→Pro, CTG→CCG(β)]. Patient 2 had hemolytic anemia and jaundice from the neonatal period. Genetic testing showed Hb Evans [α62(E11)Val→Met, GTG→ATG(α2)]. His mother also had hemolytic anemia and the same mutation. Patient 3 was referred to us because of persistently low levels of oxygen saturation measured using a pulse oximeter. He had mild anemia and normal arterial oxygen saturation. DNA sequencing analysis showed Hb Hazebrouck [β38(C4)Thr→Pro, ACC→CCC(β)]. His father also had low levels of oxygen saturation and the same mutation. All cases had various degrees of anemia and showed low levels of percutaneous arterial oxygen saturation. Inclusion bodies were stained with antibodies to band3 and EMA in patient 1 and the mother of patient 2. These complexes presumably caused membrane injuries and hemolysis even after splenectomy.

Human parvovirus B19 (PVB19) is linked to several clinical manifestations, such as erythema infectiosum, aplastic crisis in patients suffering from chronic hemolytic anemia, and nonimmune hydrops fetalis. Recently, other unusual petechial or purpuric skin eruptions have been noted in association with PVB19 infection. Here, we report a rare case of aplastic crisis with petechial eruption, mainly on the trunk, in a 9-year-old boy with hereditary spherocytosis. In addition, a rash indicating erythema infectiosum developed during the sixth week of the disease. Purpuric-petechial eruption may be a good predictor of aplastic crisis in patients with chronic hemolytic disease.

A 15-year-old girl with catastrophic antiphospholipid syndrome (CAPS) presented with severe thrombocytopenia and hemolytic anemia and became brain dead on the fourth day of hospitalization because of hemorrhagic stroke. She visited the hospital because of fever and malaise. She had thrombocytopenia (Plt 8,000/μL) and hemolytic anemia (Hb 3.2 g/dL). She was refractory to various treatments including blood transfusions, intravenous methylprednisolone, plasma exchange, multiple doses of intravenous immunoglobulin infusion, and percutaneous splenic artery obliteration. Despite these treatments, her platelets were less than 10,000/μL, and she had hemorrhagic stroke. Progressing cerebral hemorrhage led to brain death. CAPS is one of the most important diseases when we examine a patient who has thrombophilia. This case illustrates that it is difficult to diagnose CAPS early; despite its acute fulminant course, initial treatments with CAPS requires assessments and treatments many times. Physicians must keep this possibility in mind.