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Among pediatric malignancies, solid tumors, particularly within the central nervous system (CNS), are common. Thiotepa, a myeloablative, high-dose chemotherapeutic (HDT) treatment administered prior to autologous hematopoietic stem cell transplantation (HSCT), can cross the blood-brain barrier and rapidly penetrate the CNS. We evaluated thiotepa HDT in conjunction with melphalan in Japanese patients with pediatric CNS/non-CNS solid tumors in a multicenter, open-label, non-comparative study. Thiotepa (200 mg/m2/day) was administered intravenously (IV) over 24 h on days −12, −11, −5, and −4 before scheduled HSCT. Melphalan (70 mg/m2/day) was administered IV over 1 h on days −11, −5, and −4. The safety analysis population comprised 41 patients, of whom 16 (39.0%) had solid tumors and 25 (61.0%) had brain tumors. The most frequently reported adverse events were diarrhea (40/41 [97.6%] patients) and febrile neutropenia (34/41 [82.9%]). No unexpected safety events were observed, and no events resulted in death or treatment discontinuation. All patients experienced bone marrow suppression and 39/41 (95.1%) achieved engraftment (neutrophil count ≥500/mm3 for 3 consecutive days after HSCT). The survival rate at day 100 post-autologous HSCT was 100%. These data confirm the safety of IV thiotepa plus melphalan HDT prior to autologous HSCT for patients with pediatric CNS/non-CNS solid tumors. Trial registration: JapicCTI-173654.

Neuroblastoma (NB) and pheochromocytoma (PCC) are derived from neural crest cells (NCCs); however, composite tumors with NB and PCC are rare, and their underlying molecular mechanisms remain unknown. To address this issue, we performed exome and transcriptome sequencing with formalin-fixed paraffin-embedded (FFPE) samples from the NB, PCC, and mixed lesions in a patient with a composite tumor. Whole-exome sequencing revealed that most mutations (80%) were shared by all samples, indicating that NB and PCC evolved from the same clone. Notably, all samples harbored both mutation and focal amplification in the FGFR1 oncogene, resulting in an extraordinarily high expression, likely to be the main driver of this tumor. Transcriptome sequencing revealed undifferentiated expression profiles for the NB lesions. Considering that a metastatic lesion was also composite, most likely, the primitive founding lesions should differentiate into both NB and PCC. This is the first reported case with composite-NB and PCC genetically proven to harbor an oncogenic FGFR1 alteration of a common cellular origin.

2010年８月～2013年３月までに訪問診療依頼があった167件のうち、重度嚥下障害と診断を受け、非経口摂取であった60歳以上の在宅療養患者19名（藤島摂食・嚥下能力グレード１）に対して嚥下評価と食事姿勢の指導を行った。このうち初診時の嚥下内視鏡検査において、経口摂取が可能（藤島摂食・嚥下能力グレード５以上）と評価された者は19名中10名であった。食事姿勢に関しては座位２名、30度仰臥位１名、完全側臥位７名であった。従来の誤嚥予防指導では安全な経口摂取が困難であると評価される対象者に完全側臥位法を導入することは経口摂取獲得に有効であることが示唆された。対象者は経口摂取獲得後も代替栄養を継続とした。経口摂取のみでは不足する水分量及び栄養量を適切な代替栄養で補い全身状態を整えることが「食べることを楽しむ」QOL向上の背景となることも併せて示唆された。Among 167 requests for home medical care between August 2010 and March 2013, we provided evaluation of swallowing function and eating posture guidance to 19 home care patients aged 60 years or older who had been diagnosed with severe dysphagia and were taking parenteral food（ Fujishima dysphagia scale FILS 1）. Of these 19 patients, 10 were assessed as being able to take food orally（ Fujishima dysphagia scale FILS ≧5 ） during the initial video endoscopic examination of swallowing. In terms of eating posture, two patients were in the sitting position, one in the 30-degree supine position, and seven in the flat lateral lying position. Our results suggest that the introduction of the flat lateral position is effective in helping patients who have difficulty with safe oral intake with conventional aspiration prevention instruction to obtain oral intake. The subject continued to receive alternative nutrition after acquiring oral intake. It was also suggested that supplementing the amount of water and nutrients that are insufficient for oral intake alone with appropriate alternative nutrition and improving the general condition of the patient can be the background for improving quality of life（ QOL）, which is the ability to enjoy eating.

Background Autoimmune mediated encephalitis (AME), which includes autoantibody-associated encephalitis and acute disseminated encephalomyelitis, is a common cause of encephalitis as well as infectious encephalitis in children. AME may be triggered by autoimmune responses to paraneoplastic syndromes and infections. Infectious encephalitis associated with an immunocompromised status caused by anti-cancer chemotherapy is well recognized; however, there have been few reports on the relationship between AME and chemotherapy. Case report A ten-year-old previously healthy, developmentally normal girl was diagnosed with a pure germinoma in the suprasellar region. Following 30 days of induction chemotherapy, she developed a depressed level of consciousness with accompanying right hemiplegia, aphasia, and unexplained fever. Cerebrospinal fluid (CSF) analysis revealed positive oligoclonal bands and elevated neopterin levels. Neither atypical cells suggesting tumor exacerbation nor pathogens known to cause encephalitis were identified in the CSF. She was administrated immunosuppressive therapy and her symptoms rapidly improved. No known autoantibodies associated with autoantibody-associated encephalitis were identified in blood or CSF. However, the presence of oligoclonal bands and elevated neopterin levels in the CSF, and the favorable response to immunosuppressive therapy were consistent with an AME diagnosis. Thirteen days after the third course of chemotherapy, the patient developed a depressed level of consciousness again. Due to the recurrence of encephalitis, re-administration of immunosuppressive therapy was performed, which led to improvement in her symptoms. Recurrence of encephalitis has not occurred for 1 year after completion of chemotherapy. Conclusion The chemotherapy-induced abnormal immune response might have triggered the AME.

Introduction. An on-going coronavirus disease 2019 (COVID-19) has become a challenge all over the world. Since an endoscopy unit and its staff are at potentially high risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we conducted a survey for the management of the gastrointestinal endoscopic practice, personal protective equipment (PPE), and risk assessment for COVID-19 during the pandemic at multiple facilities. Methods. The 11-item survey questionnaire was sent to representative respondent of Department of Gastroenterology, Osaka City University Hospital, and its 19 related facilities. Results. A total of 18 facilities submitted valid responses and a total of 373 health care professionals (HCPs) participated. All facilities (18/18: 100%) were screening patients at risk for SARS-CoV-2 infection before endoscopy. During the pandemic, we found that the total volume of endoscopic procedures decreased by 44%. Eleven facilities (11/18: 61%) followed recommendations of the Japan Gastroenterological Endoscopy Society (JGES); consequently, about 35%–50% of esophagogastroduodenoscopy and colonoscopy were canceled. Mask (surgical mask or N95 mask), face shield/goggle, gloves (one or two sets), and gown (with long or short sleeves) were being used by endoscopists, nurses, endoscopy technicians, and endoscope cleaning staff in all the facilities (18/18: 100%). SARS-CoV-2 infection risk assessment of HCPs was conducted daily in all the facilities (18/18: 100%), resulting in no subsequent SARS-CoV-2 infection in HCPs. Conclusion. COVID-19 has had a dramatic impact on the gastrointestinal endoscopic practice. The recommendations of the JGES were appropriate as preventive measures for the SARSCoV-2 infection in the endoscopy unit and its staff.

Background Central nervous system (CNS) germ cell tumors account for 15.3% of all CNS tumors in children and adolescents and young adults. Five histologic types and mixed types exist and can be classified into the following clinical risk groups: germinomas, malignant germ cell tumors, and other germ cell tumors. In germinomas, platinum-based chemotherapy and whole ventricle/brain irradiations 23.4 Gy/13 fraction are the standard of care, but late adverse events related to radiation therapy are a problem. In malignant germ cell tumors, chemotherapy with alkylating agents and platinum, craniospinal irradiation (CSI), and local radiation therapy (local dose 50-59.4 Gy/25-33 fractions) have become the standard of care, but the 10-year OS is poor at about 60% and late radiation therapy-related adverse events are an issue. For various reasons, it is not easy to establish a standard of care for mature teratomas and immature teratomas, which constitute the other germ cell tumors, but it is essential to collect knowledge on tumor characteristics and prognosis. Methods and Patients The Japan Children's Cancer Group Brain Tumor Committee has planned a study to validate the classification by histological diagnosis and ancillary tumor markers, a phase III study to test the non-inferiority of radiation dose reduction to standard therapy for germinomas, a phase II study to test the superiority of high-dose chemoradiation with methotrexate intrathecal injection excluding CSI to standard therapy for malignant germ cell tumors, observational studies to elucidate pathogenesis of other germ cell tumors. Discussion If these hypotheses are proven, it is expected to reduce late adverse events and prolong survival with radiotherapy in children and adolescent/young adult generation patients.

Background Diffuse midline glioma (DMG) occurs mainly in the brain stem and most of patients have the mutation of histone (H3K27M). The prognosis is poor, and median overall survival (OS) is less than 12 months. OP-10 (ONC201) have antagonistic activity against dopamine D2 ha and to activate ClpP, a mitochondrial protease, leading tumor cells to apoptosis. We conducted a multicenter, single-arm, open-label phase I/II study of OP-10 in Japan. Methods A 3 + 3 design was used to determine the recommended dose of OP-10 for nine patients with recurrent or refractory glioma in the phase-I trial. Patients with recurrent or refractory DMG in the phase-II trial orally received OP-10 once weekly until discontinuation because of progression or adverse events. The efficacy and safety of OP-10 were evaluated in the phase-II part. The tumor objective response rate (ORR), the primary endpoint of the phase-II trial, was assessed through a blinded, independent central review according to RANO-LGG criteria. Results A total of 9 (age: 24-72 years) and 31 (age: 4-39 years) patients were administered in the phase-I and phase-II trials, respectively. Although the lower limit of the 90% confidence interval for ORR did not exceed the pre-specified threshold (5%), nine of 31 patients showed tumor regression on T2/FLAIR images. In the phase-II trial, the median OS was 28.4 weeks, and the OS rate at 6 months was 54.8%. Adverse events of grade ≥ 3 were reported in five of 31 (16.1%) patients in the phase-II part, with death of disease, hyperuricemia, malaise, pyrexia, alanine transaminase elevation, and aspartate transaminase elevation. Conclusion The results of this study suggested that OP-10 might be efficacious in some patients with recurrent or refractory DMG, without major safety concerns.

Tamibarotene is a synthetic retinoid that inhibits proliferation and induces differentiation of malignant cells by binding to the retinoic acid receptor α/β. Previous in vitro studies have shown that some pediatric solid tumors with retinoic acid receptors differentiate in response to retinoic acid. We conducted a phase I dose-escalation study to determine the recommended dose of tamibarotene for further study in pediatric and young adult patients with recurrent/refractory solid tumors. Pediatric and young adult patients with recurrent/refractory solid tumors were administered tamibarotene at 4, 6, 8, 10, and 12 mg/m2/day for 14 or 21 days of a 28 day cycle. Safety, efficacy, and pharmacokinetics of tamibarotene were evaluated. Twenty-two patients (median age 8 years) were enrolled in this study. No dose-limiting toxicity (DLT) was encountered, and tamibarotene was generally well tolerated. Two patients experienced severe adverse events (AEs), leading to discontinuation of the treatment. One grade 4 venous thrombosis and one grade 2 erythema multiforme were observed, which promptly resolved after tamibarotene discontinuance. The grade 4 venous thrombosis was a severe AE but not DLT because it occurred after the evaluation period. Pharmacokinetic analyses showed a dose-dependent increase in the maximum drug concentration (Cmax) and area under the concentration–time curve (AUC). None of the patients achieved a complete response or partial response. Seven patients had stable disease lasting longer than 18 weeks. The recommended dose for phase II study of tamibarotene in pediatric and young adult patients with refractory solid tumors is 12 mg/m2/day for 21 days in a 28 day cycle.

This study focused on children as well as adolescents and young adults (AYAs) and aimed to examine trends in survival of leukemia over time using population‐based cancer registry data from Osaka, Japan. The study subjects comprised 2254 children (0‐14 years) and 2,905 AYAs (15‐39 years) who were diagnosed with leukemia during 1975‐2011. Leukemia was divided into four types: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and other leukemias. We analyzed 5‐year overall survival probability (5y‐OS), using the Kaplan‐Meier method and expressed time trends using the joinpoint regression model. For recently diagnosed (2006‐2011) patients, a Cox proportional hazards model was applied to determine predictors of 5y‐OS, using age group, gender, and treatment hospital as covariates. Over the 37‐year period, 5y‐OS greatly improved among both children and AYAs, for each leukemia type. Among AYAs, 5y‐OS of ALL improved, especially after 2000 (65% in 2006‐2011), when the pediatric regimen was introduced but was still lower than that among children (87% in 2006‐2011, P, Survival of each type of leukemia in children, adolescents, and young adults has improved dramatically over the past 30 years.

Ponatinib is a third-generation tyrosine kinase inhibitor (TKI) reported to show a higher efficacy for adult Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) than other TKIs. However, few studies describe ponatinib for pediatric Ph+ALL; therefore, the efficacy, safety, and optimal dosage have not been determined. Here, we report a 3-year-old girl with Ph+ALL treated by a ponatinib-containing regimen with therapeutic drug monitoring in the plasma and cerebrospinal fluid (CSF). In our case, a ponatinib-containing regimen was able to keep minimal residual disease negative, and the pharmacokinetics (PKs) of plasma ponatinib resembled that previously reported in adults. Penetration to the CSF was extremely limited. Thus, ponatinib was feasible and effective for a child with Ph+ALL, although the plasma concentration of ponatinib varied significantly throughout the treatment. The appropriate dosage should be confirmed in a prospective trial, including a detailed PK study.

We report a case of rhabdoid tumor predisposition syndrome with a renal tumor developing 10 years after a brain tumor, which demonstrated an unexpectedly favorable outcome. A 2-year-old boy underwent gross total resection of a brain tumor located in the fourth ventricle, and received adjuvant chemotherapy and radiotherapy. At the age of 11 years, a renal tumor was found and nephrectomy was performed. He is currently alive without evidence of disease over 2 years without postoperative therapy. Histologically, rhabdoid cells were observed in both brain and renal tumors. Loss of SMARCB1 (also known as INI1) expression was found in the nucleus of both tumor cells. Genetic testing revealed pathogenic variants of SMARCB1 exon 5 in the renal tumor and SMARCB1 exon 9 in the brain tumor. In addition, heterozygous deletion of 22q11.21-q11.23 containing the SMARCB1 locus was shared by both tumors and this deletion was identified in normal peripheral blood. Considering the histopathological and genetic findings, our case was considered to be rhabdoid tumor predisposition syndrome with atypical teratoid/rhabdoid tumor and late-onset rhabdoid tumor of the kidney.

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare intracranial tumor occurring predominantly in young children. The prognosis is poor, and no effective treatment is currently available. To develop novel effective therapies, there is a need for experimental models for AT/RT. In this research, we established a cell line from a patient's AT/RT tissue (designated ATRT_OCGH) and performed drug screening using 164 FDA-approved anti-cancer agents, to identify candidates for therapeutic options. We found that bortezomib, a proteasome inhibitor, was among the agents for which the cell line showed high sensitivity, along with tyrosine kinase inhibitors, topoisomerase inhibitors, and histone deacetylase inhibitors, which are known to exert anti-AT/RT effects. Concomitant use of panobinostat potentiated the inhibitory effect of bortezomib on AT/RT cell proliferation. Our findings may provide a rationale for considering combination therapy of panobinostat and bortezomib for treatment of AT/RT.

Background Almost all pediatric patients with renal tumors are diagnosed with nephroblastoma (Wilms tumor), clear cell sarcoma, or malignant rhabdoid tumor. The choice of treatment is important for relapsed and refractory patients with nephroblastoma. Furthermore, clear cell sarcoma of the kidney (CCSK) and malignant rhabdoid tumor of the kidney (MRTK) have a poor prognosis compared with nephroblastoma. Thus, stem cell transplantation (SCT) is sometimes selected to treat these tumors. Patients and methods The authors targeted a total of 84 patients with nephroblastoma, CCSK, and MRTK who underwent a first autologous SCT between 1992 and 2014, and were registered in the Japanese Transplant Registry Unified Management Program system. The authors retrospectively analyzed the SCT data for survival rate. Results Five-year overall survival rates for nephroblastoma, CCSK, and MRTK were 72.4%±6.3%, 46.8%±13.8%, and 36.4%±14.5%, respectively. The event-free survival rates at 5 years were 64.9%±6.7%, 35.7%±12.8%, and 27.3%±13.4%, respectively. The relapse rates at 5 years were 25.3%±11.4%, 46.2%±28.4%, and 60.0%±43.1%, respectively. Conclusion Although the survival rate for nephroblastoma was relatively high, those of CCSK and MRTK were poor.

This study was a second multicenter trial on childhood ALL by the Japan Childhood Leukemia Study Group (JACLS) to improve outcomes in non-T ALL. Between April 2002 and March 2008, 1138 children with non-T ALL were enrolled in the JACLS ALL-02 trial. Patients were stratified into three groups using age, white blood cell count, unfavorable genetic abnormalities, and treatment response: standard risk (SR), high risk (HR), and extremely high risk (ER). Prophylactic cranial radiation therapy (PCRT) was abolished except for CNS leukemia. Four-year event-free survival (4yr-EFS) and 4-year overall survival (4yr-OS) rates for all patients were 85.4% ± 1.1% and 91.2% ± 0.9%, respectively. Risk-adjusted therapy resulted in 4yr-EFS rates of 90.4% ± 1.4% for SR, 84.9% ± 1.6% for HR, and 66.5% ± 4.0% for ER. Based on NCI risk classification, 4yr-EFS rates were 88.2% in NCI-SR and 76.4% in NCI-HR patients, respectively. Compared to previous trial ALL-97, 4yr-EFS of NCI-SR patients was significantly improved (88.2% vs 81.2%, log rank p = 0.0004). The 4-year cumulative incidence of isolated (0.9%) and total (1.5%) CNS relapse were significantly lower than those reported previously. In conclusion, improved EFS in NCI-SR patients and abolish of PCRT was achieved in ALL-02.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. As overall cure rates of childhood ALL have improved, reduction of overall treatment intensity while still ensuring excellent outcomes is imperative for low-risk patients. We report the outcomes of patients treated following the standard-risk protocol from the prospective Japan Association of Childhood Leukemia Study (JACLS) ALL-02 study, which was conducted between 2002 and 2008 for patients with newly diagnosed ALL aged 1-18 years. Of 1138 patients with B-cell precursor ALL, 388 (34.1%) were allocated to this protocol. Excellent outcomes were achieved despite the overall treatment intensity being lower than that of most contemporary protocols: 4 years event-free survival (EFS) was 92.3% and 4 years overall survival 98.2%. Patients with high hyperdiploidy (HHD) involving triple trisomy (trisomy of chromosomes 4, 10, and 17) or ETV6-RUNX1 had even better outcomes (4 years EFS 97.6% and 100%, respectively). Unique characteristics of this protocol include a selection of low-risk patients with a low initial WBC count and good early treatment response and reduction of cumulative doses of chemotherapeutic agents while maintaining dose density. In Japan, we are currently investigating the feasibility of this protocol while incorporating minimal residual disease into the patient stratification strategy.

Diamond-Blackfan anaemia (DBA) shares clinical features with two recently reported sporadic cases of dyserythropoietic anaemia with a cryptic

In this study, we performed a retrospective analysis of a cohort of Japanese paediatric patients with B-cell precursor (BCP)-acute lymphoblastic leukaemia (ALL) treated with a Berlin-Frankfurt-Münster (BFM)95-based protocol, to clarify the incidence, clinical characteristics, and risk factors of osteonecrosis (ON) in comparison to the ALL-02 protocol. We identified a high frequency of ON with the BFM95-based protocol compared to the ALL-02 protocol. The incidence of symptomatic ON with the BFM95-based protocol is comparable to previous studies in Western countries. We believe that the type of treatment regimen has more impact on the incidence of symptomatic ON in paediatric ALL than ethnicity.

Primary CNS germ cell tumors (GCTs) are rare neoplasms predominantly observed in the pediatric and young adult populations. In line with the hypothesis that the primordial germ cell is the cell-of-origin, histopathological examinations for this pathology involve a diverse range of components mirroring the embryogenic developmental dimensions. Chemotherapy and radiotherapy are the mainstays of treatment, with surgery having a limited role for diagnosis and debulking of residual tissue after treatment. While better management has been achieved over recent decades by modifying radiation coverage and selecting appropriate chemotherapy, standardization of treatment remains challenging, partly due to the low volume of cases encountered in each institution. As the incidence is higher in East Asia, including Japan, the Japan Society for Neuro-Oncology established a multidisciplinary task force to create an evidence-based guideline for CNS GCTs. This guideline provides recommendations for multiple dimensions of clinical management for CNS GCTs, with particular focus on diagnostic measures including serum markers, treatment algorithms including surgery, radiotherapy, and chemotherapy, and under-investigated but important areas such as treatment for recurrent cases, long-term follow-up protocols, and long-term sequelae. This guideline serves the purpose of helping healthcare professionals keep up to date with current knowledge and standards of management for patients with this rare disease in daily clinical practice, as well as driving future translational and clinical research by recognizing unmet needs concerning this tumor.

Background: Treatment of intracranial germ cell tumors (GCTs) involves radiation therapy to the whole ventricle or the whole neuroaxis, but late sequelae are a concern. Therefore, an alternative modality is needed to reduce the overreliance on radiation therapy. Intrathecal methotrexate (IT-MTX) was examined as a partial alternative to radiotherapy. Procedure: Low-risk (LR) patients (germinoma) were treated with four cycles of cisplatin, etoposide, and IT-MTX, while intermediate-risk (IR) (human chorionic gonadotropin [HCG]-producing germinoma) and high-risk (HR) (non-germinomatous GCT) patients were treated with five cycles of cisplatin, etoposide, cyclophosphamide, and IT-MTX. Local irradiation of 24 Gy was performed for the LR and IR patients, while irradiation with 51.2 Gy was performed for the HR cases. For patients with multifocal diseases and/or tumors extending to the 3rd ventricle, whole ventricle irradiation was performed. Results: A total of 57 patients were enrolled, of which three withdrew consent. Thus, 54 patients were included in the outcome analysis. The 5-year progression-free survival and overall survival were 92.0% (standard error 4.4%) and 100%, respectively, for 28 LR and 10 IR patients (median follow-up: 63 months), and 86.7% (8.8%) and 93.3% (6.4%) (median follow-up: 67 months), respectively, for 16 HR patients. The major toxicity was hematological, and most patients experienced grade 4. Conclusion: The toxicity of chemotherapy containing IT-MTX was limited, and the results suggested that this regimen could reduce the need for radiotherapy.

SMARCA4 pathogenic variants are rarely detected in pediatric brain tumors other than atypical teratoid rhabdoid tumors (AT/RTs) without INI1 deficiency or in some cases of medulloblastoma. Here, we report an atypical intracranial immature teratoma that recurred as a yolk sac tumor with metastatic spinal and lung lesions. Sequencing of the tumor revealed two SMARCA4 variants, including a splice-site variant and a non-synonymous variant of uncertain significance. Additionally, the methylation signature of the tumor was close to that of AT/RTs. Our case might be a yet-unrecognized subtype of pediatric tumors in which inactivation of SMARCA4 contributes to the pathogenesis.

Pediatric refractory solid tumors are aggressive malignant diseases, resulting in an extremely poor prognosis. KOC1, FOXM1, and KIF20A are cancer antigens that could be ideal targets for anticancer immunotherapy against pediatric refractory solid tumors with positive expression for these antigens. This nonrandomized, open‐label, phase I clinical trial evaluated the safety and efficacy of the NCCV Cocktail‐1 vaccine, which is a cocktail of cancer peptides derived from KOC1, FOXM1, and KIF20A, in patients with pediatric refractory solid tumors. Twelve patients with refractory pediatric solid tumors underwent NCCV Cocktail‐1 vaccination weekly by intradermal injections. The primary endpoint was the safety of the NCCV Cocktail‐1 vaccination, and the secondary endpoints were the immune response, as measured by interferon‐r enzyme‐linked immunospot assay, and the clinical outcomes including tumor response and progression‐free survival. The NCCV Cocktail‐1 vaccine was well tolerated. The clinical response of this trial showed that 4 patients had stable disease after 8 weeks and 2 patients maintained remission for >11 months. In 4, 8, and 5 patients, the NCCV Cocktail‐1 vaccine induced the sufficient number of peptide‐specific CTLs for KOC1, FOXM1, and KIF20A, respectively. Patients with high peptide‐specific CTL frequencies for KOC1, FOXM1, and KIF20A had better progression‐free survival than those with low frequencies. The findings of this clinical trial showed that the NCCV Cocktail‐1 vaccine could be a novel therapeutic strategy, with adequate effects against pediatric refractory solid tumors. Future large‐scale trials should evaluate the efficacy of the NCCV Cocktail‐1 vaccination., Kaplan‐Meier curves for progression‐free survival. We found that patients with higher numbers of cancer antigens (KOC1, FOXM1, and KIF20A) that induced peptide‐specific CTLs by vaccination had better progression‐free survival.

Purpose Thiotepa is used in high-dose chemotherapy (HDT) before autologous hematopoietic stem cell transplantation (HSCT) to treat solid tumors and hematological malignancies. This Phase 1 study was conducted to establish the pharmacokinetics (PK) of thiotepa in a Japanese population. Methods HDT/HSCT was performed in pediatric patients (≥ 2 years) with solid tumors or brain tumors (thiotepa 200 mg/m2/day IV-infused over 24 h on HSCT Days − 12, − 11, − 5, and − 4 and melphalan 70 mg/m2/day IV-infused over 1 h on Days − 11, − 5, and − 4) and adult patients (≥ 16 years) with malignant lymphoma (thiotepa 200 mg/m2/day 2-h IV-infusion on HSCT Days − 4 and − 3 plus busulfan 0.8 mg/kg 2-h IV-infusion every 6 h from HSCT Days − 8 to − 5). Pharmacokinetics of thiotepa were assessed following initial dose. Safety and efficacy were also evaluated. Results Nine pediatric and 10 adult patients were enrolled. Mean volume of distribution (Vz) of thiotepa normalized with body surface area (BSA) was lower for pediatric patients (16.4 L/m2) compared with adult patients (26.4 L/m2) as expected due to the higher specific surface area of children. Clearance and biological half-life were similar between pediatric and adult patients. Two serious adverse events (cardiac arrest and pulmonary edema) were observed. Survival rate (Day 100 post-HSCT) was 77.8% (95% CI 36.5–93.9%) for pediatric patients and 100% for adult patients. Conclusion Thiotepa elimination was comparable in pediatric and adult patients with cancer. Lower Vz in pediatric compared with adult patients was expected. HDT with thiotepa prior to autologous HSCT was well tolerated. Study registration Japic CTI-163433. Electronic supplementary material The online version of this article (10.1007/s00280-019-03914-2) contains supplementary material, which is available to authorized users.

We report a case of 2-year-old female with lateral ventricular glioma harboring both H3F3A K27M and BRAF V600E mutations. By the methylation analysis, the tumor was classified as a diffuse midline glioma H3 K27M mutant, WHO grade IV. However, the tumor was pathologically low-grade and likely localized rather than diffusely infiltrating. Further, the patient has survived more than 8 years after gross total resection of the tumor. Whereas both H3F3A K27M and BRAF V600E have been reported as poor prognostic markers in pediatric glioma, our case, along with several other reported cases, suggests that the coexistence of these two mutations might not indicate poor prognosis. The case emphasizes the importance of comprehensive assessment based on pathological, genetic and clinical findings and calls for further investigations of non-diffuse glioma with H3F3A K27M and glioma with H3F3A K27M and BRAF V600E.

LBA2002 Background: LGG is the most common pediatric brain cancer, and BRAF V600 mutation has been detected in ≈17% of cases. Most patients (pts) with pLGG have disease progression and require post-surgical therapy. The standard of care is chemotherapy, such as carboplatin + vincristine (C+V), which may be less effective in BRAF V600–mutant disease; thus, alternative treatment options are needed. Dab + tram showed encouraging efficacy in a Phase I/II study (NCT02124772) in pts with previously treated BRAF V600–mutant pLGG. We describe the results of a randomized Phase II study (NCT02684058) of first-line dab + tram vs C+V in BRAF V600–mutant pLGG. Methods: Pts aged 1 to

2009 Background: HGGs comprise ≈10% of pediatric central nervous system tumors and are a leading cause of childhood cancer-related death. Overall response rates (ORRs) with current standards of care are low, particularly in the second line, and 2-y overall survival (OS) rates are ≤35%. BRAF V600 mutation is infrequent (≈5% of pHGGs) but associated with improved survival from time of initial diagnosis. In previous trials, dab monotherapy and dab + tram yielded encouraging outcomes in BRAF V600–mutant HGG in pediatric and adult patients (pts), respectively. We describe the results of a Phase II study (NCT02684058) of dab + tram in r/r BRAF V600–mutant pHGG. Methods: Pts aged 1 to

BACKGROUND: Intracranial germ cell tumors (iGCT) are heterogeneous tumors with several histopathology. Chemoradiotherapy is effective and required for treatment against them, but optimal treatment intensity should be selected from the viewpoint of both improvement of clinical outcome and avoidance of late complications. We introduced a protocol with reduced-dose radiotherapy and intensified chemotherapy for iGCT. OBJECTIVE: We retrospectively analysed the clinical outcome, especially for non-germinomatous germ cell tumors and long-term clinical outcome of late complications, enrollment and employment, as indicators of quality of life (QOL). MATERIALS AND METHODS: Thirty-eight children and young adults (28 men and 10 women) with iGCTs treated in our institution from 1997 to 2013 were enrolled in this study. They consisted of 26 germinomas including HCG-producing cases and 12 non-germinomatous GCTs (NGGCT). Local irradiation was selected for all patients, and the dose of irradiation was 23.4-54 Gy. The whole-brain irradiation was made in patients who had intracranial dissemination, but any prophylactic irradiation to the whole brain and spinal cord was not performed. For NGGCT, high-dose chemotherapy and peripheral blood stem cell transplantation (PBSCT) were introduced. Second-look surgeries were performed for cases with residual tumors after induction chemotherapies. RESULTS: In germinoma group and NGGCT group, 10-year progression-free survival was 86% and 84%, 10-year overall survival was 93% and 91%, respectively. About late complications, endocrinological replacement (39%), cerebrovascular disease such as cavernous hemangioma and arterial stenosis (18%), secondary neoplasm (2.6%) were observed. Regarding QOL, enrollment and return to school rate was 92% and employment and the return rate was 89%, which were influenced by hemipararesis associated with basal ganglia lesion, intractable epilepsy and whole-brain irradiation. CONCLUSION: Reduced-dose radiotherapy and intensified chemotherapy for iGCT, especially NGGCT, improved the clinical outcome and QOL of long-term survivors, suppressing late complications. Further comprehensive follow-up and analysis are needed.

Gemcitabine and Docetaxel(GEM/DTX)are well known chemotherapeutic drugs for the treatment of soft tissue sarcomas. However, the efficacy of these drugs in the treatment of malignant rhabdoid tumors(MRTs)has not been well described. We used GEM/DTX as salvage chemotherapy for relapsed and refractory MRTs, including 2 patients with malignant rhabdoid tumor of the kidney(MRTK)and 2 with atypical teratoid rhabdoid tumor(ATRT). At the best, partial response was observed in 3 patients(2 MRTK and 1 ATRT). The remaining patient with ATRT had stable disease. Localized edema in the field of recent radiation therapy was discovered in 2 patients. In addition, one had pleural effusion without any evidence of tumor progression. GEM/DTX can be used as a potential chemotherapeutic drug for relapsed or refractory MRTs, although attention should be paid to its unique adverse events.

BACKGROUND: The CpG island methylator phenotype of neuroblastoma (NBL) is strongly associated with poor prognosis and can be targeted by 5-aza-2’-deoxycytidine (5-aza-dC). Differentiation therapy is a standard maintenance therapy for high-risk NBLs. However, the in vivo effect of tamibarotene, a synthetic retinoic acid, and the efficacy of its combination with 5-aza-dC have not been studied. Here, we conducted a preclinical study to assess the in vivo tamibarotene effect and the combination. METHODS: Treatment effects were analysed by in vitro cell growth and differentiation state and by in vivo xenograft suppression. Demethylated genes were analysed by DNA methylation microarrays and geneset enrichment. RESULTS: Tamibarotene monotherapy induced neural extension and upregulation of differentiation markers of NBL cells in vitro, and tumour regression without severe side effects in vivo. 5-Aza-dC monotherapy suppressed tumour growth both in vitro and in vivo, and induced demethylation of genes related to nervous system development and function. Pre-treatment with 5-aza-dC in vitro enhanced upregulation of differentiation markers and genes involved in retinoic acid signaling. Pre-treatment with 5-aza-dC in vivo significantly suppressed tumour growth and reduced the variation in tumour sizes. CONCLUSIONS: Epigenetic drug-based differentiation therapy using 5-aza-dC and TBT is a promising strategy for refractory NBLs.