Search

Deficiency of adenosine deaminase-2 (DADA2) is an autoinflammatory disease caused by loss-of-function homozygous or compound heterozygous mutations in I CECR1 i (cat eye syndrome chromosome region 1) ([1], [2]). Although anti-TNF agents prevent strokes and improve the manifestations of vasculitis in DADA2, their efficacy for treating PRCA and bone marrow failure is less clear ([3]). DADA2 may be lurking among those diagnosed with idiopathic PRCA, and CyA may be useful for treating PRCA associated with DADA2, as in our patient. [Extracted from the article]

FBXW7 (F-box and WD-repeat domain-containing 7) is a tumor suppressor gene, and its germline variants have been causally linked to Wilms tumors. Furthermore, germline variants of FBXW7 have also been implicated in a neurodevelopmental syndrome. However, little is known regarding the occurrence of Wilms tumor in patients with FBXW7-related neurodevelopmental syndrome. We identified a novel constitutional pathogenic variant of FBXW7 in a patient with intellectual disability, who also developed Wilms tumor. The variant was derived from his apparently normal mother, and was also detected in his sister who exhibited developmental delay. Furthermore, we detected a somatic nonsense variant on the paternal allele of FBXW7 in the tumor DNA. These results suggest that the development of Wilms tumor along with FBXW7-related neurodevelopmental syndrome follows the two-hit model, which needs to be validated to establish appropriate follow-up management and tumor surveillance., (© 2024. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Silent inactivation (SI) of L-asparaginase (ASP) is a phenomenon by which a neutralizing antibody for ASP (AAA) decreases ASP activity (ASA) in patients without a clinical allergy to ASP. Acute lymphoblastic leukemia (ALL) has a poor prognosis in patients with SI. Therefore, measurement of ASA levels, not AAA levels, is needed to identify patients with SI. We herein report the results of the prospective clinical trial ALL-ASP19, the first study in Japan to measure ASA and AAA to identify patients with SI. A total of 110 newly diagnosed ALL patients were enrolled, and ASA levels were measured three times during ALL treatment. Besides the 12 patients who discontinued the study, 32 were excluded due to inappropriate frequency and timing of ASA measurements and inappropriate ASP dosing. The remaining 66 patients were analyzed, and 3 patients with SI (4.5%) were identified. The incidence of SI is lower in Japan than in other countries. AAA was detected in all patients with SI, but four of the seven patients with AAA did not develop SI. Clinical characteristics did not significantly differ between patients with and without SI. Therefore, ASA levels must be measured to identify patients receiving insufficient ASP treatment., (© 2024. Japanese Society of Hematology.)

Background: IL10RA (IL10 receptor subunit alpha) deficiency is an autosomal recessive disease that causes inflammatory bowel disease during early infancy. Its clinical course is often fatal and the only curative treatment is allogeneic hematopoietic cell transplantation (HCT). In Japan, only case reports are available, and there are no comprehensive reports of treatment outcomes., Methods: We retrospectively analyzed patients with IL10RA deficiency in Japan., Results: Two newly identified and five previously reported patients were included in this study. Five patients underwent HCT; one untransplanted patient survived to age 14, and one died of influenza encephalopathy before transplantation. All five HCT recipients underwent HCT at the age before 2 years. They all were conditioned with fludarabine/busulfan- or fludarabine /melphalan-based regimens. The donor source was human leukocyte antigen haploidentical donor bone marrow (BM) for two patients and unrelated umbilical cord blood (CB) for two patients. One patient experienced graft failure with unrelated CB and required a second transplant with unrelated BM. All patients who underwent HCT survived and demonstrated an improved performance status., Conclusion: In cases of IL10RA deficiency, the need for transplantation should be promptly assessed, and early transplantation should be considered. (190/250)., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Metronomic chemotherapy (MC) is based on chronic administration of chemotherapeutic agents at minimally toxic doses without prolonged drug-free breaks, that inhibits tumor angiogenesis and induces tumor dormancy. This study aimed to determine the efficacy of MC for pediatric refractory solid tumors. We retrospectively analyzed the data of pediatric patients with relapsed/refractory solid tumors who received treatment, including low-dose continuous administration of anticancer drugs, at our institute. Of the 18 patients, the disease statuses at the initiation of MC were complete remission (n=2), partial remission/stable disease (n=5), and progressive disease (n=11). The overall survival rate was 61% at 12 months and 34% at 24 months, and the progression-free survival rate was 21% at 12 and 24 months. Although only 5 of the 18 patients showed certain tumor regression or maintained remission, tumors that stabilized, maintained remission/stable disease, and showed certain advantages in terms of overall survival rate, even if limited to progressive disease. Approximately half of the patients demonstrated temporal tumor stabilization and improved survival time. Overall, previous reports and the present study support the conclusion that MC has the potential to play an important role in pediatric cancer treatment during the advanced stage., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Alemtuzumab is used with reduced-toxicity conditioning (RTC) in allogeneic hematopoietic cell transplantation (HCT), demonstrating efficacy and feasibility for patients with inborn errors of immunity (IEI) in Western countries; however, the clinical experience in Asian patients with IEI is limited. We retrospectively analyzed patients with IEI who underwent the first allogeneic HCT with alemtuzumab combined with RTC regimens in Japan. A total of 19 patients were included and followed up for a median of 18 months. The donors were haploidentical parents (n = 10), matched siblings (n = 2), and unrelated bone marrow donors (n = 7). Most patients received RTC regimens containing fludarabine and busulfan and were treated with 0.8 mg/kg alemtuzumab with intermediate timing. Eighteen patients survived and achieved stable engraftment, and no grade 3-4 acute graft-versus-host disease was observed. Viral infections were observed in 11 patients (58%) and 6 of them presented symptomatic. The median CD4 + T cell count was low at 6 months (241/µL) but improved at 1 year (577/µL) after HCT. Whole blood cells continued to exhibit > 80% donor type in most cases; however, 3/10 patients exhibited poor donor chimerism only among T cells and also showed undetectable levels of T-cell receptor recombination excision circles (TRECs) at 1 year post-HCT. This study demonstrated the efficacy and safety of alemtuzumab; however, patients frequently developed viral infections and slow reconstitution or low donor chimerism in T cells, emphasizing the importance of monitoring viral status and T-cell-specific chimerism. (238 < 250 words)., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Survival rates of patients with Philadelphia chromosome-positive ALL (Ph+ALL) have improved considerably with the introduction of tyrosine kinase inhibitors (TKI); however, hematopoietic stem cell transplantation (HSCT) continues to play an important role. Reduced-intensity conditioning (RIC) regimens have been widely applied particularly for older patients, but their validity for children and adolescents with Ph+ALL has not been investigated. In this study, data from patients receiving HSCT for de novo Ph+ALL in first or second remission at ages younger than 25 years and with a history of pre-HSCT TKI therapy were retrospectively collected through the nationwide registry in Japan. In 265 patients who received myeloablative conditioning (MAC) and 33 patients receiving RIC, 5-year leukemia-free survival (LFS) rates were 67.3% and 79.8%, respectively (p = 0.142). Multivariate analysis of LFS, focusing on patients with good performance status, identified RIC as a significant prognostic factor for LFS (hazard ratio 0.32, p = 0.032), as well as older age, higher leukocyte count at diagnosis, and disease with additional chromosomal abnormalities. These trends were similar when we focused on patients who received prophylactic post-HSCT TKI treatment, as 5-year LFS was 81.0% for MAC and 84.4% for RIC (p = 0.748). In summary, HSCT with RIC regimen showed at least comparable LFS to HSCT with MAC regimen, and RIC was an independent favorable prognostic factor on multivariate analysis adjusting potential prognostic factors. While patient numbers were limited, our data suggest that RIC may be safely applied in this group, particularly combined with prophylactic post-HSCT TKI maintenance therapy., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Germline genetic variants influence development of pediatric B cell acute lymphoblastic leukemia (B-ALL). Genome-wide association studies (GWAS) have identified several pediatric B-ALL susceptibility loci. IKZF1 and PAX5 , transcription factors involved in B cell development, have been reported as susceptibility genes for B-ALL development. Therefore, we hypothesized that rare variants of genes involved in B cell development would be candidate susceptibility loci for pediatric B-ALL. Thus, we sequenced TCF3 , a key transcription factor gene involving in B cell development. Saliva DNA from 527 pediatric patients with pediatric B-ALL in remission who were registered with the Tokyo Children's Cancer Study Group (TCCSG) were examined. As a TCF3 gene-based evaluation, the numbers of rare deleterious germline TCF3 sequence variants in patients with pediatric B-ALL were compared with those in cancer-free individuals using data in public databases. As a TCF3 single-variant evaluation, the frequencies of rare deleterious germline TCF3 sequence variants in patients with pediatric B-ALL were also compared with those in control data. TCF3 gene-based analysis revealed significant associations between rare deleterious variants and pediatric B-ALL development. In addition, TCF3 variant-based analysis showed particularly strong association between variant rs372168347 (three in 521 TCCSG and three in the 15780 gnomAD whole genome analysis cohort, p  = 0.0006) and pediatric B-ALL development. TCF3 variants are known to influence B cell maturation and may increase the risk of preleukemic clone emergence.

Purpose: Recently, direct communication with children about cancer seems to have shifted, but little is known about communication regarding discussions of future infertility risk due to cancer therapy. This study conducted cross-cultural comparisons between Japan and the United States to clarify communication patterns about cancer notification and develop appropriate information about fertility issues. Methods: An online survey was distributed to members of the Japanese Society of Pediatric Hematology/Oncology in July 2019 and the American Society of Pediatric Hematology/Oncology in July 2020. Based on the results from the survey, we developed three types of educational videos: a prepubertal version A, B, and a pubertal version. Next, we conducted a survey to assess whether these were appropriate for clinical practice. Results: We analyzed 325 physicians in Japan and 46 in the United States. In Japan, 80.5%, 91.7%, and 92.1% of the physicians notified patients aged 7-9, 10-14, and 15-17 years of their cancer diagnosis directly, respectively, compared within the United States, where the rate was 100%, regardless of age. Further, 9% and 45% of physicians in Japan and the United States, respectively, discuss fertility issues directly with patients aged 7-9 years. In the survey to assess the educational videos, 85% of the physicians preferred to use the educational videos in clinical practice. Conclusion: This is the first step in bringing concordance to communication patters for emerging cancer care around the globe and that this study and its intervention arm provide guidance in ways that ensure global equity in care.

Background: One of the most significant challenges in patients with medulloblastoma is reducing the dose of craniospinal irradiation (CSI) to minimize neurological sequelae in survivors. Molecular characterization of patients receiving lower than standard dose of CSI therapy is important to facilitate further reduction of treatment burden., Methods: We conducted DNA methylation analysis using an Illumina Methylation EPIC array to investigate molecular prognostic markers in 38 patients with medulloblastoma who were registered in the Japan Pediatric Molecular Neuro-Oncology Group and treated with reduced-dose CSI., Results: Among the patients, 23 were classified as having a standard-risk and 15 as high-risk according to the classic classification based on tumor resection rate and presence of metastasis, respectively. The median follow-up period was 71.5 months (12.0-231.0). The median CSI dose was 18 Gy (15.0-24.0) in both groups, and 5 patients in the high-risk group received a CSI dose of 18.0 Gy. Molecular subgrouping revealed that the standard-risk cohort included 5 WNT, 2 SHH, and 16 Group 3/4 cases; all 15 patients in the high-risk cohort had Group 3/4 medulloblastoma. Among the patients with Group 3/4 medulloblastoma, 9 of the 31 Group 3/4 cases were subclassified as subclass II, III, and V, which were known to an association with poor prognosis according to the novel subtyping among the subgroups. Patients with poor prognostic subtype showed worse prognosis than that of others (5-year progression survival rate 90.4% vs. 22.2%; p < 0.0001). The result was replicated in the multivariate analysis (hazard ratio12.77, 95% confidence interval for hazard ratio 2.38-99.21, p value 0.0026 for progression-free survival, hazard ratio 5.02, 95% confidence interval for hazard ratio 1.03-29.11, p value 0.044 for overall survival)., Conclusion: Although these findings require validation in a larger cohort, the present findings suggest that novel subtyping of Group 3/4 medulloblastoma may be a promising prognostic biomarker even among patients treated with lower-dose CSI than standard treatment., (© 2023. BioMed Central Ltd., part of Springer Nature.)

We herein report a case of hepatitis-associated aplastic anemia (HAAA) that occurred after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. In this patient, progressive pancytopenia observed two months after acute hepatitis following the second dose of the SARS-CoV-2 vaccine indicated the development of HAAA. Although some reports have suggested that SARS-CoV-2 vaccination may be involved in the development of autoimmune diseases, no cases of HAAA developing after SARS-CoV-2 vaccination have been reported. SARS-CoV-2 vaccination in children has only started relatively recently, so the range of side effects in children has not yet been thoroughly described. Therefore, we need to strengthen surveillance for symptoms of children who are vaccinated.

Minimal residual disease (MRD) is usually defined as the small number of cancer cells that remain in the body after treatment. The clinical significance of MRD kinetics is well recognized in treatment of hematologic malignancies, particularly acute lymphoblastic leukemia (ALL). Real time quantitative PCR targeting immunoglobulin (Ig) or T-cell receptor (TCR) rearrangement (PCR-MRD), as well as multiparametric flow cytometric analysis targeting antigen expression, are widely used in MRD detection. In this study, we devised an alternative method to detect MRD using droplet digital PCR (ddPCR), targeting somatic single nucleotide variants (SNVs). This ddPCR-based method (ddPCR-MRD) had sensitivity up to 1E-4. We assessed ddPCR-MRD at 26 time points from eight T-ALL patients, and compared it to the results of PCR-MRD. Almost all results were concordant between the two methods, but ddPCR-MRD detected micro-residual disease that was missed by PCR-MRD in one patient. We also measured MRD in stored ovarian tissue of four pediatric cancer patients, and detected 1E-2 of submicroscopic infiltration. Considering the universality of ddPCR-MRD, the methods can be used as a complement for not only ALL, but also other malignant diseases regardless of tumor-specific Ig/TCR or surface antigen patterns., (© 2023. The Author(s).)

Objective: To verify understanding and awareness of fertility preservation (FP) in pediatric patients undergoing FP treatments., Methods: A questionnaire survey was conducted before and after explanation of fertility issues and FP treatments for patients 6-17 years old who visited or were hospitalized for the purpose of ovarian tissue cryopreservation (OTC) or oocyte cryopreservation (OC), or sperm cryopreservation between October 2018 and April 2022. This study was approved by the institutional review board at St. Marianna University School of Medicine (No. 4123, UMIN000046125)., Result: Participants in the study comprised 36 children (34 girls, 2 boys). Overall mean age was 13.3 ± 3.0 years. The underlying diseases were diverse, with leukemia in 14 patients (38.9%), brain tumor in 4 patients (11.1%). The questionnaire survey before the explanation showed that 19 patients (52.8%) wanted to have children in the future, but 15 (41.7%) were unsure of future wishes to raise children. And most children expressed some degree of understanding of the treatment being planned for the underlying disease (34, 94.4%). Similarly, most children understood that the treatment would affect their fertility (33, 91.7%). When asked if they would like to hear a story about how to become a mother or father after FP which including information of FP, half answered "Don't mind" (18, 50.0%). After being provided with information about FP treatment, all participants answered that they understood the adverse effects on fertility of treatments for the underlying disease. Regarding FP treatment, 32 children (88.9%) expressed understanding for FP and 26 (72.2%) wished to receive FP. "Fear" and "Pain" and "Costs" were frequently cited as concerns about FP. Following explanations, 33 children (91.7%) answered "Happy I heard the story" and no children answered, "Wish I hadn't heard the story". Finally, 28 of the 34 girls (82.4%) underwent OTC and one girl underwent OC., Discussion: The fact that all patients responded positively to the explanations of FP treatment is very informative. This is considered largely attributable to the patients themselves being involved in the decision-making process for FP., Conclusions: Explanations of FP for children appear valid if age-appropriate explanations are provided., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Takae, Iwahata, Sugishita, Iwahata, Kanamori, Shiraishi, Ito, Suzuki, Yamaya, Tanaka, Oyama, Keino, Nakamura, Odawara, Horage, Meng, Igualada, Faizal, Aworet, Furuta, Sakamoto, Mori, Kitagawa and Suzuki.)

Inherited genetic variation is associated with 6-mercaptopurine (6-MP) dose reduction and frequent toxicities induced by 6-MP. However, the tolerable dose for 6-MP is not fully predicted by the known variation in NUDT15 and TPMT among Asian children with acute lymphoblastic leukaemia (ALL). We performed a genome-wide association study (GWAS) related to 6-MP dose among Japanese children with ALL. This GWAS comprised 224 patients previously enrolled in Tokyo Children's Cancer Study Group clinical studies with replication attempted in 55 patients. Genome-wide single nucleotide polymorphism (SNP) genotypes were evaluated for association with average 6-MP dose during the initial 168 days of maintenance therapy. Possible associations were observed across five gene-coding regions, among which only variants at 13q14.2 were significant and replicated genome-wide (rs116855232, NUDT15, β = -10.99, p = 3.7 × 10 -13 ). Notable findings were observed for variants in AFF3 (rs75364948, p = 2.05 × 10 -6 ) and CHST11 (rs1148407, p = 2.09 × 10 -6 ), but were not replicated possibly due to small numbers. A previously reported candidate SNP in MTHFR was associated with higher average 6-MP dose (rs1801133, p = 0.045), and FOLH1 (rs12574928) was associated in an evaluation of candidate regions (p adjust  = 0.013). This study provides strong evidence that rs116855232 in NUDT15 is the genetic factor predominantly associated with 6-MP tolerable dose in children in Japan., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Research Question: Are the revised patient selection criteria for fertility preservation of children and adolescents appropriate?, Design: A retrospective and prospective observational cohort study implemented at a university hospital approved for fertility preservation by an academic society. The characteristics of children and the process of fertility preservation consultation were investigated. Mortality, the longitudinal course of the endocrine profile and the menstrual cycle were confirmed in patients who underwent ovarian tissue cryopreservation (OTC) before the age of 18 years., Results: Of the 74 children and adolescents referred for a fertility preservation consultation, 40 (54.1%) had haematological disease, which included patients with rare diseases. The mean age of patients was 11.1 ± 4.3 years (median 12 years, range 1-17 years). In accordance with the revised criteria, 31 (41.9%) patients had their ovarian tissue cryopreserved. Two out of 31 had complications after surgery (infection and drug allergy) and one patient with leukaemia (3.2%) had minimum residual disease on the extracted ovarian tissue. Of the 14 patients (>12 years) who completed treatment, 12 (85.7%) had primary ovarian insufficiency (POI) more than a year after treatment. Two out of 31 (6.5%) died because of recurrence of their underlying disease (median 28 months, range 0-60 months). Oocyte cryopreservation, as an additional and salvage fertility preservation treatment, was suggested to five patients with biochemical status POI (procedures pending)., Conclusion: The primary disease and patients' ages varied in fertility preservation for children and adolescents. Our patient selection criteria might be appropriate over a short follow-up period., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: We conducted a questionnaire survey in 15 pediatric oncology hospitals in Japan to better understand the current status of fertility preservation in childhood and adolescents. Methods: The survey period was from September 2020 to December 2020. We mailed questionnaires to 64 departments involved in pediatric cancer treatments at the 15 hospitals. The primary outcomes were the timing of providing explanations on fertility preservation, presence of health care provider while providing explanations, cooperation between medical staff, and cooperation between hospitals. Results: The response rate was 100% (64/64). Regarding the time at which this information was provided, 79.6% of patients (43/54) received it before cancer treatment; 5.6% (3/54), after remission; and 14.8% (8/54), both time points. Nurses were mostly in attendance (70%) when oncologists provided information to patients. Nine (60%) hospitals did not have a reproductive department. Among these, 28.6% of the respondents referred patients to a reproductive facility that performed fertility preservation. Providing information about fertility preservation was challenging owing to the shortage of specific explanatory materials (35.1%) and the lack of cooperation between pediatric oncologists and reproductive endocrinologists (24.6%). Conclusion: Based on this survey, educational activities regarding fertility preservation centered on pediatric oncologists and nurses are needed. Furthermore, a system for providing explanatory materials for fertility preservation and encouraging cooperation at the physician and hospital levels is also needed (IRB No. H2020-111).

Approximately 20% of patients with transient abnormal myelopoiesis (TAM) die due to hepatic or multiorgan failure. To identify potential new treatments for TAM, we performed in vitro drug sensitivity testing (DST) using the peripheral blood samples of eight patients with TAM. DST screened 41 agents for cytotoxic properties against TAM blasts. Compared with the reference samples of healthy subjects, TAM blasts were more sensitive to glucocorticoids, the mitogen-activated protein kinase kinase (MAP2K) inhibitor trametinib, and cytarabine. Our present results support the therapeutic potential of glucocorticoids and the role of the RAS/MAP2K signalling pathway in TAM pathogenesis., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

IKAROS and CTLA4 deficiencies are inborn errors of immunity and show similar clinical phenotypes, including hypogammaglobulinemia and autoimmune diseases (ADs). However, the differences in clinical features and pathogenesis of these are not fully understood. Therefore, we performed systematic literature reviews for IKAROS and CTLA4 deficiencies. The reviews suggested that patients with IKAROS deficiency develop AD earlier than hypogammaglobulinemia. However, no study assessed the detailed changes in clinical manifestations over time; this was likely due to the cross-sectional nature of the studies. Therefore, we conducted a retrospective longitudinal study on IKAROS and CTLA4 deficiencies in our cohort to evaluate the clinical course over time. In patients with IKAROS deficiency, AD and hypogammaglobulinemia often develop in that order, and AD often resolves before the onset of hypogammaglobulinemia; these observations were not found in patients with CTLA4 deficiency. Understanding this difference in the clinical course helps in the clinical management of both. Furthermore, our results suggest B- and T-cell-mediated ADs in patients with IKAROS and CTLA4 deficiencies, respectively., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hoshino, Toyofuku, Mitsuiki, Yamashita, Okamoto, Yamamoto, Kanda, Yamato, Keino, Yoshimoto-Suzuki, Kamizono, Onoe, Ichimura, Nagao, Yoshimura, Tsugawa, Igarashi, Mitsui-Sekinaka, Sekinaka, Doi, Yasumi, Nakazawa, Takagi, Imai, Nonoyama, Morio, Latour and Kanegane.)

Central nervous system (CNS) involvement in anaplastic large cell lymphoma (ALCL) is uncommon. CNS prophylaxis is not regularly included in second-line treatments for patients who develop CNS-negative relapses. We report a pediatric case of recurrent ALK-negative ALCL who developed isolated CNS progression during the treatment with brentuximab vedotin monotherapy. The patient achieved CNS remission after receiving the CNS-directed treatments including craniospinal irradiation. There is no evidence regarding whether brentuximab vedotin can cross the blood-brain barrier. CNS prophylaxis should be considered in high-risk patients with relapsed ALCL who receive second-line treatments containing agents with limited CNS penetration., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Fertility preservation (FP) for children is still challenging due to an information gap. In particular, there is little information about the surgical aspects of ovarian tissue cryopreservation (OTC) for children. In the present study, the appropriateness of preoperative management and the criteria of our cases were investigated with the aim of establishing a safe OTC procedure., Methods: A total of 25 girls who underwent OTC from November 2015 through May 2020 were retrospectively analyzed with IRB approval., Results: The median age of the patients was 13 (1-17) years. The medical indications were varied (e.g., leukemia, lymphoma, brain tumor), and included rare diseases. Seventeen cases (68%) underwent OTC during chemotherapy or radiotherapy, and 21 (84%) had comorbidities. All cases underwent ovarian tissue retrieval (OTR) with laparoscopy, and the median operating time was 64 (36-97) min, with little bleeding. Although two had complications, all patients started treatment on schedule. The median WBC and CRP increases a day after OTR were 0 (- 4400 to + 5200)/µl and 0.21 (- 0.2 to 0.87) mg/dl, respectively, with no complications., Conclusion: As long as the preoperative criteria are met, OTC could be possible even for children with a severe blood condition. In such cases, the degrees of the WBC and CRP elevations are useful to assess surgical infection.

Background: Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive inflammatory disease caused by loss-of-function mutations in both alleles of the ADA2 gene. Most patients with DADA2 exhibit systemic vasculopathy consistent with polyarteritis nodosa, but large phenotypic variability has been reported, and the pathogenesis of DADA2 remains unclear., Objectives: This study sought to assess the clinical and genetic characteristics of Japanese patients with DADA2 and to gain insight into the pathogenesis of DADA2 by multi-omics analysis., Methods: Clinical and genetic data were collected from 8 Japanese patients with DADA2 diagnosed between 2016 and 2019. ADA2 variants in this cohort were functionally analyzed by in vitro overexpression analysis. PBMCs from 4 patients with DADA2 were subjected to transcriptome and proteome analyses. Patient samples were collected before and after introduction of anti- TNF-α therapies. Transcriptome data were compared with those of normal controls and patients with other autoinflammatory diseases., Results: Five novel ADA2 variants were identified in these 8 patients and were confirmed pathogenic by in vitro analysis. Anti-TNF-α therapy controlled inflammation in all 8 patients. Transcriptome and proteome analyses showed that upregulation of type II interferon signaling was characteristic of DADA2. Network analysis identified STAT1 as a key regulator and a hub molecule in DADA2 pathogenesis, a finding supported by the hyperactivation of STAT1 in patients' monocytes and B cells after IFN-γ stimulation., Conclusions: Type II interferon signaling and STAT1 are associated with the pathogenesis of DADA2., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Cerebrospinal fluid (CSF) cytology and spinal MR imaging are routinely performed for staging before treatment of intracranial germinoma. However, the interpretation of the results of CSF cytology poses 2 unresolved clinical questions: (1) Does positive CSF cytology correlate with the presence of spinal lesion before treatment? and (2) Is craniospinal irradiation (CSI) necessary for patients with positive CSF cytology in the absence of spinal lesion?, Methods: Multicenter retrospective analyses were performed based on a questionnaire on clinical features, spinal MR imaging finding, results of CSF cytology, treatments, and outcomes which was sent to 86 neurosurgical and 35 pediatrics departments in Japan. Pretreatment frequencies of spinal lesion on MR imaging were compared between the patients with positive and negative cytology. Progression-free survival (PFS) rates were compared between patients with positive CSF cytology without spinal lesion on MR imaging treated with CSI and with whole brain or whole ventricular irradiation (non-CSI)., Results: A total of 92 germinoma patients from 45 institutes were evaluated by both CSF cytology and spinal MR images, but 26 patients were excluded because of tumor markers, the timing of CSF sampling or incomplete estimation of spinal lesion. Of the remaining 66 germinoma patients, spinal lesions were equally identified in patients with negative CSF cytology and positive cytology (4.9% and 8.0%, respectively). Eleven patients treated with non-CSI had excellent PFS comparable to 11 patients treated with CSI., Conclusion: CSI is unnecessary for germinoma patients with positive CSF cytology without spinal lesions on MR imaging., (© The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Tracheal tumors are rare in children and manifest symptoms of airway obstruction. A 14-year-old boy with a 5-month history of dyspnea and wheezing was referred to our hospital. Although he had been initially diagnosed with bronchial asthma, computed tomography revealed tracheal tumors. Histologic examination showed only necrotic tissue. Thereafter, the systemic steroid treatment for bronchial asthma was tapered off. A second computed tomography scan revealed new lesions in the pancreas and lung. Biopsy of the pancreatic lesion revealed a diffuse large B-cell lymphoma. The patient was administered standard chemotherapy, following which he went into complete remission., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The Delphi consensus statements on the management of germ cell tumors (GCTs) failed to reach agreements on the statement that the cases with (i) pineal and neurohypophyseal bifocal lesion, (ii) with diabetes insipidus, and (iii) with negative tumor markers can be diagnosed as germinoma without histological verification. To answer this, multicenter retrospective analysis was performed., Methods: A questionnaire on clinical findings, histological diagnosis, and details of surgical procedures was sent to 86 neurosurgical and 35 pediatrics departments in Japan., Results: Fifty-one institutes reported 132 cases that fulfilled the 3 criteria. Tissue sampling was performed in 91 cases from pineal (n = 44), neurohypophyseal (n = 32), both (n = 6), and distant (n = 9) lesions. Histological diagnosis was established in 89 cases: pure germinoma or germinoma with syncytiotrophoblastic giant cells in 82 (92.1%) cases, germinoma and mature teratoma in 2 cases, and granulomatous inflammation in 2 cases. Histological diagnosis was not established in 2 cases. Although no tumors other than GCTs were identified, 3 (3.4%) patients had non-germinomatous GCTs (NGGCTs). None of the patients developed permanent complications after endoscopic or stereotactic biopsy. Thirty-nine patients underwent simultaneous procedure for acute hydrocephalus without permanent complications, and hydrocephalus was controlled in 94.9% of them., Conclusion: All patients who fulfilled the 3 criteria had GCTs or granulomatous inflammation, but not other types of tumors. However, no fewer than 3.4% of the patients had NGGCTs. Considering the safety and the effects of simultaneous procedures for acute hydrocephalus, biopsy was recommended in such patients., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Preclinical observations suggested a synergistic effect of sorafenib (SFN) and irinotecan (CPT-11) in hepatoblastoma (HB). Thus, we conducted a feasibility study of fractionated CPT-11 combined with SFN to develop a new therapy against relapsed/refractory pediatric hepatic cancer (HC)., Procedure: The study was originally designed as a phase I, standard 3+3 dose-finding study to evaluate dose-limiting toxicities (DLTs) for the regimen and the optimal CPT-11 dose in combination with SFN against relapsed/refractory pediatric HC, including HB and hepatocellular carcinoma (HCC). The enrolled patients received SFN at 200 mg/m 2 every 12 hours or 400 mg/m 2 every 24 hours daily combined with CPT-11 at 20 mg/m 2 /day on days 1 to 5 as an initial level 1 dose., Results: Six patients with HB (n = 4) or HCC (n = 2) were enrolled and treated with CPT-11 dose level 1. The median age at enrollment was 8.7 (6.2-16.3) years. All patients received platinum-containing chemotherapy, and five or two patients received CPT-11 or SFN before enrollment, respectively. Regimen toxicities were evaluable in all patients. One of six patients experienced a grade 4 transaminase levels increase, which was defined as a DLT per protocol. Grade 3/4 neutropenia and a grade 3 transaminase level increase occurred in three patients and one patient, respectively. All patients reported grade 1/2 toxicities such as anemia, skin toxicity, gastrointestinal symptoms, and hypoalbuminemia., Conclusions: Although the study was terminated before determining the maximum-tolerated CPT-11 dose, SFN and CPT-11 at the level 1 dose were concluded to be tolerable in pediatric patients with HC., (© 2020 Wiley Periodicals LLC.)

Acute myeloid leukemia (AML) accounts for ~20% of pediatric leukemia cases. The prognosis of pediatric AML has been improved in recent decades, but it trails that of most other types of pediatric cancer, with mortality rates of 30-40%. Consequently, newer more targeted drugs are required for incorporation into treatment plans. These newer drugs selectively target AML cells with specific gene alterations. However, there are significant differences in genetic alterations between adult and pediatric patients with AML. In the present study, inexpensive and rapid next-generation sequencing (NGS) of >150 cancer-related genes was performed for matched diagnostic, remission and relapse (if any) samples from 27 pediatric patients with AML. In this analysis, seven genes were recurrently mutated. KRAS was mutated in seven patients, NRAS was mutated in three patients, and KIT , GATA1 , WT1 , PTPN11 , JAK3 and FLT3 were each mutated in two patients. Among patients with relapsed AML, six harbored KRAS mutations at diagnosis; however, four of these patients lost these mutations at relapse. Additionally, two genetic alterations ( FLT3 -ITD and TP53 alterations) were detected among patients who eventually relapsed, and these mutations are reported to be adverse prognostic factors for adult patients with AML. This panel-based, targeted sequencing approach may be useful in determining the genetic background of pediatric AML and improving the prediction of treatment response and detection of potentially targetable gene alterations. RAS pathway mutations were highly unstable at relapse; therefore, these mutations should be chosen as a target with caution. Incorporating this panel-based NGS approach into the clinical setting may allow for a patient-oriented strategy of precision treatment for childhood AML., (Copyright: © Ishida et al.)

Background: Abnormal blood cell counts are characteristic of patients with Down syndrome and transient abnormal myelopoiesis (TAM). Although some patients with TAM experience prolonged anemia or thrombocytopenia, hematological factors predicting blood cell count recovery have not been reported yet. The aim of this study was to investigate the factors influencing platelet normalization in TAM., Methods: A retrospective review of the medical records of 21 patients with TAM admitted to the neonatal intensive care unit at Kanagawa Children's Medical Center between January 2007 and October 2014 was undertaken., Results: In the 16 of 21 patients (76%) experiencing transient thrombocytopenia, a large number of blasts at diagnosis was found to be significantly associated with late platelet recovery (R = 0.669, P < 0.05), and higher platelet counts at diagnosis were significantly associated with later recovery (R = 0.719, P < 0.01). Indeed, a strong positive correlation between blast and platelet counts at diagnosis was found (R = 0.730, P < 0.01)., Conclusions: Our data suggest that high platelet counts at TAM diagnosis might reflect abnormal thrombocyte production from blasts. Thus, physicians should be aware of the possibility of prolonged thrombocytopenia in patients with TAM who exhibit a high platelet and/or blast count at diagnosis., (© 2020 Japan Pediatric Society.)

Purpose: Acute lymphoblastic leukemia (ALL) is curable with standardized chemotherapy. However, the development of novel therapies is still required, especially for patients with relapsed or refractory disease. By utilizing an in vitro drug screening system, active molecular targeting agents against ALL were explored in this study., Methods: By the in vitro drug sensitivity test, 81 agents with various actions were screened for their cytotoxicity in a panel of 22 ALL cell lines and ALL clinical samples. The drug effect score (DES) was calculated from the dose-response of each drug for comparison among drugs or samples. Normal peripheral blood mononuclear cells were also applied onto the drug screening to provide the reference control values. The drug combination effect was screened based on the Bliss independent model, and validated by the improved isobologram method., Results: On sensitivity screening in a cell line panel, barasertib-HQPA which is an active metabolite of barasertib, an aurora B kinase inhibitor, alisertib, an aurora A kinase inhibitor, and YM155, a survivin inhibitor, were effective against the broadest range of ALL cells. The DES of barasertib-HQPA was significantly higher in ALL clinical samples compared to the reference value. There were significant correlations in DES between barasertib-HQPA and vincristine or docetaxel. In the drug combination assay, barasertib-HQPA and eribulin showed additive to synergistic effects., Conclusion: Aurora B kinase was identified to be an active therapeutic target in a broad range of ALL cells. Combination therapy of barasertib and a microtubule-targeting drug is of clinical interest.

Background: Liposomal amphotericin (L-AMB) is a widely used broad-spectrum antifungal drug. Although L-AMB demonstrates better safety compared with amphotericin, renal dysfunction and hypokalemia are well-known adverse effects of L-AMB., Method: We analyzed 56 episodes in 40 children and adolescents who received L-AMB therapy to determine risk factors of hypokalemia., Results: Hypokalemia (<3.0 mEq/L continuously for more than 2 episodes) was observed in 31 of 56 episodes (55.4%). The median onset of hypokalemia was at 10 days on L-AMB (range, 3-54 days), and the median cumulative dose of L-AMB at occurrence of hypokalemia was 25 mg/kg (range, 10-167.5 mg/kg). None of the patients with hypokalemia had solid tumors, and they had significantly higher estimated glomerular filtration rates than those with normokalemia (P = 0.013). Seven of 25 (28.0%) patients in the normokalemia group and 1 of 31 (3.2%) patients in the hypokalemia group had eGFRs of <90 mL/min/1.73 m(2) (P = 0.017)., Conclusion: Although the reason for the association between estimated glomerular filtration rates and hypokalemia is unclear, assessing the estimated glomerular filtration rates before L-AMB administration may predict the development of hypokalemia.

Genome-wide association studies (GWAS) performed mostly in populations of European and Hispanic ancestry have confirmed an inherited genetic basis for childhood acute lymphoblastic leukemia (ALL), but these associations are less clear in other races/ethnicities. DNA samples from ALL patients (aged 0-19 years) previously enrolled onto a Tokyo Children's Cancer Study Group trial were collected during 2013-2015, and underwent single nucleotide polymorphism (SNP) microarray genotyping resulting in 527 B-cell ALL for analysis. Cases and control data for 3,882 samples from the Nagahama Study Group and Aichi Cancer Center Study were combined, and association analyses across 10 previous GWAS-identified regions were performed after targeted SNP imputation. Linkage disequilibrium (LD) patterns in Japanese and other populations were evaluated using the varLD score based on 1000 Genomes data. Risk associations for ARID5B (rs10821936, OR = 1.84, P = 6 × 10 -17 ) and PIP4K2A (rs7088318, OR = 0.76, P = 2 × 10 -4 ) directly transferred to Japanese, and the IKZF1 association was detected by an alternate SNP (rs1451367, OR = 1.52, P = 2 × 10 -6 ). Marked regional LD differences between Japanese and Europeans was observed for most of the remaining loci for which associations did not transfer, including CEBPE, CDKN2A, CDKN2B, and ELK3. This study represents a first step towards characterizing the role of genetic susceptibility in childhood ALL risk in Japanese.

There are few treatment options for patients with unresectable or refractory hepatoblastoma which has failed to respond to the standard treatment. The rarity of the disease and lack of experimental materials have hampered the development of new treatments. In this study, the collagen gel droplet-embedded culture drug sensitivity test was used to evaluate the effectiveness of the multikinase inhibitors sorafenib and sunitinib, and other drugs, in relapsed hepatoblastoma tumor tissues. Tumor samples from 6 patients with relapsed hepatoblastoma were tested for drug sensitivity by the collagen gel droplet-embedded culture drug sensitivity test; evaluable results were obtained from 5 of them. All samples were judged to be sensitive to sorafenib with a 50% growth inhibitory concentration (IC50) of 0.5 to 3.1 μg/mL. Sunitinib did not achieve IC50 in 2 of 3 samples within the tested concentration range based on clinically observed serum concentrations. In the drug combination assay using a hepatoblastoma cell line, sorafenib showed synergistic effects with SN-38, an active metabolite of irinotecan. Our results provide the basic science background warranting future clinical trials of a combination of sorafenib and irinotecan for relapsed or refractory hepatoblastoma.

Residual disease (RD) after induction chemotherapy may predict clinical outcome in acute myeloid leukemia (AML). In the present study, we investigated the prognostic significance of RD detected by multidimensional flow cytometry (MDF) among 34 children treated for AML in a clinical trial (JPLSG AML-05) in Japan. Bone marrow samples were analyzed at the points of the end of the first induction course (BMA-1) and second induction course (BMA-2) by MDF. RD was evaluated by detecting the immature cells showing abnormal antigen expression pattern; CD34(+), CD15(+), CD7(+). Thirteen (39.4 %) of 34 patients at BMA-1 and 8 (27.6 %) of 34 at BMA-2 had RD levels ≥0.1 %. There was no significant difference in 3y-EFS and 3y-OS between patients with RD levels ≥0.1 % and those with RD levels <0.1 % (53.8 versus 70.0 %, P = 0.30 and 50.0 versus 66.7 %, P = 0.27, respectively). However, IR cytogenetics and negative FLT3-ITD patients with RD levels ≥0.1 % exhibited significantly lower 3y-EFS and 3y-OS than those with RD levels <0.1 % (33.3 versus 83.3 %, P = 0.02 and 20.0 versus 76.9 %, P = 0.005, respectively). Our study suggests that RD shows prognostic relevance in pediatric patients with IR cytogenetics and negative FLT3-ITD AML.

There have been few reports regarding infective endocarditis (IE) in patients with leukemia. In the first case, a 15-year-old girl with Down syndrome was diagnosed with acute lymphoblastic leukemia. On admission, methicillin-sensitive Staphylococcus aureus (MSSA) was detected on blood culture. Echocardiography was performed because MSSA was detected repeatedly even after treatment. Vegetation in all of the atria and ventricles met the Duke criteria defining IE. She died of multiple organ failure 21 days after diagnosis. In the second case, an 11-year-old boy with acute myeloid leukemia underwent peripheral blood stem cell transplantation (PBSCT). He had fever 68 days after PBSCT, and methicillin-resistant S. aureus (MRSA) was detected on blood culture. Echocardiography showed vegetation in the right atrium and ventricle. Daptomycin was administered for 7 weeks, and recurrence was not observed. IE should be considered when S. aureus bacteremia is documented even in patients with leukemia., (© 2015 Japan Pediatric Society.)

Acroscyphodysplasia (OMIM250215) is a distinctive form of metaphyseal dysplasia characterized by the distal femoral and proximal tibial epiphyses embedded in cup-shaped, large metaphyses known as metaphyseal scypho ("scypho" = cup) deformity. It is also associated with severe growth retardation and brachydactyly. The underlying molecular mechanism of acroscyphodysplasia has not yet been elucidated, although scypho-deformity of the knee has been reported in three patients with acrodysostosis due to a mutation in the PDE4D gene. We report on the clinical, radiological, and molecular findings of five female patients with acroscyphodysplasia; two were diagnosed as pseudohypoparathyroidism (PHP) or Albright hereditary osteodystropy, and the other three as acrodysostosis. They all had radiological findings consistent with severe metaphyseal scypho-deformity and brachydactyly. Heterozygous mutations were identified in the PHP patients consisting of one novel (p.Q19X) and one recurrent (p.R231C) mutation of the GNAS gene, as well as, in the acrodysostosis patients consisting of two novel mutations (p.T224I and p.I333T) of the PDE4D gene. We conclude that metaphyseal acroscyphodysplasia is a phenotypic variation of PHP or acrodysostosis caused by either a GNAS or PDE4D mutation, respectively., (© 2014 Wiley Periodicals, Inc.)

Bortezomib (BZM), a proteasome inhibitor, was recently reported to be effective against acute lymphoblastic leukemia (ALL). We report two cases of relapsed/refractory ALL, who were treated with BZM (1.3 mg/m2/dose, 2 doses/week for 2 weeks) in combination with vincristine, doxorubicin, dexamethasone, and L-asparaginase (L-ASP). The first patient was a 16-year-old girl who developed a bone marrow relapse 8 months after the initial diagnosis during consolidation chemotherapy. She received BZM-combined chemotherapy without L-ASP considering her previous history of an allergic reaction to L-ASP. The BZM-combined regimen was discontinued due to interstitial pneumonia development on day 13, and the interstitial pneumonia was successfully treated with steroid pulse therapy. Although her elevated serum LDH transiently normalized on day 16, blasts in peripheral blood did not disappear, and she died of leukemia without achieving remission. The second patient was a 17-year-old girl who developed a third bone marrow relapse after cord blood transplantation. She was given the same BZM combined regimen. Although the BZM-combined regimen was discontinued due to acute pancreatitis development on day 12, complete remission without platelet recovery was confirmed on day 62. Our experience suggests not only the effectiveness of BZM-combined chemotherapy but also the importance of controlling its toxicities when administered as a salvage therapy for advanced ALL patients.

A 15-yr-old boy presented with an anterior mediastinal mass, multiple lung metastases and obstruction of the left brachiocephalic vein, the superior vena cava and the subclavian vein. Tumor biopsy by CT guidance confirmed a diagnosis of GCT. Five courses of BEP therapy were performed, and CT of the chest revealed reduction in the anterior mediastinal mass and disappearance of the multiple lung metastases. We performed the anterior mediastinal mass extraction followed by adjuvant chemotherapy consisting of ICE and TIP. However, the AFP levels became elevated soon after. Abnormal accumulation was observed in the right upper lung by DW-MRI. After the operation, two courses of TI chemotherapy and two courses of HDCT followed by auto-PBSCT were performed. He was complicated with auditory disorder and renal dysfunction. Although HDCT followed by auto-PBSCT was effective for the relapsed primary mediastinal GCT, a treatment strategy avoiding late complications is warranted., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

T-LGL leukemia has been rarely reported in children. We report a child with T-LGL leukemia who presented with anemia and went on to develop Crohn's disease. Although prednisolone treatment proved effective in the treatment of anemia, large granular lymphocyte counts increased as the doses were tapered. T-cell rearrangement studies revealed a clonal rearrangement of the TCR Vβ/jβ2 gene. Concurrently, the patient developed severe diarrhea. Inflammatory changes across the upper and lower intestines led to the diagnosis of Crohn's disease. This case highlights that T-LGL leukemia could be occurred in children. Flow cytometry and/or T-cell gene rearrangement studies are recommend in patients of anemia and various kind of autoimmune diseases including Crohn's disease, even in children., (© 2013 The Authors. Pediatrics International © 2013 Japan Pediatric Society.)