Publications by authors named "Junko Takita"

159 Publications

Isolated sixth nerve palsy as an initial presentation of primary angiitis of the central nervous system.

Brain Dev 2021 May 27. Epub 2021 May 27.

Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background: Primary angiitis of the central nervous system (PACNS) is a newly-emerging disease, and it is known that early diagnosis with treatment is important for the improvement of prognosis.

Case Description: Here, we report the case of a previously healthy 13-year-old girl who presented with right eye abduction failure, attributed to isolated right sixth nerve palsy, as the initial symptom of PACNS. Magnetic resonance angiography (MRA) showed stenosis in the distal portion of the right internal carotid artery, and delay alternating with nutation for tailored excitation (DANTE)-prepared contrast-enhanced magnetic resonance imaging confirmed vasculitis at the same site. The patient was subsequently treated with three courses of pulse corticosteroid therapy (methylprednisolone intravenously 30 mg/kg/day for three consecutive days). Diplopia completely resolved within 3 months after three course of steroid pulse therapy, and when taking 10 mg PSL daily. Follow-up MRA confirmed complete resolution of the arterial narrowing, and no relapse was observed after 2 months of steroid cessation.

Discussion: This case report illustrates an unusual presentation of PACNS with isolated sixth nerve palsy. PACNS was thought to cause insults on a single cranial nerve either through local spread of inflammation or hypoxic-ischemic insults on the nerve root due to involvement of feeding microvessels. The decision to perform imaging studies in cases of isolated sixth nerve palsy remains controversial because of the possibility of spontaneous recovery. Our case supports the existing literature that recommends that even an isolated symptom of unilateral abducens nerve palsy requires timely imaging studies.
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http://dx.doi.org/10.1016/j.braindev.2021.05.003DOI Listing
May 2021

Augmentation of STING-induced type I interferon production in COPA syndrome.

Arthritis Rheumatol 2021 May 13. Epub 2021 May 13.

Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan.

Objectives: COPA syndrome, also known as an autoinflammatory interstitial lung, joint, and kidney (AILJK) disease, is caused by heterozygous mutations in the coatomer subunit alpha (COPA) gene. We found a novel COPA variant in four patients in one family. We aimed to elucidate whether and how the variant causes manifestations of COPA syndrome by studying these four patients and in a gene-targeted mouse model.

Method: We performed whole exome sequencing in seven family members and measured type I interferon (IFN) signature of the peripheral blood cells. We analyzed the effects of COPA variants in in vitro experiments and Copa mutant mice we generated.

Results: We identified a heterozygous variant of COPA gene in the four affected members of the family (c.725T>G, p.Val242Gly). IFN score was high in the members carrying the variant. In vitro analysis revealed that COPA V242G as well as the previously reported disease-causing variants augmented the stimulator of interferon genes (STING)-induced type I IFN promoter activities. Copa mice manifested interstitial lung disease and STING-dependent elevation of IFN-stimulated genes (ISGs) expression. In Copa dendritic cells, the STING pathway was not constitutively activated, but hyperactivated upon stimulation and led to increased type I IFN production.

Conclusion: V242G, a novel COPA variant, was found in four patients from one family. The gene-targeted mice with V242G variant recapitulated the interstitial lung disease and showed augmented responses of the STING pathway leading to increase of type I IFN production.
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http://dx.doi.org/10.1002/art.41790DOI Listing
May 2021

Clonal evidence for the development of neuroblastoma with extensive copy-neutral loss of heterozygosity arising in a mature teratoma.

Cancer Sci 2021 May 2. Epub 2021 May 2.

Department of Pediatrics, St. Luke's International Hospital, Tokyo, Japan.

Mature teratomas are usually benign tumors that rarely undergo malignant transformation. We report an advanced neuroblastoma arising in a mature teratoma of the ovary. Whole-exome sequencing identified extensive copy-neutral loss of heterozygosity (LOH) in both neuroblastoma and teratoma elements, suggesting that the neuroblastoma evolved from the teratoma. In addition, several truncating germline heterozygous variants in tumor suppressor genes, including RBL2 and FBXW12, became homozygous as a result of LOH. Collectively, we speculate that extensive LOH in teratoma cells may force heterozygous germline variants to become homozygous, which, in turn, may contribute to the development of neuroblastoma with the acquisition of additional chromosomal changes.
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http://dx.doi.org/10.1111/cas.14931DOI Listing
May 2021

Improvement of Bone Marrow Necrosis by Tyrosine Kinase Inhibitor Substitution in a Pediatric Patient With Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia.

J Pediatr Hematol Oncol 2021 Apr 9. Epub 2021 Apr 9.

Departments of Pediatrics Orthopaedic Surgery Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Bone marrow necrosis (BMN) describes necrosis of the myeloid tissues without cortical bone involvement. Imatinib, a tyrosine kinase inhibitor, can trigger BMN during the treatment of malignant disease. In such cases, it is necessary to reduce imatinib dose or discontinue its administration, which could influence treatment outcomes. Here, we report a 6-year-old boy with Philadelphia chromosome-positive acute lymphoblastic leukemia, who developed BMN in response to imatinib. We replaced imatinib with dasatinib, and necrotic lesions gradually disappeared and were never exacerbated. In Philadelphia chromosome-positive acute lymphoblastic leukemia with BMN, tyrosine kinase inhibitor replacement may allow continued chemotherapy without intensity reduction.
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http://dx.doi.org/10.1097/MPH.0000000000002157DOI Listing
April 2021

Effect of electrical activity of the diaphragm waveform patterns on SpO for extremely preterm infants ventilated with neurally adjusted ventilatory assist.

Pediatr Pulmonol 2021 Apr 6. Epub 2021 Apr 6.

Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Objective: This study aimed to evaluate the association between electrical activity of the diaphragm (Edi) waveform patterns and peripheral oxygen saturation (SpO ) in extremely preterm infants who are ventilated with neurally adjusted ventilatory assist (NAVA).

Study Design: We conducted a retrospective cohort study at a level III neonatal intensive care unit. Extremely preterm infants born at our hospital between November 2019 and November 2020 and ventilated with NAVA were included. We collected Edi waveform data and classified them into four Edi waveform patterns, including the phasic pattern, central apnea pattern, irregular low-voltage pattern, and tonic burst pattern. We analyzed the Edi waveform pattern for the first 15 h of collectable data in each patient. To investigate the association between Edi waveform patterns and SpO , we analyzed the dataset every 5 min as one data unit. We compared the proportion of each waveform pattern between the desaturation (Desat [+]) and non-desaturation (Desat [-]) groups.

Results: We analyzed collected data for 105 h (1260 data units). The proportion of the phasic pattern in the Desat (+) group was significantly lower than that in the Desat (-) group (p < .001). However, the proportions of the central apnea, irregular low-voltage, and tonic burst patterns in the Desat (+) group were significantly higher than those in the Desat (-) group (all p < .05).

Conclusion: Our results indicate that proportions of Edi waveform patterns have an effect on desaturation of SpO in extremely preterm infants who are ventilated with NAVA.
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http://dx.doi.org/10.1002/ppul.25396DOI Listing
April 2021

Rapid Flow Cytometry-Based Assay for the Functional Classification of MEFV Variants.

J Clin Immunol 2021 Mar 17. Epub 2021 Mar 17.

Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan.

Purpose: Pathogenic MEFV variants cause pyrin-associated autoinflammatory diseases (PAADs), which include familial Mediterranean fever (FMF), FMF-like disease, and pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND). The diagnosis of PAADs is established by clinical phenotypic and genetic analyses. However, the pathogenicity of most MEFV variants remains controversial, as they have not been functionally evaluated. This study aimed to establish and validate a new functional assay to evaluate the pathogenicity of MEFV variants.

Methods: We transfected THP-1 monocytes with 32 MEFV variants and analyzed their effects on cell death with or without stimulation with Clostridium difficile toxin A (TcdA) or UCN-01. These variants were classified using hierarchical cluster analysis. Macrophages were obtained from three healthy controls and two patients with a novel homozygous MEFV variant, for comparison of IL-1β secretion using a cell-based assay and a novel THP-1-based assay.

Results: Disease-associated MEFV variants induced variable degrees of spontaneous or TcdA/UCN-01-induced cell death in THP-1. Cell death was caspase-1 dependent and was accompanied by ASC speck formation and IL-1β secretion, indicating that pathogenic MEFV variants induced abnormal pyrin inflammasome activation and subsequent pyroptotic cell deaths in this assay. The MEFV variants (n = 32) exhibiting distinct response signatures were classified into 6 clusters, which showed a good correlation with the clinical phenotypes. Regarding the pathogenicity of MEFV variants, the results were consistent between the cell-based assay and the THP-1-based assay.

Conclusion: Our assay facilitates a rapid and comprehensive assessment of the pathogenicity of MEFV variants and contributes to a refined definition of PAAD subtypes.
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http://dx.doi.org/10.1007/s10875-021-01021-7DOI Listing
March 2021

Post-transplant Lymphoproliferative Disorders After Liver Transplantation: A Retrospective Cohort Study Including 1,954 Transplants.

Liver Transpl 2021 Mar 2. Epub 2021 Mar 2.

Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery and Transplantation/Pediatric Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Post-transplant lymphoproliferative disorders (PTLDs) are life-threatening neoplasms after organ transplantation. Because of their rarity and multiple grades of malignancy, the incidence, outcomes, and clinicopathological features affecting patient survival after liver transplantation (LT) remain unclear. We reviewed 1,954 LTs in 1,849 recipients (1990-2020), including 886 pediatric (<18 years of age) and 963 adult recipients. The following clinicopathological factors were studied: age, sex, liver etiologies, malignancy grades, Epstein-Barr virus status, performance status (PS), Ann Arbor stage, international prognostic index, and histopathological diagnosis. Of 1,849 recipients, 79 PTLD lesions (4.3%) were identified in 70 patients (3.8%). After excluding 3 autopsy cases incidentally found, 67 (45 pediatric [5.1%] and 22 adult [2.3%]) patients were finally enrolled. Comorbid PTLDs significantly worsened recipient survival compared with non-complicated cases (P < 0.001). The 3-year, 5-year, and 10-year overall survival rates after PTLD diagnosis were 74%, 66%, and 58%, respectively. The incidence of PTLDs after LT (LT-PTLDs) was significantly higher (P < 0.001) with earlier onset (P = 0.002) in children, whereas patient survival was significantly worse in adults (P = 0.002). Univariate and multivariate analyses identified the following 3 prognostic factors: age at PTLD diagnosis ≥18 years (hazard ratio [HR], 11.2; 95% confidence interval [CI], 2.63-47.4; P = 0.001), PS ≥2 at diagnosis (HR, 6.77; 95% CI, 1.56-29.3; P = 0.01), and monomorphic type (HR, 6.78; 95% CI, 1.40-32.9; P = 0.02). A prognostic index, the "LT-PTLD score," that consists of these 3 factors effectively stratified patient survival and progression-free survival (P = 0.003 and <0.001, respectively). In conclusion, comorbid PTLDs significantly worsened patient survival after LT. Age ≥18 years and PS ≥2 at PTLD diagnosis, and monomorphic type are independent prognostic factors, and the LT-PTLD score that consists of these 3 factors may distinguish high-risk cases and guide adequate interventions.
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http://dx.doi.org/10.1002/lt.26034DOI Listing
March 2021

Detailed analysis of Japanese patients with adenosine deaminase 2 deficiency reveals characteristic elevation of type II interferon signature and STAT1 hyperactivation.

J Allergy Clin Immunol 2021 Jan 30. Epub 2021 Jan 30.

Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan.

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.
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http://dx.doi.org/10.1016/j.jaci.2021.01.018DOI Listing
January 2021

Association of high-risk neuroblastoma classification based on expression profiles with differentiation and metabolism.

PLoS One 2021 19;16(1):e0245526. Epub 2021 Jan 19.

Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Neuroblastoma, the most common extracranial solid malignancy among children, originates from undifferentiated neural crest cells (NCC). Despite recent intensified treatment, high-risk patients still have a high mortality rate. To explore a new therapeutic strategy, we performed an integrated genomic and transcriptomic analysis of 30 high-risk neuroblastoma cases. Based on the expression profiling of RNA sequencing, neuroblastoma was classified into Mesenchymal (MES; n = 5) and Noradrenergic (ADRN; n = 25) clusters, as previously reported in the super-enhancer landscape. The expression patterns in MES-cluster cases were similar to normal adrenal glands, with enrichment in secretion-related pathways, suggesting chromaffin cell-like features built from NCC-derived Schwann cell precursors (SCPs). In contrast, neuron-related pathways were enriched in the ADRN-cluster, indicating sympathoblast features reported to originate from NCC but not via SCPs. Thus, MES- and ADRN-clusters were assumed to be corresponding to differentiation pathways through SCP and sympathoblast, respectively. ADRN-cluster cases were further classified into MYCN- and ATRX-clusters, characterized by genetic alterations, MYCN amplifications and ATRX alterations, respectively. MYCN-cluster cases showed high expression of ALDH18A1, encoding P5CS related to proline production. As reported in other cancers, this might cause reprogramming of proline metabolism leading to tumor specific proline vulnerability candidate for a target therapy of metabolic pathway. In ATRX-cluster, SLC18A2 (VMAT2), an enzyme known to prevent cell toxicity due to the oxidation of dopamine, was highly expressed and VMAT2 inhibitor (GZ-793A) represented significant attenuation of cell growth in NB-69 cell line (high SLC18A2 expression, no MYCN amplification) but not in IMR-32 cell line (MYCN amplification). In addition, the correlation of VMAT2 expression with metaiodobenzylguanidine (MIBG) avidity suggested a combination of VMAT2 inhibitor and MIBG radiation for a novel potential therapeutic strategy in ATRX-cluster cases. Thus, targeting the characteristics of unique neuroblastomas may prospectively improve prognosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245526PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815088PMC
June 2021

Copy Number Alteration Analysis for Neuroblastoma using Droplet Digital PCR.

Pediatr Int 2021 Jan 19. Epub 2021 Jan 19.

Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Yushima 1-5-45, Bunkyo-Ku, Tokyo, 113-8519, Japan.

Background: Neuroblastoma (NB) is a malignant tumor derived from the neural crest. MYCN amplification is a well-known adverse molecular prognostic factor for NB. Genome copy number alterations (CNAs) such as chromosome (Chr) 11q deletion, 1p deletion, and 17q gain are associated with a poor prognosis. Fluorescence in situ hybridization (FISH) and Southern blotting analysis are frequently used to detect MYCN amplification. Although comparative genomic hybridization (CGH) and single-nucleotide polymorphism (SNP) chip arrays can easily detect CNAs, these methods are impractical for clinical use due to their cost and run time. Consequently, genome copy number analysis using digital droplet PCR (ddPCR) has become widely used to monitor CNAs.

Methods: In this study, we used ddPCR to detect MYCN amplification and Chr 11q CNA, which was used for risk stratification according to the International Neuroblastoma Risk Group (INRG) classification system. We compared the results with data from SNP chip arrays in seven NB cell lines and eight primary NB samples.

Results: ddPCR assays successfully detected MYCN amplification and 11q CNA. The results of ddPCR were highly consistent with those obtained by SNP chip assay.

Conclusion: ddPCR can be conducted more rapidly than FISH or Southern blotting. Accordingly, it should be useful for on-site clinical applications aimed at detecting CNAs in NB and performing risk stratification promptly after diagnosis.
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http://dx.doi.org/10.1111/ped.14606DOI Listing
January 2021

Expanded indications for lung transplantation for pulmonary complications after hematopoietic stem cell transplantation.

J Thorac Cardiovasc Surg 2020 Oct 29. Epub 2020 Oct 29.

Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Objectives: Pulmonary complications after hematopoietic stem cell transplantation (HSCT) are associated with poor survival and can be treated by lung transplantation (LT). However, the indications for LT in patients with pulmonary complications after HSCT remain unclear due to low number of cases. HSCT is frequently conducted for hematologic malignancies, which have different recurrence patterns from solid-organ malignancies. Some patients also experience ABO blood type changes post-HSCT. This study aimed to reassess the indication of LT for pulmonary complications post-HSCT, focusing on disease-free interval (DFI) and ABO-incompatibility.

Methods: Retrospective chart reviews were performed in patients who underwent LT for post-HSCT pulmonary complications. In patients with previous hematologic malignancy, indication was based on estimated recurrence rate instead of DFI. Donors were selected based on the recipient anti-A/B antibody profile rather than ABO type. Post-LT survival and complication rates were examined.

Results: Forty consecutive patients undergoing LT after HSCT (including 31 with previous hematologic malignancy) were analyzed. The median DFI between HSCT and LT was 64.5 months. Thirteen patients with previous hematologic malignancy had DFI <5 years but none experienced recurrence. There was no significant difference in 5-year post-LT survival between patients undergoing (74.7%) and not undergoing HSCT (68.4%). There was no significant difference in survival between patients with DFI ≥5 years (63.8%) and patients with DFI <5 years (83.3%). Five patients underwent LTs from major ABO-incompatible donors, but none developed incompatibility-related complications.

Conclusions: Indications based on estimated recurrence rates and recipients' anti-A/B antibody profiles may increase the use of LT for patients after HSCT.
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http://dx.doi.org/10.1016/j.jtcvs.2020.10.065DOI Listing
October 2020

Suppression of malignant rhabdoid tumors through Chb-M'-mediated RUNX1 inhibition.

Pediatr Blood Cancer 2021 02 12;68(2):e28789. Epub 2020 Nov 12.

Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.

Malignant rhabdoid tumor (MRT) is a rare and highly aggressive pediatric malignancy primarily affecting infants and young children. Intensive multimodal therapies currently given to MRT patients are not sufficiently potent to control this highly malignant tumor. Therefore, additive or alternative therapy for these patients with a poor prognosis is necessary. We herein demonstrated that the inhibition of runt-related transcription factor 1 (RUNX1) by novel alkylating conjugated pyrrole-imidazole (PI) polyamides, which specifically recognize and bind to RUNX-binding DNA sequences, was highly effective in the treatment of rhabdoid tumor cell lines in vitro as well as in an in vivo mouse model. Therefore, suppression of RUNX1 activity may be a novel strategy for MRT therapy.
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http://dx.doi.org/10.1002/pbc.28789DOI Listing
February 2021

-rearranged diffuse large B-cell lymphoma in a child: a case report and molecular characterization.

Pediatr Hematol Oncol 2021 Apr 5;38(3):281-289. Epub 2020 Nov 5.

Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

-rearranged diffuse large B-cell lymphoma (DLBCL) is rare in both the adult and pediatric populations, and its biological features are unclear. We here report the case of a 19-month-old female with a right temporal bone tumor that was ultimately diagnosed as DLBCL by tumor biopsy. There was no morphological evidence of bone marrow infiltration at diagnosis. The tumor nearly completely dissolved after scheduled chemotherapy for mature B-cell lymphoma; however, leukemic conversion occurred 2 months after completion of chemotherapy. Additional chemotherapy including hematopoietic cell transplantation in a non-remission state was unsuccessful, and disease progression ultimately resulted in the death of the patient 18 months after the diagnosis. We detected the fused transcript in the bone marrow of the patient with primary and recurrent cancer. RNA-sequencing of the bone marrow with recurrent cancer confirmed the fusion gene, although fusion genes involving , , or were not detected. Moreover, RNA-sequencing revealed overexpression of and , which are highly expressed in -rearranged leukemia, whereas the HOXA gene cluster was not overexpressed. The current case formed part of the -rearranged acute lymphoblastic leukemia cluster in a T-distributed stochastic neighbor embedding plot. The aggressive clinical course and RNA-sequencing results of the present case suggest that -rearranged DLBCL shares biological features with -rearranged leukemia.
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http://dx.doi.org/10.1080/08880018.2020.1838013DOI Listing
April 2021

Effects of passage through the digestive tract on incretin secretion: Before and after birth.

J Diabetes Investig 2021 Jun 28;12(6):970-977. Epub 2020 Nov 28.

Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Aims/introduction: It was reported that fetuses secrete endogenous incretin; however, the stimulants of fetal incretin secretion are not fully understood. To investigate the association between the passage of amniotic fluid through the intestinal tract and fetal secretion of incretin, we analyzed umbilical cord incretin levels of infants with duodenum atresia.

Materials And Methods: Infants born from July 2017 to July 2019 (infants with duodenum atresia and normal term or preterm infants) were enrolled. We measured and compared the concentrations of glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide/glucose-dependent insulinotropic polypeptide (GIP) in the umbilical vein and preprandial blood samples after birth.

Results: A total of 98 infants (47 term, 46 preterm and 5 with duodenum atresia) were included. In patients with duodenum atresia, umbilical vein GLP-1 and GIP levels were the same as those in normal infants. In postnatal samples, there were positive correlations between the amount of enteral feeding and preprandial serum concentrations of GLP-1 (r = 0.47) or GIP (r = 0.49).

Conclusions: Our results show that enteral feeding is important for secretion of GLP-1 and GIP in postnatal infants, whereas the passage of amniotic fluid is not important for fetal secretion of GLP-1 and GIP. The effect of ingested material passing through the digestive tract on incretin secretion might change before and after birth. Other factors might stimulate secretion of GLP-1 and GIP during the fetal period.
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http://dx.doi.org/10.1111/jdi.13447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169361PMC
June 2021

Landscape of driver mutations and their clinical impacts in pediatric B-cell precursor acute lymphoblastic leukemia.

Blood Adv 2020 10;4(20):5165-5173

Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Recent genetic studies using high-throughput sequencing have disclosed genetic alterations in B-cell precursor acute lymphoblastic leukemia (B-ALL). However, their effects on clinical outcomes have not been fully investigated. To address this, we comprehensively examined genetic alterations and their prognostic impact in a large series of pediatric B-ALL cases. We performed targeted capture sequencing in a total of 1003 pediatric patients with B-ALL from 2 Japanese cohorts. Transcriptome sequencing (n = 116) and/or array-based gene expression analysis (n = 120) were also performed in 203 (84%) of 243 patients who were not categorized into any disease subgroup by panel sequencing or routine reverse transcription polymerase chain reaction analysis for major fusions in B-ALL. Our panel sequencing identified novel recurrent mutations in 2 genes (CCND3 and CIC), and both had positive correlations with ETV6-RUNX1 and hypodiploid ALL, respectively. In addition, positive correlations were also newly reported between TCF3-PBX1 ALL with PHF6 mutations. In multivariate Cox proportional hazards regression models for overall survival, TP53 mutation/deletion, hypodiploid, and MEF2D fusions were selected in both cohorts. For TP53 mutations, the negative effect on overall survival was confirmed in an independent external cohort (n = 466). TP53 mutation was frequently found in IGH-DUX4 (5 of 57 [9%]) ALL, with 4 cases having 17p LOH and negatively affecting overall survival therein, whereas TP53 mutation was not associated with poor outcomes among NCI (National Cancer Institute) standard risk (SR) patients. A conventional treatment approach might be enough, and further treatment intensification might not be necessary, for patients with TP53 mutations if they are categorized into NCI SR.
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http://dx.doi.org/10.1182/bloodadvances.2019001307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594377PMC
October 2020

Signal Intensity and Volume of Pituitary and Thyroid Glands in Preterm and Term Infants.

J Magn Reson Imaging 2021 04 16;53(4):1151-1161. Epub 2020 Oct 16.

Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background: Hypothalamic-pituitary-thyroid (HPT) maturation has not been extensively evaluated using neonatal MRI, even though both structures are visualized on MRI.

Hypothesis: That signal intensity and volume of pituitary and thyroid (T) glands on MRI in neonates may be interrelated.

Study Type: Retrospective.

Subjects: In all, 102 participants.

Field Strength/sequence: 3.0T, T -weighted pointwise encoding time reduction with radial acquisition (PETRA).

Assessment: The volume of interest of the anterior pituitary (AP), posterior pituitary (PP), and T on MRI were defined on T -PETRA by two radiologists, and volumes of AP (AP_vol) and thyroid (T_vol) were calculated. Gestational age (GA), chronological age (CA), GA+CA, birth weight (BW), and thyroid function were recorded. Mean and maximum signal intensities of AP, PP, and T were normalized using signals from the pons and spinal cord as follows: signal ratio of anterior pituitary/pons (AP/pons), signal ratio of posterior pituitary/pons (PP/pons), and signal ratio of thyroid/cord (T/cord) T/cord, respectively.

Statistical Tests: Correlations between signal intensity and volume measures and GA, CA, GA+CA, and BW were assessed using Pearson's correlation coefficient or Spearman's rank correlation coefficient. Thyroid function analysis and T /cord, T /cord, and T_vol were evaluated using the Steel-Dwass test.

Results: AP /pons correlated positively with GA (ρ = 0.62, P < 0.001) and BW (ρ = 0.74, P < 0.001), and negatively with CA (ρ = -0.86, P < 0.001) and GA+CA (ρ = -0.46, P < 0.001). PP /pons correlated positively with GA (ρ = 0.49, P < 0.001) and BW (ρ = 0.63, P < 0.001), and negatively with CA (ρ = -0.70, P < 0.001) and GA+CA (r = -0.38, P < 0.001). T /cord correlated positively with GA (ρ = 0.48, P < 0.001) and BW (ρ = 0.55, P < 0.001), and negatively with CA (ρ = -0.59, P < 0.001) and GA+CA (ρ = -0.22, P = 0.03). AP_vol correlated positively with GA (ρ = 0.68, P < 0.001) and BW (ρ = 0.73, P < 0.001), and negatively with CA (ρ = -0.72, P < 0.001). T_vol correlated positively with GA (ρ = 0.50, P < 0.001) and BW (ρ = 0.61, P < 0.001), and negatively with CA (ρ = -0.54, P < 0.001). AP /pons correlated positively with T /cord (ρ = 0.61, P < 0.001).

Data Conclusion: Signal and volume of pituitary and thyroid glands correlated positively with GA and BW, and negatively with CA in neonates.

Level Of Evidence: 4 TECHNICAL EFFICACY STAGE: 5.
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http://dx.doi.org/10.1002/jmri.27395DOI Listing
April 2021

Cold agglutinin disease in an infant: remission after intravenous immunoglobulin.

Pediatr Int 2020 Oct 8;62(10):1214-1216. Epub 2020 Oct 8.

Department of Pediatrics, The University of Tokyo, Tokyo, Japan.

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http://dx.doi.org/10.1111/ped.14289DOI Listing
October 2020

Distinct clonal evolution in a case with anaplastic embryonal rhabdomyosarcoma.

Pediatr Int 2020 Oct 5. Epub 2020 Oct 5.

Division of Pediatric Hematology and Oncology, Ibaraki Children's Hospital, Mito, Ibaraki, Japan.

Background: Clonal evolution of malignancy is a complex process related to intratumoral heterogeneity, as recent studies have also demonstrated in rhabdomyosarcoma. The purpose of this study is to present a distinct clonal feature of a case with anaplastic embryonal type rhabdomyosarcoma (ERMS) using molecular analysis.

Methods: A five-year-old girl developed a metastatic pelvic tumor. We cultured neoplastic cells isolated from the biopsy sample. Next, to characterize the current case, we analyzed the biopsy sample, autopsy sample, and established cell line using combined modalities, including histopathological, cytogenetic, and molecular assay. Furthermore, we undertook the backtrack mutation-specific polymerase chain reaction to reveal clonal composition.

Result: The histology of the biopsy sample was consistent with ERMS with focal anaplasia. We established a permanently growing cell line, ICH-ERMS-1, from the biopsy sample. On molecular analysis, the biopsied tissue revealed a missense mutation at codon 245 of TP53. In contrast, the autopsy tumor tissue and the cell line established from the biopsied tissue showed a missense mutation at codon 248. A backtrack study using mutation-specific PCR detected a TP53 codon 248 mutation in the original biopsy sample. All the specimens examined had a missense mutation at PTPN11 codon 69.

Conclusion: This study highlights intratumoral heterogeneity and distinct clonal change related to the functional context in our anaplastic ERMS case, supporting the concept of intratumoral heterogeneity and clonal evolution. It requires further case collection to reveal whether p14ARF-p53-MDM2 tumor suppressor pathway alteration considered a late event in ERMS tumorigenesis is responsible for anaplasia in ERMS.
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http://dx.doi.org/10.1111/ped.14499DOI Listing
October 2020

Comprehensive genetic analysis of pediatric germ cell tumors identifies potential drug targets.

Commun Biol 2020 09 30;3(1):544. Epub 2020 Sep 30.

Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

To elucidate the molecular pathogenesis of pediatric germ cell tumors (GCTs), we performed DNA methylation array analysis, whole transcriptome sequencing, targeted capture sequencing, and single-nucleotide polymorphism array analysis using 51 GCT samples (25 female, 26 male), including 6 germinomas, 2 embryonal carcinomas, 4 immature teratomas, 3 mature teratomas, 30 yolk sac tumors, and 6 mixed germ cell tumors. Among the 51 samples, 11 were from infants, 23 were from young children, and 17 were from those aged ≥10 years. Sixteen of the 51 samples developed in the extragonadal regions. Germinomas showed upregulation of pluripotent genes and global hypomethylation. Pluripotent genes were also highly expressed in embryonal carcinomas. These genes may play essential roles in embryonal carcinomas given that their binding sites are hypomethylated. Yolk sac tumors exhibited overexpression of endodermal genes, such as GATA6 and FOXA2, the binding sites of which were hypomethylated. Interestingly, infant yolk sac tumors had different DNA methylation patterns from those observed in older children. Teratomas had higher expression of ectodermal genes, suggesting a tridermal nature. Based on our results, we suggest that KIT, TNFRSF8, and ERBB4 may be suitable targets for the treatment of germinoma, embryonal carcinomas, and yolk sac tumors, respectively.
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http://dx.doi.org/10.1038/s42003-020-01267-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528104PMC
September 2020

Long-term outcome in patients with Fanconi anemia who received hematopoietic stem cell transplantation: a retrospective nationwide analysis.

Int J Hematol 2021 Jan 19;113(1):134-144. Epub 2020 Sep 19.

Department of Innovative Medical Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.

We retrospectively analyzed nationwide records of 163 Fanconi anemia (FA) patients [aplastic anemia (AA), n = 118; myelodysplastic syndrome (MDS), n = 30; acute leukemia, n = 15] who underwent first allogeneic hematopoietic stem cell transplantation (HSCT) between 1987 and 2015 in Japan. An alternative donor was used in 119 (73%) patients, and 160 (98%) patients received a non-T-cell-depleted graft. With an 8.7-year median follow-up, 5-year overall survival (OS) was 81%. The 5-year OS was significantly higher in AA patients than in MDS and acute leukemia patients (89%, 71%, and 44%, respectively). In the MDS/leukemia group, factors associated with poor outcome in univariate analysis were older age at HSCT (≥ 18 years), conditioning regimen without anti-thymocyte or lymphocyte globulin, and grade II-IV acute graft-versus-host disease. After 1 year, of 137 survivors, 15 developed subsequent malignancies, of whom 12 were diagnosed with head and neck (HN)/esophageal cancer. An irradiation regimen and older age were associated with the risk of HN/esophageal cancer. Five of seven deaths were attributed to subsequent malignancies more than 5 years after HSCT. On the basis of the risk factors for HSCT in MDS/leukemia patients and subsequent malignancies, a more effective HSCT approach is required.
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http://dx.doi.org/10.1007/s12185-020-02991-xDOI Listing
January 2021

Pluripotent stem cell model of Shwachman-Diamond syndrome reveals apoptotic predisposition of hemoangiogenic progenitors.

Sci Rep 2020 09 9;10(1):14859. Epub 2020 Sep 9.

Department of Pediatrics, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

Shwachman-Diamond syndrome (SDS), an autosomal recessive disorder characterized by bone marrow failure, exocrine pancreatic insufficiency, and skeletal abnormalities, is caused by mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene, which plays a role in ribosome biogenesis. Although the causative genes of congenital disorders frequently involve regulation of embryogenesis, the role of the SBDS gene in early hematopoiesis remains unclear, primarily due to the lack of a suitable experimental model for this syndrome. In this study, we established induced pluripotent stem cells (iPSCs) from patients with SDS (SDS-iPSCs) and analyzed their in vitro hematopoietic and endothelial differentiation potentials. SDS-iPSCs generated hematopoietic and endothelial cells less efficiently than iPSCs derived from healthy donors, principally due to the apoptotic predisposition of KDRCD34 common hemoangiogenic progenitors. By contrast, forced expression of SBDS gene in SDS-iPSCs or treatment with a caspase inhibitor reversed the deficiency in hematopoietic and endothelial development, and decreased apoptosis of their progenitors, mainly via p53-independent mechanisms. Patient-derived iPSCs exhibited the hematological abnormalities associated with SDS even at the earliest hematopoietic stages. These findings will enable us to dissect the pathogenesis of multiple disorders associated with ribosomal dysfunction.
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http://dx.doi.org/10.1038/s41598-020-71844-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481313PMC
September 2020

SIX6 is a TAL1-regulated transcription factor in T-ALL and associated with inferior outcome.

Leuk Lymphoma 2020 12 24;61(13):3089-3100. Epub 2020 Aug 24.

Faculty of Medicine and Health Technology, Tampere Center for Child Health Research, Tampere University, Tampere, Finland.

T-cell acute lymphoblastic leukemia (T-ALL) is a hematological malignancy driven by abnormal activity of transcription factors. Here we report an aberrant expression of the developmental transcription factor in the TAL1-subtype of T-ALL. Our results demonstrate that the binding of TAL1 and GATA3 transcription factors into an upstream enhancer element directly regulates SIX6 expression. High expression of SIX6 was associated with inferior event-free survival within three independent patient cohorts. At a functional level, CRISPR-Cas9-mediated knockout of the gene in TAL1 positive Jurkat cells induced changes in genes associated with the mTOR-, K-RAS-, and TNFα-related molecular signatures but did not impair cell proliferation or viability. There was also no acceleration of T-ALL development within a Myc driven zebrafish tumor model . Taken together, our results show that SIX6 belongs to the TAL1 regulatory gene network in T-ALL but is alone insufficient to influence the development or maintenance of T-ALL.
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http://dx.doi.org/10.1080/10428194.2020.1804560DOI Listing
December 2020

Appropriate Phosphorus Intake by Parenteral Nutrition Prevents Metabolic Bone Disease of Prematurity in Extremely Low-Birth-Weight Infants.

JPEN J Parenter Enteral Nutr 2020 Aug 12. Epub 2020 Aug 12.

Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background: Metabolic bone disease (MBD) is a common disorder in extremely low-birth-weight (ELBW) infants. However, no studies have investigated whether high-dose calcium (Ca) and phosphorus (P) supplementation by parenteral nutrition (PN) prevents MBD in ELBW infants. This study aimed to identify the effect of PN on MBD in ELBW infants.

Methods: We retrospectively analyzed ELBW infants who were admitted between April 2011 and March 2017. ELBW infants were divided into the low-P group (n = 22) and the high-P group (n = 26) according to the dose of parenteral P supply. Biochemical and radiological markers of MBD and treatments were analyzed.

Results: Mean daily parenteral intake of Ca and P in the first week was significantly higher in the high-P group than in the low-P group (both P ≤ .001). Serum alkaline phosphatase (ALP) levels were significantly higher in the low-P group than in the high-P group in the first month. ELBW infants in the low-P group received alfacalcidol much more frequently than those in the high-P group. There was a trend of a higher rate of x-ray changes in the low-P group than in the high-P group. No infants developed bone fractures.

Conclusion: Appropriate P intake by PN is required to ensure high Ca intake, reduce ALP levels in the first month, and prevent MBD from hyperparathyroidism and does not worsen x-ray findings in ELBW infants.
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http://dx.doi.org/10.1002/jpen.1993DOI Listing
August 2020

Intracranial Growing Teratoma Syndrome With Intraventricular Lipid Accumulation.

J Pediatr Hematol Oncol 2021 05;43(4):e505-e507

Departments of Pediatrics.

Growing teratoma syndrome is a well-recognized condition associated with both intracranial and extracranial nongerminomatous germ cell tumors (NGGCTs), which mostly manifest as rapid growth of cystic and solid components during or within several months after treatment. Here, we report a patient with NGGCT who experienced slow growth of intracranial growing teratoma syndrome with intraventricular lipid accumulation over 10 years without any clinical symptoms. Considering the clinicopathologic heterogeneity of this syndrome, long-term clinical and radiologic follow-up is required for all patients with intracranial NGGCT.
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http://dx.doi.org/10.1097/MPH.0000000000001905DOI Listing
May 2021