Publications by authors named "Atsuko Nakazawa"

133 Publications

Pediatric liver failure with massive sinusoidal infiltration of histiocytes.

J Clin Exp Hematop 2021 Nov 26. Epub 2021 Nov 26.

Department of Clinical Research, Saitama Children's Medical Center, Saitama, Japan.

Histiocytic neoplasms, such as Langerhans cell histiocytosis (LCH) and disseminated juvenile xanthogranuloma (JXG), can involve the liver and sometimes cause liver failure. We aimed to classify non-LCH histiocytic proliferating disorders that do not exhibit typical disseminated JXG histology. We examined four pediatric patients who presented with liver failure and splenomegaly. Two patients with liver cirrhosis without cholestasis underwent liver transplantation (LT). The other two patients presented with giant cell hepatitis causing neonatal/infantile acute liver failure (ALF). The infantile ALF patient also underwent LT. Liver dysfunction developed after LT in all three transplant cases and the grafts exhibited massive sinusoidal infiltration of histiocytes with hemophagocytosis, similar to the native liver. The neonatal ALF patient was treated with an LCH-type chemotherapy regimen, and is alive and well at 18 months. Infiltrating histiocytes were positive for CD68 and CD163, and negative for CD1a, CD207, and S-100 protein. The BRAF V600E mutation was not present. Liver histological findings were not consistent with conventional disseminated JXG or LCH, although the histological findings in other organs overlapped those of well-known histiocytic neoplasms. The histological and immunohistochemical findings of infiltrating histiocytes suggest that these four cases constituted a disseminated JXG-like systemic disease.
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http://dx.doi.org/10.3960/jslrt.21022DOI Listing
November 2021

Establishment of multiplex RT-PCR to detect fusion genes for the diagnosis of Ewing sarcoma.

Diagn Pathol 2021 Nov 8;16(1):102. Epub 2021 Nov 8.

Department of Pathology, National Center for Child Health and Development, Tokyo, 157-8535, Japan.

Background: Detection of the tumor-specific EWSR1/FUS-ETS fusion gene is essential to diagnose Ewing sarcoma. Reverse transcription-polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization are commonly used to detect the fusion gene, and assays using next-generation sequencing have recently been reported. However, at least 28 fusion transcript variants have been reported, making rapid and accurate detection difficult.

Methods: We constructed two sets of multiplex PCR assays and evaluated their utility using cell lines and clinical samples.

Results: EWSR1/FUS-ETS was detected in five of six tumors by the first set, and in all six tumors by the second set. The fusion gene detected only by the latter was EWSR1-ERG, which completely lacked exon 7 of EWSR1. The fusion had a short N-terminal region of EWSR1 and showed pathologically atypical features.

Conclusions: We developed multiplex RT-PCR assays to detect EWSR1-ETS and FUS-ETS simultaneously. These assays will aid the rapid and accurate diagnosis of Ewing sarcoma. In addition, variants of EWSR1/FUS-ETS with a short N-terminal region that may have been previously missed can be easily detected.
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http://dx.doi.org/10.1186/s13000-021-01164-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8573982PMC
November 2021

A Case of Adult Pancreatoblastoma With Novel Mutation and Genetic Heterogeneity.

Front Oncol 2021 27;11:725290. Epub 2021 Aug 27.

Oncology Pathology, Department of Pathology and Host-Defense, Faculty of Medicine, Kagawa University, Kita-gun, Japan.

Background: Pancreatoblastoma is a rare malignant epithelial neoplasm of the pancreas that mainly occurs in children and involves abnormalities in the WNT/β-catenin pathway, such as mutation. However, the molecular abnormalities in adult pancreatoblastoma are not well known.

Case Presentation: An elderly man, who underwent elective distal pancreatectomy and splenectomy, was referred to our hospital with a mass in the tail of the pancreas. Histologically, the lesion revealed proliferation of clear, basophilic, and cartilaginous tumor cells with lymphatic metastasis. Each of the morphologically distinct tumor components showed different immunohistochemical patterns, indicating heterogeneous differentiation, including epithelial (both acinar and ductal), mesenchymal, and neuroendocrine differentiation. All tumor components showed nuclear expression of β-catenin and cyclin D1. Per next-generation sequencing (NGS), the clear and basophilic tumor cells shared mutations in , , and . Among the mutations, , c.1816_1817insA showed the highest frequency in both cell types, indicating that mutation was a driver mutation of the tumor. A diagnosis of PB was rendered.

Summary: In conclusion, the clear and basophilic cells of the tumor were supposedly derived from the same clone and subsequently acquired additional mutations. This is the first report of clonal evolution in pancreatoblastoma.
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http://dx.doi.org/10.3389/fonc.2021.725290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432961PMC
August 2021

Molecular features of non-anaplastic peripheral T-cell lymphoma in children and adolescents.

Pediatr Blood Cancer 2021 Nov 13;68(11):e29285. Epub 2021 Aug 13.

Department of Pathology, Hematopathology Section and Lymph Node Registry, University of Kiel/University Hospital Schleswig-Holstein, Kiel, Germany.

Non-anaplasticperipheral T-cell lymphomas (PTCL) are rare tumors in children, adolescents, and young adults (CAYA) with poor prognosis and scarce genetic data. We analyzed lymphoma tissue from 36 patients up to 18 years old with PTCL, not otherwise specified (PTCL-NOS), hepatosplenic T-cell lymphoma, Epstein-Barr virus (EBV)-positive T-lymphoproliferative diseases, subcutaneous panniculitis-like T-cell lymphoma, and other PTCL types. Twenty-three patients (64%) had at least one genetic variant detectable, including TET2, KMT2C, PIK3D, and DMNT3A. TP53 and RHOA variants, commonly found in adults, were not identified. Eight of 20 (40%) CAYA PTCL-NOS had no detectable mutations. The genetic findings suggest that CAYA PTCL differ from adult cases.
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http://dx.doi.org/10.1002/pbc.29285DOI Listing
November 2021

Clinicopathological features and prognostic significance of programmed death ligand 1 in pediatric ALK-positive anaplastic large cell lymphoma: results of the ALCL99 treatment in Japan.

Hum Pathol 2021 Oct 4;116:112-121. Epub 2021 Aug 4.

Department of Pediatrics, Sapporo Hokuyu Hospital, Sapporo, 003-0006, Japan.

Programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) blockade is a promising therapy for hematological malignancies. However, the association of PD-L1 expression with the clinicopathological features and prognosis in pediatric ALK-positive anaplastic large cell lymphoma (ALCL) remains unclear. Using PD-L1/ALK immunofluorescence double staining, we evaluated the PD-L1 expression on tumor cells/tumor-infiltrating immune cells (TIICs) and the quantity of TIICs in 54 children with ALK-positive ALCL treated with the ALCL99 protocol. The percentages of PD-L1-positive tumor cells were significantly lower in patients with skin/mediastinum involvement, clinical high-risk group, present minimal disseminated disease (MDD), and a low ALK-antibody titer. The percentages of PD-L1-positive TIICs were significantly higher in patients with absent MDD. The percentages of TIICs were significantly lower in patients with absent MDD and a common morphological pattern. We classified patients according to the PD-L1 expression on tumor cells (Tumor-PD-L1), PD-L1 expression on TIICs (TIIC-PD-L1), and quantity of TIICs (TIIC-quantity). The progression-free survival (PFS) did not differ between Tumor-PD-L1 and Tumor-PD-L1 ALCL; TIIC-PD-L1 and TIIC-PD-L1 ALCL; and TIIC-quantity and TIIC-quantity ALCL. According to the combined parameters of Tumor-PD-L1 and TIIC-quantity, Tumor-PD-L1/TIIC-quantity ALCL had a worse 5-year PFS than other ALCL (50% versus 83%; P = .009). Tumor-PD-L1/TIIC-quantity ALCL remained a significant prognostic factor in multivariate analysis (P = .044). This is the first study to demonstrate that a high tumoral PD-L1 expression with a high quantity of TIICs was associated with a poor prognosis in pediatric ALK-positive ALCL. The tumor microenvironment of ALK-positive ALCL may be relevant to the clinicopathological features and prognosis.
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http://dx.doi.org/10.1016/j.humpath.2021.07.011DOI Listing
October 2021

All trans retinoic acid alleviates coronary stenosis by regulating smooth muscle cell function in a mouse model of Kawasaki disease.

Sci Rep 2021 07 5;11(1):13856. Epub 2021 Jul 5.

Division of Clinical Research, Saitama Children's Medical Center, Saitama, Japan.

Coronary artery (CA) stenosis is a detrimental and often life-threatening sequela in Kawasaki disease (KD) patients with coronary artery aneurysm (CAA). Therapeutic strategies for these patients have not yet been established. All-trans-retinoic acid (atRA) is a modulator of smooth muscle cell functions. The purpose of this study was to investigate the effect of atRA on CA stenosis in a mouse model of KD. Lactobacillus casei cell wall extract (LCWE) was intraperitoneally injected into 5-week-old male C57BL/6 J mice to induce CA stenosis. Two weeks later, the mice were orally administered atRA (30 mg/kg) 5 days per week for 14 weeks (LCWE + atRA group, n = 7). Mice in the untreated group (LCWE group, n = 6) received corn oil alone. Control mice were injected with phosphate-buffered saline (PBS, n = 5). Treatment with atRA significantly suppressed CA inflammation (19.3 ± 2.8 vs 4.4 ± 2.8, p < 0.0001) and reduced the incidence of CA stenosis (100% vs 18.5%, p < 0.05). In addition, atRA suppressed the migration of human coronary artery smooth muscle cells (HCASMCs) induced by platelet-derived growth factor subunit B homodimer (PDGF-BB). In conclusion, atRA dramatically alleviated CA stenosis by suppressing SMC migration. Therefore, it is expected to have clinical applications preventing CA stenosis in KD patients with CAA.
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http://dx.doi.org/10.1038/s41598-021-93459-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257698PMC
July 2021

Integrated diagnosis based on transcriptome analysis in suspected pediatric sarcomas.

NPJ Genom Med 2021 Jun 15;6(1):49. Epub 2021 Jun 15.

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

Pediatric solid tumors are a heterogeneous group of neoplasms with over 100 subtypes. Clinical and histopathological diagnosis remains challenging due to the overlapping morphological and immunohistochemical findings and the presence of atypical cases. To evaluate the potential utility of including RNA-sequencing (RNA-seq) in the diagnostic process, we performed RNA-seq in 47 patients with suspected pediatric sarcomas. Histopathologists specialized in pediatric cancer re-evaluated pathological specimens to reach a consensus diagnosis; 42 patients were diagnosed with known subtypes of solid tumors whereas 5 patients were diagnosed with undifferentiated sarcoma. RNA-seq analysis confirmed and refined consensus diagnoses and further identified diagnostic genetic variants in four of the five patients with undifferentiated sarcoma. Genetic lesions were detected in 23 patients, including the novel SMARCA4-THOP1 fusion gene and 22 conventional or recently reported genetic events. Unsupervised clustering analysis of the RNA-seq data identified a distinct cluster defined by the overexpression of rhabdomyosarcoma-associated genes including MYOG and CHRNG. These findings suggest that RNA-seq-based genetic analysis may aid in the diagnosis of suspected pediatric sarcomas, which would be useful for the development of stratified treatment strategies.
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http://dx.doi.org/10.1038/s41525-021-00210-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206218PMC
June 2021

Ammonia-based enrichment and long-term propagation of zone I hepatocyte-like cells.

Sci Rep 2021 05 31;11(1):11381. Epub 2021 May 31.

Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan.

Ammonia has a cytotoxic effect and can therefore be used as a selection agent for enrichment of zone I hepatocytes. However, it has not yet been determined whether ammonia-treated hepatocyte-like cells are able to proliferate in vitro. In this study, we employed an ammonia selection strategy to purify hepatocyte-like cells that were differentiated from human embryonic stem cells (ESCs) and from induced pluripotent stem cells (iPSCs). The resistance to cytotoxicity or cell death by ammonia is likely attributable to the metabolism of ammonia in the cells. In addition to ammonia metabolism-related genes, ammonia-selected hepatocytes showed increased expression of the cytochrome P450 genes. Additionally, the ammonia-selected cells achieved immortality or at least an equivalent life span to human pluripotent stem cells without affecting expression of the liver-associated genes. Ammonia treatment in combination with in vitro propagation is useful for obtaining large quantities of hepatocytes.
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http://dx.doi.org/10.1038/s41598-021-90708-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166824PMC
May 2021

Asian population may have a lower incidence of hip osteonecrosis in childhood acute lymphoblastic leukemia.

Int J Hematol 2021 Aug 18;114(2):271-279. Epub 2021 May 18.

Department of Hematology/Oncology, Saitama Children's Medical Center, 1-2 Shintoshin, Chuou-ku, Saitama, 330-8777, Japan.

Osteonecrosis (ON), a long-term complication of acute lymphoblastic leukemia (ALL) treatment affects patients' quality of life. Although the incidence of any ON, including asymptomatic, was 21.7% among children with ALL in the U.S., the actual incidence and risk factors in Asia remain unknown. For over 11 years, we performed hip magnetic resonance imaging (MRI) screening to detect asymptomatic ON while initiating maintenance chemotherapy in newly diagnosed children with ALL. Overall, 164 of 175 patients underwent hip MRI screening. The incidence of symptomatic or any ON was 3.0% and 11.6%, respectively. Asymptomatic ON in patients < 10 and ≥ 10 years old was 4.0% and 35.9%, respectively (P < 0.001). In multivariate analysis, age ≥ 10 years was the only significant risk factor. Asymptomatic ON with necrosis of > 30% of the epiphyseal surface of the femoral head was detected in four patients (2.4%). All were ≥ 10 years. Three of them progressed to severe symptomatic ON. The incidence of any ON in Asia may be lower than that seen in the only screening study in the U.S. Future studies should clarify factors affecting such regional differences and develop an effective approach to avoid the progression of ON in children with ALL.
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http://dx.doi.org/10.1007/s12185-021-03163-1DOI Listing
August 2021

Application of Genome-Wide DNA Methylation Analysis to Differentiate a Case of Radiation-Induced Glioblastoma From Late-Relapsed Medulloblastoma.

J Neuropathol Exp Neurol 2021 Jun;80(6):552-557

From Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan.

Recurrent medulloblastoma can be difficult to diagnose with conventional diagnostic methods because other lesions mimic tumor relapse, particularly at later stages. We report 2 cases of medulloblastoma, both of which seemed to develop late recurrences. Case 1 was a 6-year-old girl who had a medulloblastoma with focal desmoplasia. She was in complete remission for 9 years after treatment but developed an intradural lesion in her thoracic spine, which was pathologically confirmed as tumor recurrence by biopsy. Case 2 was a 10-year-old girl who had a nonmetastatic medulloblastoma. She developed a left cerebellar mass 5 years after the initial diagnosis; the pathological diagnosis was tumor relapse. We performed t-distributed stochastic neighbor embedding of the methylation data from these cases and reference data. In contrast to the consistency of methylation profiling and copy number abnormalities between primary and recurrent tumors of Case 1, the analysis of the recurrent tumor in Case 2 was distinct from medulloblastomas and clustered with "IDH-wild type glioblastomas," suggesting that the recurrent tumor was a radiation-induced glioblastoma. This report highlights the clinical utility of molecular genetic/epigenetic analysis combined with a standard diagnostic approach to confirm the diagnosis of brain tumor recurrence.
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http://dx.doi.org/10.1093/jnen/nlab043DOI Listing
June 2021

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

Cancer Sci 2021 Jul 6;112(7):2921-2927. Epub 2021 May 6.

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253283PMC
July 2021

Biological categories of neuroblastoma based on the international neuroblastoma pathology classification for treatment stratification.

Authors:
Atsuko Nakazawa

Pathol Int 2021 Apr 3;71(4):232-244. Epub 2021 Mar 3.

Department of Clinical Research, Saitama Children's Medical Center, Saitama, Japan.

The International Neuroblastoma Pathology Classification (INPC), which distinguishes a favorable histology (FH) and an unfavorable histology (UH), is one of the most powerful prognostic factors in patients with neuroblastoma. FH that shows spontaneous regression or age-appropriate tumor differentiation/maturation, is common in infants and has mutual interaction with Schwann cells via the NGF/NTRK1 pathway and gain of whole chromosome 17. In contrast, UH is prevalent in older children and is molecularly heterogeneous. MYCN amplification is the most frequent genomic abnormality in tumors with UH. MYCN-amplified tumors demonstrate characteristic histology, the same as MYC-positive neuroblastoma. Chromosome 1pLOH is often associated with MYCN amplification, but on the other hand, chromosome 11qLOH rarely occurs in combination with MYCN amplification. 11qLOH has an inferior prognostic impact in UH without MYCN amplification. The high expression of ALK protein is a negative prognostic factor in both ALK mutated or amplified tumors and FH, but not in UH. Abnormal maintenance/elongation of telomeres; overexpression of telomerase reverse transcriptase (TERT) and the alternative lengthening of telomeres (ALT) phenotype due to ATRX mutation, are another molecular event in UH. The INPC, incorporating immunohistochemistry for MYCN, MYC, ALK, TERT and ATRX, represents a practical and implementable approach to create the biological category for the future management of patients with this unique disease.
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http://dx.doi.org/10.1111/pin.13085DOI Listing
April 2021

Immortalization of human hepatocytes from biliary atresia with CDK4, cyclin D1, and TERT for cytochrome P450 induction testing.

Sci Rep 2020 10 15;10(1):17503. Epub 2020 Oct 15.

Center for Regenerative Medicine, National Center for Child Health and Development Research Institute, Tokyo, 157-8535, Japan.

Hepatocytes are an important tool for in vitro toxicology testing. In addition to primary cultures, a limited number of immortalized cell lines have been developed. We here describe a new cell line, designated as HepaMN, which has been established from a liver associated with biliary atresia. Hepatocytes were isolated from a liver of 4-year-old girl with biliary atresia and immortalized by inoculation with CSII-CMV-TERT, CSII-CMV-Tet-Off, CSII-TRE-Tight-cyclin D1 and CSII-TRE-Tight-CDK4 (mutant CDK4: an INK4a-resistant form of CDK4) lentiviruses at the multiplicity of infection of 3 to 10. HepaMN cells exhibited morphological homogeneity, displaying hepatocyte-like phenotypes. Phenotypic studies in vivo and in vitro revealed that HepaMN cells showed polarized and functional hepatocyte features along with a canalicular cell phenotype under defined conditions, and constitutively expressed albumin and carbamoyl phosphate synthetase I in addition to epithelial markers. Since HepaMN cells are immortal and subcloned, kinetics and expression profiles were independent of population doublings. HepaMN cells showed increased CYP3A4 expression after exposure to rifampicin, implying that their close resemblance to normal human hepatocytes makes them suitable for research applications including drug metabolism studies.
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http://dx.doi.org/10.1038/s41598-020-73992-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567112PMC
October 2020

Prognostic Factors in Childhood Anaplastic Large Cell Lymphoma: Long Term Results of the International ALCL99 Trial.

Cancers (Basel) 2020 Sep 24;12(10). Epub 2020 Sep 24.

Pediatric Hematology, Oncology and Stem Cell Transplant Division, Padua University Hospital, 35128 Padua, Italy.

With the aim of describing the long-term follow-up and to define the prognostic role of the clinical/pathological/molecular characteristics at diagnosis for childhood, adolescent and young adults affected by anaplastic large cell lymphoma (ALCL), we analyzed 420 patients aged up to 22 years homogeneously treated within the international ALCL99 trial. The 10-year progression free survival (PFS) was 70% and overall survival was 90%, rare late relapses occurred but no secondary malignancies were reported. Among clinical/pathological characteristics, only patients presenting a small cell/lymphohistiocytic (SC/LH) pattern were independently associated with risk of failure (hazard ratio = 2.49). Analysis of minimal disseminated disease (MDD), available for 162 patients, showed that both SC/LH pattern (hazard ratio = 2.4) and MDD positivity (hazard ratio = 2.15) were significantly associated with risk of failure in multivariate analysis. Considering MDD and SC/LH results, patients were separated into three biological/pathological (bp) risk groups: a high-risk group (bpHR) including MDD-positive patients with SC/LH pattern; a low-risk group (bpLR) including MDD-negative patients without SC/LH pattern; and an intermediate-risk group (bpIR) including remaining patients. The 10-year PFS was 40%, 75% and 86% for bpHR, bpIR and bpLR, respectively ( < 0.0001). These results should be considered in the design of future ALCL trials to tailor individual treatments.
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http://dx.doi.org/10.3390/cancers12102747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598675PMC
September 2020

A familial case of alveolar capillary dysplasia with misalignment of the pulmonary veins: the clinicopathological features and unusual glomeruloid endothelial proliferation.

Diagn Pathol 2020 May 9;15(1):48. Epub 2020 May 9.

Department of Diagnostic Pathology, Kyoto University Hospital, 54 Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.

Background: Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare disorder of pulmonary vascular abnormality with persistent pulmonary hypertension of the newborn. The symptom usually presents within hours after birth, leading to an early demise. Heterozygous de novo point mutations and genomic deletions of the FOXF1 (forkhead box F1) gene or its upstream enhancer have been identified in most patients with ACD/MPV. Most cases of ACD/MPV are sporadic; however, familial cases are also reported in 10% of patients.

Case Presentation: We herein report a case of familial ACD/MPV that showed unusual glomeruloid proliferation of endothelial cells. In this family, three of the four siblings died within two to 3 days after birth because of persistent pulmonary hypertension and respiratory failure. Only the second child remains alive and healthy. An autopsy was performed for the third and fourth children, resulting in a diagnosis of ACD/MPV based on the characteristic features, including misalignment of smaller pulmonary veins and lymphangiectasis. In both of these children, glomeruloid endothelial proliferation of vessels was noted in the interlobular septa. The vessels were immunohistochemically positive for D2-40, CD31, Factor VIII, and ERG, suggestive of differentiation for both lymphatic and blood vessels.

Conclusions: Unusual glomeruloid endothelial proliferation was observed in a familial ACD/MPV case. This histologic feature has not been described previously in ACD/MPV or any other pulmonary disease. Although the histogenesis of this histologic feature is unclear, this finding may suggest that ACD/MPV is a compound vascular and lymphovascular system disorder that exhibits various histologic features.
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http://dx.doi.org/10.1186/s13000-020-00972-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211333PMC
May 2020

Outcome for Pediatric Recipients of Macrosteatotic Liver Grafts From Living Donors.

Liver Transpl 2020 07 23;26(7):899-905. Epub 2020 Jun 23.

Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan.

In deceased donor liver transplantation, a donor liver with moderate (>30%) macrosteatosis used to be considered inappropriate for grafting. We examined the outcomes of children who underwent living donor liver transplantation (LDLT) at the National Center for Child Health and Development whose donor livers had moderate-to-severe macrosteatosis. Twelve children were enrolled who had received a moderate-to-severe macrosteatotic liver graft and underwent liver biopsy soon after LDLT. The primary diseases were biliary atresia in 7 patients, acute liver failure in 3 patients, glycogen storage disease type 1 in 1 patient, and primary sclerosing cholangitis in 1 patient. Median age was 11 months. There were 4 recipients who received grafts from their fathers, and 8 received grafts from their mothers. Median donor age was 35.5 years. We compared the degree of donor liver steatosis with the results of graft liver biopsies that were collected 4-105 days after LDLT. The levels of donor liver macrovesicular steatosis were moderate (34%-66%) in 9 patients and severe (>66%) in 3 patients. The nonalcoholic fatty liver disease activity score was 3 in 7 patients and 4 in 5 patients. Shortly after LDLT, 11 of 12 patients showed improvement in steatosis compared with the donor livers. One biopsy specimen taken 22 days after LDLT showed 60% macrosteatosis, which was the same as that in the donor liver. However, this patient was alive and well 6 years after LDLT. One patient died after LDLT because of infection and respiratory failure. The levels of steatosis of the donor liver grafts improved soon after LDLT in children, and the outcomes of children receiving a moderate-to-severe macrosteatotic liver from their parents were excellent.
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http://dx.doi.org/10.1002/lt.25784DOI Listing
July 2020

Living donor liver transplantation for congenital hepatic fibrosis in children.

Pathol Int 2020 Jun 2;70(6):348-354. Epub 2020 Mar 2.

Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan.

Congenital hepatic fibrosis (CHF) often accompanies autosomal recessive polycystic kidney disease (ARPKD), which stems from a PKHD1 gene mutation. The aim of this study was to clarify the prognosis of children with CHF who received living donor liver transplantation (LDLT) from donors who might be heterozygous carriers of a hepatorenal fibrocystic disease. Fourteen children with CHF who underwent LDLT at our center were enrolled. Eight and two patients had ARPKD and nephronophthisis, respectively. Eight of the donors were the recipients' fathers, and six donors were their mothers. We examined the histological and radiological findings of the donor livers and complications in the recipients following the liver transplantation. Seven of the donor livers presented morphological abnormalities of the bile ducts. Abdominal computed tomography revealed liver cysts in eight donors. One recipient underwent re-LT for graft failure due to rejection. Three patients presented with rejection, and one presented with sepsis. The overall survival rate was 100% and the original graft survival rate was 93%. In conclusion, the prognosis of recipients who received a LDLT from their parents for CHF was excellent. However, the morphology of half the donor livers was abnormal. Careful follow-up is needed to ensure long-term graft survival.
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http://dx.doi.org/10.1111/pin.12917DOI Listing
June 2020

Novel zinc alloys for biodegradable surgical staples.

World J Clin Cases 2020 Feb;8(3):504-516

Department of Pediatric Surgery, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.

Background: The development of biodegradable surgical staples is desirable as non-biodegradable Ti alloy staples reside in the human body long after wound healing, which can cause allergic/foreign-body reactions, adhesion, or other adverse effects. In order to develop a biodegradable alloy suitable for the fabrication of surgical staples, we hypothesized that Zn, a known biodegradable metal, could be alloyed with various elements to improve the mechanical properties while retaining biodegradability and biocompatibility. Considering their biocompatibility, Mg, Ca, Mn, and Cu were selected as candidate alloying elements, alongside Ti, the main material of clinically available surgical staples.

Aim: To investigate the mechanical properties and degradation behavior and safety and feasibility of biodegradable Zn alloy staples.

Methods: Tensile and bending tests were conducted to evaluate the mechanical properties of binary Zn alloys with 0.1-6 wt.% Mg, Ca, Mn, Cu, or Ti. Based on the results, three promising Zn alloy compositions were devised for staple applications (wt.%): Zn-1.0Cu-0.2Mn-0.1Ti (Zn alloy 1), Zn-1.0Mn-0.1Ti (Zn alloy 2), and Zn-1.0Cu-0.1Ti (Zn alloy 3). Immersion tests were performed at 37 °C for 4 wk using fed-state simulated intestinal fluid (FeSSIF) and Hank's balanced salt solution (HBSS). The corrosion rate was estimated from the weight loss of staples during immersion. Nine rabbits were subjected to gastric resection using each Zn alloy staple, and a clinically available Ti staple was used for another group of nine rabbits. Three in each group were sacrificed at 1, 4, and 12 wk post-operation.

Results: Additions of ≤1 wt.% Mn or Cu and 0.1 wt.% Ti improved the yield strength without excessive deterioration of elongation or bendability. Immersion tests revealed no gas evolution or staple fracture in any of the Zn alloy staples. The corrosion rates of Zn alloy staples 1, 2, and 3 were 0.02 mm/year in HBSS and 0.12, 0.11, and 0.13 mm/year, respectively, in FeSSIF. These degradation times are sufficient for wound healing. The degradation rate is notably increased under low pH conditions. Scanning electron microscopy and energy dispersive spectrometry surface analyses of the staples after immersion indicated that the component elements eluted as ions in FeSSIF, whereas corrosion products were produced in HBSS, inhibiting Zn dissolution. In the animal study, none of the Zn alloy staples caused technical failure, and all rabbits survived without complications. Histopathological analysis revealed no severe inflammatory reaction around the Zn alloy staples.

Conclusion: Staples made of Zn-1.0Cu-0.2Mn-0.1Ti, Zn-1.0Mn-0.1Ti, and Zn-1.0Cu-0.1Ti exhibit acceptable mechanical properties, proper degradation behavior, and safety and feasibility. They are promising candidates for biodegradable staples.
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http://dx.doi.org/10.12998/wjcc.v8.i3.504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031837PMC
February 2020

Proposal of a liver histology-based scoring system for bile salt export pump deficiency.

Hepatol Res 2020 Jun 25;50(6):754-762. Epub 2020 Mar 25.

Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan.

Aim: Bile salt export pump (BSEP) deficiency manifests a form of progressive intrahepatic cholestasis. This study aimed to establish a scoring system of liver histology for the uncommon genetic condition.

Methods: After a roundtable discussion and histology review, a scoring system for BSEP deficiency was established. Eleven tissue samples were independently evaluated by three pathologists based on the proposed standard for an interobserver agreement analysis. In four cases with serial tissue samples available, correlation between changes in histology scores and clinical outcome was examined.

Results: Of 14 initially listed histopathological findings, 12 were selected for scoring and grouped into the following four categories: cholestasis, parenchymal changes, portal tract changes and fibrosis. Each category consisted of two to four microscopic findings that were further divided into three to six scores; therefore, each category had a maximum score of 8-11. Interobserver agreement was highest for pericellular fibrosis (κ = 0.849) and lowest for hepatocellular cholestasis (κ = 0.241) with the mean and median κ values of the 12 parameters being 0.561 and 0.602, respectively. For two patients whose clinical features worsened, score changes between two time points were interpreted as deteriorated. In two patients, who showed a good clinical response to preprandial treatment with sodium 4-phenylbutyrate, histological changes were evaluated as improved or unchanged.

Conclusions: The proposed histology-based scoring system for BSEP deficiency with moderate interobserver agreement may be useful not only for monitoring microscopic changes in clinical practice but also for a surrogate endpoint in clinical trials.
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http://dx.doi.org/10.1111/hepr.13494DOI Listing
June 2020

Etiology of liver dysfunction after liver transplantation in children with metabolic disorders.

Hepatol Res 2020 May 3;50(5):635-642. Epub 2020 Feb 3.

Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan.

Aim: It has been reported that the long-term outcome for children with metabolic disorders after liver transplantation (LT) is excellent. However, there are several reports citing LT patients with metabolic disorders developing liver dysfunction early after LT. We examined the pathogenesis of liver dysfunction observed after LT in recipients with metabolic disorders at the National Center for Child Health and Development.

Methods: Of 106 children (aged <18 years) with metabolic disorders who underwent LT at our center, 36 patients who underwent liver biopsy within 60 days after LT were enrolled. The underlying diseases were urea cycle disorders (14 patients), methylmalonic acidemia (11 cases), Wilson's disease (3 patients), mitochondrial hepatopathy (3 patients), and others (5 patients). The median age was 1 year 2 months at LT. The reasons for biopsy were liver dysfunction (31 patients) and ascites (5 patients).

Results: The main findings of graft liver biopsy were diffuse steatosis (21 patients), rejection (8 patients), infection (3 patients), and others (4 patients). Of 21 patients who received graft biopsy showing steatosis, all the donor livers originally showed no steatosis or only mild steatosis. The liver function improved immediately after biopsy in 18 of 21 patients that showed diffuse steatosis.

Conclusions: The major cause of liver dysfunction after LT in recipients with metabolic disorders was steatosis and the risk of rejection was low. It is important to take a liver biopsy and examine the cause of liver dysfunction to avoid administration of excess immunosuppressant, and select the right therapy for recipients with metabolic disorders.
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http://dx.doi.org/10.1111/hepr.13487DOI Listing
May 2020

A novel mouse model of coronary stenosis mimicking Kawasaki disease induced by Lactobacillus casei cell wall extract.

Exp Anim 2020 Apr 13;69(2):233-241. Epub 2020 Jan 13.

Division of Clinical Research, Saitama Children's Medical Center, 1-2 Shintoshin, Chuou-ku, Saitama, Japan.

Kawasaki disease (KD), a febrile systemic vasculitis in infants associated with coronary aneurysm, is a major cause of cardiac sequelae such as myocardial infarction (MI) and sudden death. These events are caused by coronary stenosis due to intimal proliferation or thrombotic formation; however, histological evaluation is limited to autopsy cases of human KD. We therefore investigated the histological features of coronary artery (CA) stenosis in mice induced by Lactobacillus casei cell wall extract (LCWE). LCWE-induced coronary inflammation gradually progressed in a time-dependent manner and expanded to all layers of the vessel wall over 28 days. In addition, frequent elastin degradation was observed and abundant α-smooth muscle actin (SMA)-positive vascular smooth muscle cells (VSMCs) infiltrated into the intima. Furthermore, most VSMCs were positive for proliferating cell nuclear antigen (PCNA) following staining, suggesting that VSMCs likely exhibited a proliferative phenotype. In conclusion, we show a novel mouse model of coronary stenosis induced by LCWE that is characterized by coronary stenosis with severe coronary vasculitis and elastin degradation. In addition, VSMC proliferation plays an important role in the formation of coronary stenosis. This model is an appropriate model of KD coronary stenosis.
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http://dx.doi.org/10.1538/expanim.19-0124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220718PMC
April 2020

Effect of food on the pharmacokinetics and therapeutic efficacy of 4-phenylbutyrate in progressive familial intrahepatic cholestasis.

Sci Rep 2019 11 19;9(1):17075. Epub 2019 Nov 19.

Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan.

Progressive familial intrahepatic cholestasis (PFIC), a rare inherited disorder, progresses to liver failure in childhood. We have shown that sodium 4-phenylbutyrate (NaPB), a drug approved for urea cycle disorders (UCDs), has beneficial effects in PFIC. However, there is little evidence to determine an optimal regimen for NaPB therapy. Herein, a multicenter, open-label, single-dose study was performed to investigate the influence of meal timing on the pharmacokinetics of NaPB. NaPB (150 mg/kg) was administered orally 30 min before, just before, and just after breakfast following overnight fasting. Seven pediatric PFIC patients were enrolled and six completed the study. Compared with postprandial administration, an approved regimen for UCDs, preprandial administration significantly increased the peak plasma concentration and area under the plasma concentration-time curve of 4-phenylbutyrate by 2.5-fold (95% confidential interval (CI), 2.0-3.0;P = 0.003) and 2.4-fold (95% CI, 1.7-3.2;P = 0.005). The observational study over 3 years in two PFIC patients showed that preprandial, but not prandial or postprandial, oral treatment with 500 mg/kg/day NaPB improved liver function tests and clinical symptoms and suppressed the fibrosis progression. No adverse events were observed. Preprandial oral administration of NaPB was needed to maximize its potency in PFIC patients.
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http://dx.doi.org/10.1038/s41598-019-53628-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863819PMC
November 2019

Clinical features of macrophage activation syndrome as the onset manifestation of juvenile systemic lupus erythematosus.

Rheumatol Adv Pract 2019 14;3(1):rkz013. Epub 2019 May 14.

Division of Infectious Diseases and Immunology.

Objectives: Macrophage activation syndrome (MAS) is a severe complication of juvenile systemic lupus erythematosus (jSLE). However, little is known about the association between these conditions, especially in terms of MAS as the initial manifestation of jSLE. The aim of this study was to determine the clinical features of MAS as the initial manifestation of jSLE.

Methods: We carried out a retrospective review of the clinical features of MAS cases diagnosed concomitantly with jSLE from 2004 to 2016. Data from these patients were compared with those from a control group consisting of jSLE patients without MAS.

Results: Eleven (23.9%) of the 46 patients recruited for this study were diagnosed with MAS during the initial stage of jSLE. The between-group comparisons demonstrated that fever, leucopenia, hyperferritinaemia and increased aspartate aminotransferase were more frequently observed in jSLE patients with MAS than in controls (<0.01). Importantly, neurological symptoms were significantly more common in patients with MAS than in controls (<0.01), with 6 (54.6%) of the 11 MAS patients affected. For treatment, all 11 patients with both jSLE and MAS were administered CSs upon diagnosis, and 7 received immunosuppressants. No patient involved in this study died.

Conclusion: MAS can develop as the initial manifestation of jSLE. MAS with jSLE should be suspected in patients with fever, hyperferritinaemia, cytopenia and liver disorder. In addition, we found that jSLE patients with MAS had more neurological symptoms than those without. All patients with MAS were successfully treated with CSs. Early diagnosis and intensive therapy are essential in improving clinical outcomes.
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http://dx.doi.org/10.1093/rap/rkz013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649928PMC
May 2019

Results of a prospective clinical trial JN-L-10 using image-defined risk factors to inform surgical decisions for children with low-risk neuroblastoma disease: A report from the Japan Children's Cancer Group Neuroblastoma Committee.

Pediatr Blood Cancer 2019 11 24;66(11):e27914. Epub 2019 Jul 24.

Department of Pediatric Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Background: The present study sought to reduce the incidence of treatment complications of low-risk neuroblastoma by using image-defined risk factors (IDRFs) to inform the timing of surgical resection.

Procedures: Eligible patients included children (<18 years of age) with stage 1 or 2 disease, children (<365 days of age) with stage 3 disease, and infants with stage 4S disease. In IDRF-negative cases, treatment was completed with surgical resection alone. In IDRF-positive cases, the timing of surgery was determined based on the IDRFs after low-dose chemotherapy with 2-3 of the following four drugs: vincristine, cyclophosphamide, pirarubicin, and carboplatin. The outcome measures were overall survival, progression-free survival, and adverse events. This study was registered with the UMIN Clinical Trials Registry (number 000004355).

Results: Of the 60 patients screened between 2010 and 2013, 58 eligible patients were enrolled; 32 were identified as IDRF negative at diagnosis while 26 were identified as IDRF positive and underwent induction chemotherapy. The 3-year overall and progression-free survival rates of the 58 patients were 100% and 82.8% (95% confidence interval: 70.3-90.3), respectively. Neutropenia was the most frequently reported grade 3 or 4 chemotherapy-related form of toxicity (41.7%). With regard to surgical complications, 2.5% of all patients developed pleural effusion and ascites as early complications, while only 2.5% developed renal atrophy as a long-term complication. No fatal toxicities were observed.

Conclusion: Using IDRFs to inform surgical decision making for the treatment of low-risk neuroblastoma improved prognosis and reduced the incidence of long-term complications.
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http://dx.doi.org/10.1002/pbc.27914DOI Listing
November 2019

A case of malignant rhabdoid tumor mimicking yolk sac tumor.

Pediatr Blood Cancer 2019 08 29;66(8):e27784. Epub 2019 Apr 29.

Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan.

Malignant rhabdoid tumors (MRTs) are rare, highly aggressive embryonal neoplasms caused by biallelic alterations of the SMARCB1 gene. MRTs may occur in any soft tissue, but extracranial extrarenal MRTs are extremely rare. Diagnosis of MRTs in unusual locations and with an uncharacteristic cytomorphology that mimics other tumors is difficult. This was an atypical case of MRT in a 15-year-old female with tumors that closely resembled yolk sac tumors. It was extremely challenging to diagnose the tumors without confirming the SMARCB1 status.
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http://dx.doi.org/10.1002/pbc.27784DOI Listing
August 2019

Surgical treatment strategy for advanced hepatoblastoma: Resection versus transplantation.

Pediatr Blood Cancer 2018 12 7;65(12):e27383. Epub 2018 Aug 7.

Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan.

Background: Excellent outcomes of the extreme procedure of liver resection (LR) for advanced hepatoblastoma (HB) have been achieved in recent reports. However, liver transplantation (LT) remains the only surgical treatment for patients with unresectable HB. The aim of this study was to evaluate our retrospective data for cases of advanced HB necessitating surgical intervention and analyze the prognostic factors of recurrence by comparing patients with tumors resected by LR and LT.

Patients And Methods: We retrospectively reviewed 24 children with PRETEXT II/III/IV tumors that required consideration for LT between August 2011 and September 2016.

Result: The staging at the time of the diagnosis was PRETEXT II/III/IV in 1/13/10 patients, respectively, while the preoperative staging after neoadjuvant chemotherapy was POSTTEXT II/III/IV in 5/17/2 patients. Among those 24 patients, complete resection of the primary tumor was achieved with LT in 12 patients and LR in 12 patients. A high serum level of alpha-fetoprotein (AFP) at the time of surgery, no significant decrease in the rate of change of AFP, and low tumor shrinkage rate were related to the risk of tumor recurrence, and patients with tumors resected by LR with those risks had a higher recurrence rate than those without them. The overall survival was higher in patients with tumors resected by LT (100%) than in patients with tumors resected by LR.

Conclusion: Patients with advanced HB with a poor response to chemotherapy should definitively be prioritized for primary LT, given the possibility of vascular invasion and microscopic residual tumor.
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http://dx.doi.org/10.1002/pbc.27383DOI Listing
December 2018

Results of a phase II trial for high-risk neuroblastoma treatment protocol JN-H-07: a report from the Japan Childhood Cancer Group Neuroblastoma Committee (JNBSG).

Int J Clin Oncol 2018 Oct 26;23(5):965-973. Epub 2018 Apr 26.

Saga Medical Center KOSEIKAN Hospital, Saga, Japan.

Background: The Japanese Children's Cancer Group (JCCG) Neuroblastoma Committee (JNBSG) conducted a phase II clinical trial for high-risk neuroblastoma treatment. We report the result of the protocol treatment and associated genomic aberration studies.

Methods: JN-H-07 was a single-arm, late phase II trial for high-risk neuroblastoma treatment with open enrollment from June 2007 to February 2009. Eligible patients underwent five courses of induction chemotherapy followed by high-dose chemotherapy with hematopoietic stem cell rescue. Surgery for the primary tumor was scheduled after three or four courses of induction chemotherapy. Radiotherapy was administered to the primary tumor site and to any bone metastases present at the end of induction chemotherapy.

Results: The estimated 3-year progression-free and overall survival rates of the 50 patients enrolled were 36.5 ± 7.0 and 69.5 ± 6.6%, respectively. High-dose chemotherapy caused severe toxicity including three treatment-related deaths. In response to this, the high-dose chemotherapy regimen was modified during the trial by infusing melphalan before administering carboplatin and etoposide. The modified high-dose chemotherapy regimen was less toxic. Univariate analysis revealed that patients younger than 547 days and patients whose tumor showed a whole chromosomal gains / losses pattern had a significantly poor prognosis. Notably, the progression-free survival of cases with MYCN amplification were not inferior to those without MYCN amplification.

Conclusions: The outcome of patients treated with the JN-H-07 protocol showed improvement over the results reported by previous studies conducted in Japan. Molecular and genetic profiling may enable a more precise stratification of the high-risk cohort.
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http://dx.doi.org/10.1007/s10147-018-1281-8DOI Listing
October 2018

Dysregulation of Epstein-Barr Virus Infection in Hypomorphic ZAP70 Mutation.

J Infect Dis 2018 07;218(5):825-834

Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan.

Background: Some patients with genetic defects develop Epstein-Barr virus (EBV)-associated lymphoproliferative disorder (LPD)/lymphoma as the main feature. Hypomophic mutations can cause different clinical and laboratory manifestations from null mutations in the same genes.

Methods: We sought to describe the clinical and immunologic phenotype of a 21-month-old boy with EBV-associated LPD who was in good health until then. A genetic and immunologic analysis was performed.

Results: Whole-exome sequencing identified a novel compound heterozygous mutation of ZAP70 c.703-1G>A and c.1674G>A. A small amount of the normal transcript was observed. Unlike ZAP70 deficiency, which has been previously described as severe combined immunodeficiency with nonfunctional CD4+ T cells and absent CD8+ T cells, the patient had slightly low numbers of CD8+ T cells and a small amount of functional T cells. EBV-specific CD8+ T cells and invariant natural killer T (iNKT) cells were absent. The T-cell receptor repertoire, determined using next generation sequencing, was significantly restricted.

Conclusions: Our patient showed that a hypomorphic mutation of ZAP70 can lead to EBV-associated LPD and that EBV-specific CD8+ T cells and iNKT cells are critically involved in immune response against EBV infection.
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http://dx.doi.org/10.1093/infdis/jiy231DOI Listing
July 2018
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