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Background Many patients with childhood idiopathic nephrotic syndrome are steroid-sensitive. Several genome-wide association studies have suggested a polygenic contribution, particularly in the HLA DR/DQ region and a locus including nephrin, but the etiology remains unclear. Anti-nephrin antibodies have recently been reported in both adults and children with biopsy proven minimal change disease (MCD), but the presence of anti-nephrin antibodies in Japanese childhood idiopathic nephrotic syndrome (INS) has not been investigated. Methods Anti-nephrin antibodies were measured by ELISA in paired plasma samples obtained from 14 Japanese pediatric patients with INS (male/female: 8/6), at onset (active disease) and following steroid monotherapy. Results The median age at the onset was 75.5 months (interquartile range (IQR): 45-113). Steroid sensitivity resulted in complete remission in 13 patients and almost complete remission in one patient after 4 weeks of glucocorticoid monotherapy. Circulating anti-nephrin antibodies were detected in seven of 14 patients during active disease. In all cases, anti-nephrin antibodies were significantly reduced following treatment concordant with clinical response. There were no differences between the positive and negative groups in pre-treatment parameters. Of the 13 patients who achieved complete remission, nine had at least one relapse during a median follow-up of 851 days (IQR: 808-973). There was also no significant difference in the relapse-free period after the onset between the two groups (P=0.658). Conclusions We identified circulating anti-nephrin antibodies in half of Japanese pediatric patients with INS at initial presentation, which is higher than has been previously reported in a North American cohort.

Background Patients with immunoglobulin A nephropathy who present with focal mesangial proliferation (focal IgAN) can have a relatively good prognosis, and renin-angiotensin system inhibitor (RAS-i) is commonly used as the initial treatment. However, there are some complicated focal IgAN cases with resistance to RAS-i treatment or nephrotic-range proteinuria. Thus, combination therapy including corticosteroids is often used. This study aimed to evaluate the efficacy of combination therapy for complicated focal IgAN cases by comparing to diffuse mesangial proliferation (diffuse IgAN). Methods We conducted a multicenter retrospective study on 88 children who received 2-year combination therapy. The participants were classified based on pathological severity: focal IgAN (n = 26) and diffuse IgAN (n = 62). Results In total, 26 patients with focal IgAN and 52 with diffuse IgAN achieved proteinuria disappearance within 2 years (100 vs. 83.9%, P = 0.03). Moreover, the time to proteinuria disappearance was significantly shorter in the focal IgAN group than in the diffuse IgAN group (2.9 vs. 4.2 months, P < 0.01) and all patients with focal IgAN achieved proteinuria disappearance within 8 months. At the last observation (8.6 vs. 10.4 years, P = 0.13), only patients with diffuse IgAN (n = 12) had greater than stage 2 chronic kidney disease. In terms of irreversible adverse events, one patient exhibited cataracts. Conclusion Combination therapy was significantly effective in patients with complicated focal IgAN. Moreover, the long-term prognosis was good, and the duration of combination therapy for complicated focal IgAN can be decreased to reduce adverse events.

The survival of patients with high-risk, refractory, relapsed, or metastatic solid tumors remains dismal. A poly(ADP-ribose) polymerase (PARP) inhibitor could be effective for the treatment of pediatric solid tumors with defective homologous recombination.This open-label, multicenter phase 1 clinical trial evaluated the safety, tolerability, and efficacy of olaparib, a PARP inhibitor, in pediatric patients with refractory solid tumors to recommend a dose for Phase 2 trials. Olaparib (62.5, 125, and 187.5 mg/mFifteen patients were enrolled and received olaparib monotherapy, which was well tolerated. The recommended phase 2 dose for daily administration was 187.5 mg/mThis report is the first clinical trial to describe the use of a PARP inhibitor as monotherapy in children. Olaparib was well tolerated, with preliminary antitumor responses observed in DNA damage response-defective pediatric tumors.This Phase 1 trial evaluated the efficacy and safety of olaparib in patients with refractory childhood solid tumors. Olaparib was well tolerated, achieving objective response in 2/15 patients. The DNA damage response was attenuated in nearly one-half of advanced neuroblastoma patients, demonstrating the utility of the PARP inhibitor. The results support further investigation of olaparib as a new treatment for DNA damage-response or repair-defective pediatric cancers.

Supplementary Tables S1-S13. Supplementary Table S1. Clinical information and the summary of experiments performed on each sample. Supplementary Table S2. List of genes and regions captured for targeted deep sequencing. Supplementary Table S3. dbSNP ID list for which target baits were designed. Supplementary Table S4. Non-silent mutations detected in a validation cohort by targeted deep sequencing. Supplementary Table S5. Validated non-silent somatic mutations by PCR-based deep sequencing. Supplementary Table S6. Validated silent/non-silent somatic mutations used for clonal analysis of multiple samples from PBL001. Supplementary Table S7. Significantly hypo-/hyper-methylated gene sets in PBL compared to normal pancreas. Supplementary Table S8. Fusion genes detected by whole transcriptome sequencing in PBL. Supplementary Table S9. Genes with a significant differential expression between PBL and normal pancreatic samples. Supplementary Table S10. Significant gene set enrichment in comparison between PBL and normal pancreas. Supplementary Table S11. List of differentially expressed genes in each gene cluster identified by hierarchical clustering. Supplementary Table S12. Top 20 significantly enriched pathways in each gene cluster. Supplementary Table S13. Gene coefficients of PC1 and PC2.

Pancreatoblastoma is a rare pediatric pancreatic malignancy for which the molecular pathogenesis is not understood. In this study, we report the findings of an integrated multiomics study of whole-exome and RNA sequencing as well as genome-wide copy number and methylation analyses of ten pancreatoblastoma cases. The pancreatoblastoma genome was characterized by a high frequency of aberrant activation of the Wnt signaling pathway, either via somatic mutations of CTNNB1 (90%) and copy-neutral loss of heterozygosity (CN-LOH) of APC (10%). In addition, imprinting dysregulation of IGF2 as a consequence of CN-LOH (80%), gain of paternal allele (10%), and gain of methylation (10%) was universally detected. At the transcriptome level, pancreatoblastoma exhibited an expression profile characteristic of early pancreas progenitor-like cells along with upregulation of the R-spondin/LGR5/RNF43 module. Our results offer a comprehensive description of the molecular basis for pancreatoblastoma and highlight rational therapeutic targets for its treatment.Significance: Molecular genetic analysis of a rare untreatable pediatric tumor reveals Wnt/IGF2 aberrations and features of early pancreas progenitor-like cells, suggesting cellular origins and rational strategies for therapeutic targeting. Cancer Res; 78(4); 865–76. ©2017 AACR.

Supplementary Figures S1-S10. Supplementary Figure S1. Depths and coverages of targeted deep sequencing. Supplementary Figure S2. Sequencing coverages and numbers of mutations detected by WES. Supplementary Figure S3. Tumor subclonal populations in multiple samples from PBL001 estimated by PyClone. Supplementary Figure S4. Mutational signatures of primary and metastatic PBL. Supplementary Figure S5. SNP array-based copy number analysis of PBL. Supplementary Figure S6. Targeted deep sequencing based allele-specific copy number analysis of chromosome 11. Supplementary Figure S7. Bisulfite Sanger sequencing of ICR1 on chromosome 11p15.5. Supplementary Figure S8. Relative expression levels of IGF2 in CN-LOH-negative samples. Supplementary Figure S9. Aberrant activation of Wnt signaling pathway in PBL009. Supplementary Figure S10. Global DNA methylation profile of PBL.

Prospective research of children receiving heterogeneous vaccines has shown that immunization is not associated with pediatric idiopathic nephrotic syndrome (NS) relapses. However, prospective data concentrating only on influenza (flu) virus vaccines are not available.This multicenter prospective study was conducted in children with NS who received inactivated flu vaccines from June 2017 to July 2018. The day of flu vaccination was defined as day 0, and the period between prevaccination and postvaccination days was defined as - X to + Y (period from day - 180 to 0 as the precontrolled period). The primary outcome was the NS relapse rate from day 0 to + 30 as a direct association with vaccination compared with those in the precontrolled period. Exacerbation was defined as children experiencing more NS relapses after vaccination compared with those in the precontrolled period, or children starting any new immunosuppressants due to NS relapse after vaccination.Sixty-three children were included. Relapse rates were not significantly different between the precontrolled period and 0 to + 30 periods (0.38 vs. 0.19 times/person-year, p = 0.95). Although the exacerbation rate during the 0 to + 180 period in children without NS relapse in the precontrolled period was very low (4/54 [7.4 %]), children with at least one NS relapse in the precontrolled period showed a remarkable increase in the rate (4/9 [44.4%]; p = 0.01).Flu vaccination did not significantly precipitate the direct relapse of NS in children. However, it might increase the disease activity in children with at least one NS relapse within a half year before vaccination. A higher resolution version of the Graphical abstract is available as Supplementary information.

Although morphological renal abnormalities in children with febrile urinary tract infection (fUTI) have been showed a predictive factor for recurrent infection, there are no available data on recurrence regarding sonographic renal enlargement at first fUTI episode, especially focusing on whether renal enlargement is temporary or not.This cohort study reviewed the medical records of children who underwent renal ultrasound during their first fUTI during 2005-2013 and who were aged15 years at diagnosis. We defined a kidney as temporary enlarged when the kidney length was ≥2 standard deviation above normal renal length for that age on sonography or a difference of ≥1 cm in sonographic length between the right and left kidneys, following normal renal length after antibiotic treatment.A total of 132 children were enrolled, of whom 11 had sonographic temporary temporal renal enlargement during their first fUTI. After completing antibiotic therapy for a first fUTI episode, 20 (15%) children had fUTI recurrence. The clinical characteristics at first episode of fUTI were not significantly different between renal enlargement and nonrenal enlargement groups. Children with temporary renal enlargement at a first fUTI episode had significantly lower fUTI recurrence-free survival proportion than those with nonrenal enlargement according to the Kaplan-Meier method (p = 0.003) Conclusion: Identification of temporary temporal renal enlargement as a predictor of recurrent fUTI may help identify children with a first episode of fUTI who will be warned of close monitoring.

Highlights • Undifferentiated carcinoma of the liver is reported in a child for the first time. • Neoadjuvant chemotherapy with cisplatin/doxorubicin was outstandingly effective. • After chemotherapy, total excision was possible by resecting segments 4b and 5. • Aggressively malignant, recurrence caused death 9 months after successful surgery. • Neoadjuvant chemotherapy is indicated in aggressive malignancies to enable surgery., Introduction Undifferentiated carcinoma (UC) of the liver has only been reported in three adults in the English language literature and is so rare it has never been reported in a child. Our management is presented to improve knowledge of its treatment. Case presentation A 3-year-old previously well Japanese girl was referred for further assessment/management of an abdominal mass. On examination an obvious right hypocostal mass was visible extending across the midline. Diagnostic imaging identified a 12.5 cm mass on the ventral surface of the liver containing multiple cystic lesions extending along Glisson’s capsule with invasion to the portal vein. Open biopsy eventually led to a diagnosis of poorly differentiated or UC of the liver with embryonal features. Resection of hepatic segments 4b and 5 after a remarkable initial response to cisplatin/doxorubicin that shrank the tumor substantially, separating it from Glisson’s capsule enabled total excision. Surgery was successful and tolerated well with unremarkable postoperative recovery. Unfortunately, ascites due to peritoneal carcinomatosis developed 4 months postoperatively and she died 5 months later. Conclusion The initial impressive response to neoadjuvant chemotherapy and successful surgery was unexpectedly fortuitous but inadequate for controlling such an aggressive malignancy. Our case demonstrates the value of neoadjuvant chemotherapy.

Pathogenic variants of paired box gene 2 (PAX2) cause autosomal-dominant PAX2-related disorder, which includes renal coloboma syndrome (RCS). Patients with PAX2-related disorder present with renal and ophthalmological pathologies, as well as with other abnormalities, including developmental problems and hearing loss. We sequenced PAX2 in 457 patients with congenital anomalies of the kidney and urinary tract or with renal dysfunction of unknown cause and identified 19 different pathogenic variants in 38 patients from 30 families (6.5%). Thirty-four patients had renal hypodysplasia or chronic kidney disease of unknown cause, and three had focal segmental glomerulosclerosis. Although no obvious genotype–phenotype correlation was observed, six of the seven patients who developed end-stage renal disease in childhood had truncating variants. Twenty-three patients had ocular disabilities, mostly optic disc coloboma. Non-renal and non-ophthalmological manifestations included developmental disorder, electrolyte abnormality, and gonadal abnormalities. Two unrelated patients had congenital cystic adenomatoid malformations in their lungs. Six of ten probands with PAX2 mutation identified by next-generation sequencing did not show typical RCS manifestations. We conclude that PAX2-related disorder has a variable clinical presentation and can be diagnosed by next-generation sequencing even in the absence of typical RCS manifestations.

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

Background The SIOPEL-4 study has demonstrated that dose-dense cisplatin-based chemotherapy dramatically improves outcome in children with high-risk hepatoblastoma in western countries. However, the feasibility and safety of this regimen have not been clarified in Japanese patients. Methods A pilot study, JPLT3-H, was designed to evaluate the safety profile of the SIOPEL-4 regimen in Japanese children with newly diagnosed hepatoblastoma with either metastatic disease or low alpha-fetoprotein. Results A total of 15 patients (three female) were enrolled. Median age was 2 years (range, 0-14). Three patients were PRETEXT II (where PRETEXT is PRETreatment EXTent of disease), six PRETEXT III, and six PRETEXT IV. All patients had lung metastasis, none had low alpha-fetoprotein. Eight patients completed the prescribed treatment, and seven patients discontinued therapy prematurely, four due to progressive disease and three due to causes other than severe toxicity. Grade 4 neutropenia was documented in most patients in preoperative cycles A1-3 (11/15 in A1, 9/11 in A2, and 7/11 in A3) and in all considering all cycles. Grade 3-4 thrombocytopenia and grade 3 anemia were also frequently observed. Patients experienced several episodes of grade 3 febrile neutropenia, but none had grade 4 febrile neutropenia or severe infections. One patient had grade 3 heart failure only in the first cycle. Other grade 3 or 4 toxicities were hypomagnesemia, anorexia, nausea, mucositis, liver enzyme elevation, fever, infection, and fatigue. There were no unexpected severe toxicities. Conclusion The toxicity profile of JPLT3-H was comparable to that of SIOPEL-4. Dose-dense cisplatin-based chemotherapy may be feasible among Japanese patients with high-risk hepatoblastoma.

Cases of Henoch-Schönlein purpura nephritis (HSPN) with moderate severity were demonstrated to achieve good prognosis after treatment with renin-angiotensin system (RAS) inhibitors. However, some patients required additional treatment for recurrence after remission. This study aimed to clarify the effect of RAS inhibitors in HSPN cases with moderate severity, including the proportion of cases with recurrence and their response to additional treatment.Among 126 patients diagnosed with HSPN between 1996 and 2019, 71 patients with clinicopathologically diagnosed HSPN of moderate severity, defined as ISKDC grade II-IIIa and serum albumin ≥ 2.5 g/dL, were investigated.Proteinuria became negative after RAS inhibitor treatment alone in all 71 cases. However, 16 (22.5%) had recurrence. Eleven recurrent cases achieved negative proteinuria again following additional treatment. At the last follow-up (median 46.5 months; IQR, 23.2-98.2), 5 patients had persistent mild proteinuria; no patients had estimated glomerular filtration rate90 mL/min/1.73 mJapanese childhood HSPN cases with moderate severity had good outcomes without need for corticosteroids or immunosuppressants, when prescribed RAS inhibitor treatment. Even in recurrent cases, abnormal proteinuria was transient, and prognosis was excellent. A higher resolution version of the Graphical abstract is available as Supplementary information.

t(17;19)(q21‐q22;p13), responsible for TCF3‐HLF fusion, is a rare translocation in childhood B‐cell precursor acute lymphoblastic leukemia(BCP‐ALL). t(1;19)(q23;p13), producing TCF3‐PBX1 fusion, is a common translocation in childhood BCP‐ALL. Prognosis of t(17;19)‐ALL is extremely poor, while that of t(1;19)‐ALL has recently improved dramatically in intensified chemotherapy. In this study, TCF3‐HLF mRNA was detectable at a high level during induction therapy in a newly diagnosed t(17;19)‐ALL case, while TCF3‐PBX1 mRNA was undetectable at the end of induction therapy in most newly diagnosed t(1;19)‐ALL cases. Using 4 t(17;19)‐ALL and 16 t(1;19)‐ALL cell lines, drug response profiling was analyzed. t(17;19)‐ALL cell lines were found to be significantly more resistant to vincristine (VCR), daunorubicin (DNR), and prednisolone (Pred) than t(1;19)‐ALL cell lines. Sensitivities to three (Pred, VCR, and l‐asparaginase [l‐Asp]), four (Pred, VCR, l‐Asp, and DNR) and five (Pred, VCR, l‐Asp, DNR, and cyclophosphamide) agents, widely used in induction therapy, were significantly poorer for t(17;19)‐ALL cell lines than for t(1;19)‐ALL cell lines. Consistent with poor responses to VCR and DNR, gene and protein expression levels of P‐glycoprotein (P‐gp) were higher in t(17;19)‐ALL cell lines than in t(1;19)‐ALL cell lines. Inhibitors for P‐gp sensitized P‐gp‐positive t(17;19)‐ALL cell lines to VCR and DNR. Knockout of P‐gp by CRISPRCas9 overcame resistance to VCR and DNR in the P‐gp‐positive t(17;19)‐ALL cell line. A combination of cyclosporine A with DNR prolonged survival of NSG mice inoculated with P‐gp‐positive t(17;19)‐ALL cell line. These findings indicate involvement of P‐gp in resistance to VCR and DNR in Pgp positive t(17;19)‐ALL cell lines. In all four t(17;19)‐ALL cell lines, RAS pathway mutation was detected. Furthermore, among 16 t(1;19)‐ALL cell lines, multiagent resistance was usually observed in the cell lines with RAS pathway mutation in comparison to those without it, suggesting at least a partial involvement of RAS pathway mutation in multiagent resistance of t(17;19)‐ALL.

Background: Recently, comprehensive genetic approaches for steroid-resistant nephrotic syndrome (SRNS) using next-generation sequencing (NGS) have been established, but causative gene mutations could not be detected in almost 70% of SRNS patients. Main reason for the low variant detection rate is that most of them are SRNS caused not by genetic but by immunological factors. But some of them are probably because of the difficulty of detecting copy number variations (CNVs) in causative genes by NGS. Methods: In this study, we performed two analytical methods of NGS data-dependent pair analysis and custom array comparative genomic hybridization (aCGH) in addition to NGS analysis in an infantile nephrotic syndrome case. Results: We detected only one known pathogenic heterozygous missense mutation in exon 7 of COQ6 c.782C > T, p.(Pro261Leu) by NGS. With pair analysis, heterozygous exon 1–2 deletion was suspected and was confirmed by custom aCGH. As a result, a small CNV was successfully detected in the COQ6 gene. Because we could detect variants in COQ6 and could start treatment by coenzyme Q10 (CoQ10) in his very early stage of SRNS, the patient achieved complete remission. Conclusions: These relatively novel methods should be adopted in cases with negative results in gene tests by NGS analysis. Especially, in cases with CoQ10 deficiency, it is possible to delay initiating dialysis by starting treatment at their early stages.

Introduction:Gitelman syndrome (GS) is a tubulopathy exhibited by salt loss. GS cases are most oftendiagnosed by chance blood test. Aside from that, some cases are also diagnosed from tetanic symptomsassociated with hypokalemia and/or hypomagnesemia or short stature. As for complications, thyroiddysfunction and short stature are known, but the incidence rates for these complications have not yet beenelucidated. In addition, no genotype–phenotype correlation has been identified in GS. Methods:We examined the clinical characteristics and genotype–phenotype correlation in geneticallyproven GS cases with homozygous or compound heterozygous variants inSLC12A3(n¼185). Results:In our cohort, diagnostic opportunities were by chance blood tests (54.7%), tetany (32.6%), orshort stature (7.2%). Regarding complications, 16.3% had short stature, 13.7% had experienced febrileconvulsion, 4.3% had thyroid dysfunction, and 2.5% were diagnosed with epilepsy. In one case, QT pro-longation was detected. Among 29 cases with short stature, 10 were diagnosed with growth hormone (GH)deficiency and GH replacement therapy started. Interestingly, there was a strong correlation in serummagnesium levels between cases with p.Arg642Cys and/or p.Leu858His and cases without these variants,which are mutational hotspots in the Japanese population (1.76 mg/dl vs. 1.43 mg/dl,P, 論文

Recurrent fusion genes involving C11orf95, C11orf95-RELA, have been identified only in supratentorial ependymomas among primary CNS tumors. Here, we report hitherto histopathologically unclassifiable high-grade tumors, under the tentative label of "ependymoma-like tumors with mesenchymal differentiation (ELTMDs)," harboring C11orf95-NCOA1/2 or -RELA fusion. We examined the clinicopathological and molecular features in five cases of ELTMDs. Except for one adult case (50 years old), all cases were in children ranging from 1 to 2.5 years old. All patients presented with a mass lesion in the cerebral hemisphere. Histologically, all cases demonstrated a similar histology with a mixture of components. The major components were embryonal-appearing components forming well-delineated tumor cell nests composed of small uniform cells with high proliferative activity, and spindle-cell mesenchymal components with a low- to high-grade sarcoma-like appearance. The embryonal-appearing components exhibited minimal ependymal differentiation including a characteristic EMA positivity and tubular structures, but histologically did not fit with ependymoma because they lacked perivascular pseudorosettes, a histological hallmark of ependymoma, formed well-delineated nests, and had diffuse and strong staining for CAM5.2. Molecular analysis identified C11orf95-NCOA1, -NCOA2, and -RELA in two, one, and two cases, respectively. t-distributed stochastic neighbor embedding analysis of DNA methylation data from two cases with C11orf95-NCOA1 or -NCOA2 and a reference set of 380 CNS tumors revealed that these two cases were clustered together and were distinct from all subgroups of ependymomas. In conclusion, although ELTMDs exhibited morphological and genetic associations with supratentorial ependymoma with C11orf95-RELA, they cannot be regarded as ependymoma. Further analyses of more cases are needed to clarify their differences and similarities.

Pineoblastoma is a rare malignant brain tumor that occurs in infancy and young adulthood. Although its prognosis has improved in recent years, it remains one of the difficult tumor types to treat. We will retrospectively review the treatment of pineoblastoma at our hospital and propose the possibility of a new treatment for this tumor type. Three cases were studied. All of them presented at less than three years of age and were treated for hydrocephalus simultaneously as the biopsy. Chemotherapy was administered after a possible resection, and local radiotherapy was administered at the age of 3 years. Overall survival ranged from 7 to 91 months, with one case of long-term survival. To date, the prognostic factors for pineoblastoma are the age of onset and the presence of radiation therapy. This is interpreted to mean that the prognosis is worse in infants and young children who cannot be immediately treated with radiation therapy, indicating that radiation therapy is essential for treating this tumor type. On the other hand, radiation therapy for infants can significantly interfere with the development of the central nervous system, and there is much controversy about its potential compatibility with tumor control. We have identified a favorable prognosis group based on the molecular biological background of this tumor type. We propose that early radiotherapy may improve the prognosis.

In high-risk neuroblastoma, the presence of an MYCN gain/amplification (MYCN-GA) is not always a risk factor of cancer-specific death. We herein examined the effect modification of high-dose chemotherapy with autologous hematopoietic stem cell rescue (HDC-autoSCR) in terms of the interaction between MYCN status and remission status (complete remission or very good partial remission [CR/VGPR] vs. partial remission or less [≤PR]). The present study recruited patient data from 1992 to 2017 in the Japan Society of Hematopoietic Cell Transplantation’s national registry. The MYCN status was known in 586 of 950 patients with a single course of HDC-autoSCR. Cumulative hazard curves for neuroblastoma-specific death showed that a subgroup with MYCN-GA and ≤PR had a significantly poorer prognosis than three other subgroups, namely, the MYCN-NGA/ ≤ PR, MYCN-NGA/CR/VGPR, and MYCN-GA/CR/VGPR subgroups even after adjusting for non-infants and stage IV disease (hazard ratio: 2.79; 95% confidence interval: 1.91–4.09; P

Here we report a case of advanced extranodal natural killer/T cell lymphoma (ENKTL) in 11-year-old child. Positron emission tomography-magnetic resolution image is a crucial image to diagnose ENKTL in this case. Additionally, a strong regime combined with stem cell transplantation possibly improve prognosis of ENKTL.

To understand the genetics of steroid-sensitive nephrotic syndrome (SSNS), we conducted a genome-wide association study in 987 childhood SSNS patients and 3,206 healthy controls with Japanese ancestry. Beyond known associations in the HLA-DR/DQ region, common variants in NPHS1-KIRREL2 (rs56117924, P=4.94E-20, odds ratio (OR) =1.90) and TNFSF15 (rs6478109, P=2.54E-8, OR=0.72) regions achieved genome-wide significance and were replicated in Korean, South Asian and African populations. Trans-ethnic meta-analyses including Japanese, Korean, South Asian, African, European, Hispanic and Maghrebian populations confirmed the significant associations of variants in NPHS1-KIRREL2 (P(meta)=6.71E-28, OR=1.88) and TNFSF15 (P(meta)=5.40E-11, OR=1.33) loci. Analysis of the NPHS1 risk alleles with glomerular NPHS1 mRNA expression from the same person revealed allele specific expression with significantly lower expression of the transcript derived from the risk haplotype (Wilcox test p=9.3E-4). Because rare pathogenic variants in NPHS1 cause congenital nephrotic syndrome of the Finnish type (CNSF), the present study provides further evidence that variation along the allele frequency spectrum in the same gene can cause or contribute to both a rare monogenic disease (CNSF) and a more complex, polygenic disease (SSNS).

PURPOSEWe report here the outcomes and late effects of the Japanese Study Group for Pediatric Liver Tumors (JPLT)-2 protocol, on the basis of cisplatin-tetrahydropyranyl-adriamycin (CITA) with risk stratification according to the pretreatment extent of disease (PRETEXT) classification for hepatoblastoma (HB).PATIENTS AND METHODSFrom 1999 to 2012, 361 patients with untreated HB were enrolled. PRETEXT I/II patients were treated with up-front resection, followed by low-dose CITA (stratum 1) or received low-dose CITA, followed by surgery and postoperative chemotherapy (stratum 2). In the remaining patients, after 2 cycles of CITA, responders received the CITA regimen before resection (stratum 3), and nonresponders were switched to ifosfamide, pirarubicin, etoposide, and carboplatin (ITEC; stratum 4). Intensified chemotherapeutic regimens with autologous hematopoietic stem-cell transplantation (SCT) after resection were an optional treatment for patients with refractory/metastatic disease.RESULTSThe 5-year event-free and overall survival rates of HB patients were 74.2% and 89.9%, respectively, for stratum 1, 84.8% and 90.8%%, respectively, for stratum 2, 71.6% and 85.9%%, respectively, for stratum 3, and 59.1% and 67.3%%, respectively, for stratum 4. The outcomes for CITA responders were significantly better than those for nonresponders, whose outcomes remained poor despite salvage therapy with a second-line ITEC regimen or SCT. The late effects, ototoxicity, cardiotoxicity, and delayed growth, occurred in 61, 18, and 47 patients, respectively. Thirteen secondary malignant neoplasms (SMNs), including 10 leukemia, occurred, correlating with higher exposure to pirarubicin and younger age at diagnosis.CONCLUSIONThe JPLT-2 protocol achieved up-front resectability in PRETEXT I/II patients with no annotation factors, and satisfactory survival in patients who were CITA responders in the remaining patients. However, outcomes for CITA nonresponders were unsatisfactory, despite therapy intensification with ITEC regimens and SCT. JPLT-2 had a relatively low incidence of cardiotoxicity but high rates of SMNs.

Galactose-deficient IgA1 (Gd-IgA1) is important in the pathogenesis of IgA nephropathy (IgAN). A Gd-IgA1-specific monoclonal antibody (KM55) has revealed glomerular Gd-IgA1 deposition solely in patients with IgAN and IgA vasculitis with nephritis (IgAV-N). However, this specificity is controversial and has not been demonstrated in pediatric patients. Here, we conducted double-immunofluorescence staining of IgA and Gd-IgA1 in 60 pediatric patients with various glomerular diseases. We divided patients into four groups: (1) patients with IgAN and IgAV-N (n = 23); (2) patients with immunocomplex-mediated glomerulonephritis accompanied by IgA deposition, including lupus nephritis, membranoproliferative glomerulonephritis, and membranous nephropathy (n = 14); (3) patients with other glomerular diseases involving IgA deposition, including idiopathic nephrotic syndrome (INS), oligomeganephronia, Alport syndrome, dense deposit disease, and crescentic glomerulonephritis (n = 11); and (4) patients with IgA-negative diseases including INS, membranoproliferative glomerulonephritis, membranous nephropathy, oligomeganephronia, Alport syndrome, C3 glomerulonephritis, poststreptococcal acute glomerulonephritis, and hemolytic uremic syndrome (n = 12). KM55 staining revealed Gd-IgA1-positive findings in 23/23 patients in Group 1 and 13/14 patients in Group 2, but not in patients in Groups 3 or 4. Therefore, KM55 may detect incidental IgA deposition in pediatric patients. Gd-IgA1 may be involved in the pathogenesis of these immune-related diseases; alternatively, KM55 may recognize IgA-related immunocomplexes in a non-specific manner.

Background Primary breast lymphoma is rare. Occurrence rates of malignant breast tumors in children are also quite low. We herein report a B-lymphoblastic lymphoma of the breast arisen in an adolescent girl. To the best of our knowledge, this is the youngest case with primary breast non-Hodgkin’s lymphoma. Case presentation A 14-year-old Japanese girl felt a lump in her right breast and came to our hospital. A circumscribed soft mass, 30 mm in diameter, was palpable. Histological examination revealed atypical lymphoid cells diffusely spreading into the breast tissue. Based on results of immunohistochemistry and flow cytometry, her disease was diagnosed as B-lymphoblastic lymphoma (stage I). She was then referred to the pediatric department and received combination chemotherapy, based on a chemotherapy regimen for children with acute lymphoblastic leukemia. Following remission induction therapy, we confirmed no FDG uptake in the right breast on PET-CT scan. Conclusions We have described a rare malignant lymphoma arising in the breast of an adolescent female. Histological assessment is necessary for diagnosis of breast lymphoma. However, it can be challenging with several reasons, and clinical information may contribute to the assessment. Moreover, treatments for lymphoma vary according to disease types. Thus, surgeons should collaborate closely with pathologists, pediatricians, and hematologists.

Viral infections in patients with post-kidney transplantation are often difficult to diagnose as well as treat. We herein report three cases with severe viral infections after kidney transplantation. All their causative pathogens could be detected promptly by polymerase chain reaction and flow cytometry during the early stages of infection. These examinations would also be of great use to monitor therapeutic responses and disease activity. It is indeed true that no specific treatment is available for most of the viral infections, but we should be aware that some infections, such as Epstein-Barr virus infection, can be treatable with prompt and specific treatment, such as rituximab.