Surgical correction of recurrent epiblepharon in Chinese children using modified skin re-draping epicanthoplasty

AIM:To evaluate the clinical efficacy of the modified skin re-draping epicanthoplasty procedure for correction of recurrent lower lid epiblepharon in Chinese children.METHODS:From 2016 to 2018,18 children(10 males and 8 females,average age 6.2±1.7 y;30 eyes)with recurrent epiblepharon who attended Beijing Children’s Hospital were included in the study.All the children had undergone lower eyelid surgery for epiblepharon.Surgical design included using an additional incision along the upper palpebral margin,to avoid vertical scarring on the upper lid.The re-draping method was used to correct recurrent epiblepharon.Follow-up ranged from 3 to 24 mo.Postoperative surgical outcomes,complications,and subjective satisfaction were evaluated.RESULTS:Complete correction of cilia touching the cornea was observed in all patients during an average follow-up of 7.1 mo.No"dog ears"or obvious scars were formed after surgery.All parents were satisfied with the cosmetic results and none complained.Mean astigmatism decreased from 2.39±0.79 diopter(D)preoperatively to 2.19±0.79 D at 6 mo after surgery;however,the difference was not significant.Best-corrected visual acuity improved,although the change in mean visual acuity was not significant.No recurrence occurred during the follow-up period.CONCLUSION:This surgical modified skin re-draping technique is effective and highly satisfactory for correction of recurrent epiblepharon.The approach is characterized by a simple design,a straightforward procedure,inconspicuous scarring,and good postoperative appearance.

Diagnosis and treatment of pediatric anaplastic lymphoma kinasepositive large B-cell lymphoma:A case report

BACKGROUND Anaplastic lymphoma kinase-positive(ALK+)large B-cell lymphoma(LBCL)is a rare type of lymphoma with high invasiveness and rapid progression.It occurs in all age groups,but is extremely rare in children.The lesions mainly involve the lymph nodes and may present with extra-nodal involvement.Response to conventional chemotherapies and local radiotherapy is poor,with a 5-year overall survival of less than 40%.Recently,the use of ALK inhibitors for the treatment of this disease has been reported.CASE SUMMARY We present a case of a 12-year-old boy diagnosed with ALK+LBCL.The patient had a 2-mo medical history of a calvarial mass,extensive systemic involvement,and positive bone marrow clathrin heavy chain(CLTC)-ALK fusion gene.Complete remission 1(CR1)was achieved using the modified LMB89 Group C regimen followed by autologous stem cell transplantation.The patient relapsed 3 mo later.He then achieved CR2 with three short courses of chemotherapy(COP,reduceddose ICE,low-dose Ara-c+VP16)and continuous alectinib targeted therapy.Afterward,allogeneic hematopoietic stem cell transplantation(allo-HSCT)was performed.At 16 mo after the allo-HSCT,the patient was still in CR2.CONCLUSION The modified LMB89 Group C regimen and ALK inhibitors are effective.Allo-HSCT should be performed after remission.

Central nervous system relapse in a pediatric anaplastic large cell lymphoma patient with CLTC/ALK translocation treated with alectinib: A case report

BACKGROUND The aberrant expression of the anaplastic lymphoma kinase(ALK)gene in ALKpositive(ALK+)anaplastic large cell lymphoma(ALCL)is usually due to t(2;5)/NPM-ALK.However,rarely,aberrant ALK expression can also result from a rearrangement of the ALK gene with various partner genes.Central nervous system(CNS)metastasis is very rare in ALK+ALCL.Patients with CNS involvement show an inferior prognosis.CASE SUMMARY Here,we present the case of an 8-year-old girl diagnosed with ALK+ALCL.She presented with fever,skin nodules,leg swelling,and abdominal pain over the preceding 6 mo.She had extensive involvement and showed an extraordinary rare translocation,t(2;17)/CLTC-ALK,as demonstrated by RNA-seq.She underwent chemotherapy as per ALCL99,followed by vinblastine(VBL)maintenance treatment,and achieved complete remission.However,she developed CNS relapse during VBL monotherapy.The patient achieved a durable second remission with high-dose chemotherapy(including methotrexate 8 g/m2)and continuous treatment with alectinib and VBL.CONCLUSION Alectinib showed significant and durable CNS effects in this patient.However,more cases are needed to prove the efficacy and safety of alectinib for pediatric ALK+ALCL patients.

The putative NAD(P)H Nitroreductase,Rv3131,is the Probable Activating Enzyme for Metronidazole in Mycobacterium Tuberculosis

Tuberculosis(TB),which is caused by the intracellular pathogen,Mycobacterium tuberculosis(Mtb),remains one of the deadliest infectious diseases worldwide,accounting for 1.45 million deaths in 2018[1].Thus,there is an increasing need to develop new antibiotics or to repurpose old drugs that have the potential to shorten the current duration of therapy.Metronidazole(MTZ)is a 5-nitroimidazole antibiotic that is mainly used in the treatment of anaerobic and protozoal infections[2].The action of mechanism for metronidazole has not been fully established.As a prodrug,MTZ is inactive until taken up and reduced by anaerobic bacteria and protozoa.It is possible that the reduction of Mtz leads to the production of toxic metabolites,which bind to deoxyribonucleic acid and electron-transport proteins of microbial pathogens,thus blocking nucleic acid synthesis[3].The impressive potency of MTZ against anaerobic bacteria indicates the potential for killing Mtb under anaerobic conditions.A previous in vitro study demonstrated that MTZ has potent activity against tubercle bacilli under anaerobic conditions[4].In a non-human primate model,MTZ has been shown to prevent reactivation of latent Mtb infection,indicating the in vivo role in targeting Mtb within an anaerobic environment[5].Although there is strong evidence for the role of MTZ in affecting anaerobic bacilli,the mechanism of action has not been elucidated in Mtb considering that MTZ must be catalyzed to a nitro-free radical form with endogenous nitroreductase.To provide insight=into how MTZ is activated in anaerobic Mtb bacilli,we first characterized the nitroreductase gene,Rv3131,and identified the key residue conferring the activation of MTZ in Mtb.

A fatal case of liver abscess caused by hypervirulent Klebsiella pneumoniae in a diabetic adolescent:A clinical and laboratory study

Importance Hypervirulent variants of Klebsiella pneumoniae(hvKp)are capable of causing life-threatening pyogenic liver abscesses(PLAs),but hvKp caused PLAs was seldom reported in pediatric populations.Hence,there is an urgent need to raise our awareness of this phenomenon in pediatric populations.Objective This study aimed to report the clinical characteristics of hvKp that caused fatal PLA complicated by bacteremia in an adolescent and further identify the microbiological and genomic features of the causative strain.Methods A 14-year-old boy with diabetes mellitus was admitted to our hospital with a diagnosis of PLA complicated by bacteremia.A hypermucoviscous hvKp strain,KPN_19-106,was isolated from the drainage fluid present within the liver abscess cavity and blood.The hypermucoviscosity phenotype of the causative strain was determined by string test.Its virulence was measured using serum resistance assay and Galleria mellonella larvae-killing assay.Antimicrobial susceptibility was determined by broth microdilution method.Genetic information was obtained by whole-genome sequencing and bioinformatics analysis.Results KPN_19-106 belonged to sequence type 380 and serotype K2 and exhibited stronger serum resistance and higher in vivo lethality than the well-characterized hvKp NTUH-K2044 strain.Although KPN_19-106 is susceptible to most antibiotics,no sign of improvement was observed during treatment with such drugs.Whole-genome sequencing revealed that the isolate had integrated multiple mobile genetic elements related to virulence.Interpretation Antibiotic-susceptible hvKp can cause fatal PLA complicated by bacteremia in adolescents,with no improvement during antimicrobial therapy.The causative strain in this case had integrated multiple virulence genes and thus exhibited higher virulence both in vitro and in vivo when compared with NTUH-K2044.

Identification of potential pathogenic mutations in Chinese children with first branchial cleft anomalies detected by whole-exome sequencing

Importance:First branchial cleft anomalies(FBCAs)are rare congenital malformations,accounting for<8%of all branchial cleft anomalies.However,little is currently known about the cause of FBCAs at the molecular level.Objective:To identify genomic alterations related to the genetic etiology of FBCAs in Chinese children.Methods:We performed whole-exome sequencing of samples from 10 pediatric patients with FBCAs.Data analysis was carried out using the Burrow-Wheeler Alignment software package,and the dbSNP database for comparisons.Rare variants were further validated by Sanger sequencing.Insertion/deletions(indels)were examined using the Genome Analysis Toolkit.Results:We identified 14 non-synonymous mutations in seven potential FBCA-susceptibility genes(TRAPPC12,NRP2,NPNT,SH3RF2,RHPN1,TENM4,and ARMCX4).We also detected 133 shared small indels in 125 genes.Gene Ontology analysis indicated that most of the identified genes played critical roles in development and differentiation pathways involved in regulating organ development.Interpretation:We characterized the mutational landscape in pathways involved in development and differentiation in Chinese children with FBCA.The results identified potential pathogenic genes and mutations related to FBCA,and provide molecular-level support for the branchial theory of FBCA pathogenesis.

Iron deficiency in children at the time of initial neuroblastoma diagnosis

Importance:There is a high incidence of iron deficiency in children worldwide.Notably,however,while iron deficiency is the most common cause of anemia,little is known about the prevalence and different types of iron deficiency in neuroblastoma patients.Objective:The aim of the present study was to investigate the prevalence of iron deficiency in patients newly diagnosed with neuroblastoma.Methods:A total of 195 newly diagnosed neuroblastoma patients from November 2015 to January 2018 were analyzed retrospectively.The survival analysis was estimated by the Kaplan-Meier method.Results:Of the 195 neuroblastoma patients included in the study,121(62.1%)had iron deficiency,55(28.2%)had absolute iron deficiency,and 66(33.9%)had functional iron deficiency.Being aged≥18 months,tumor originating in the abdomen,International Neuroblastoma Risk Group Staging System M,high-risk neuroblastoma,lactate dehydrogenase≥1500 U/L,neuron-specific enolase≥100 U/L,unfavorable histologic category,MYCN amplification,chromosome 1p loss,and bone marrow metastasis were associated with significantly higher rates of functional iron deficiency(P<0.05).Interpretation:Functional iron deficiency at the time of initial neuroblastoma diagnosis predicted lower event-free survival.Long-term effects of iron supplementation in neuroblastoma patients with different types of iron deficiency need to be further studied.

Application of genome analysis strategies in the clinical testing for pediatric diseases

Next-generation sequencing (NGS) is being used in clinical testing.Government authorities in both China and the United States are overseeing the clinical application of NGS instruments and reagents.In addition,the US Association for Molecular Pathology and the College of American Pathologists have jointly released a guidance to standardize the analysis and interpretation of NGS data involved in clinical testing.At present,the analysis strategies and pipelines for NGS data related to the clinical detection of pediatric disease are similar to those used for adult diseases.However,for rare pediatric diseases without linkage to known genetic variants,it is currently difficult to detect the relevant pathogenic genes using NGS technology.Additionally,it is challenging to identify novel pathogenic genes of familial pediatric tumors.Therefore,characterization of the pathogenic genes associated with above diseases is important for the diagnosis and treatment of rare diseases in children.This article introduces the general pipelines for NGS data analyses of diseases and elucidates data analysis strategies for the pathogenic genes of rare pediatric diseases and familial pediatric tumors.

Genome-wide analysis of differential DNA methylation in Silver-Russell syndrome

Silver-Russell Syndrome(SRS) is clinically heterogeneous disorder characterized by low birth weight, postnatal growth restriction, and variable dysmorphic features. Current evidence strongly implicates imprinted genes as an important etiology of SRS. Although almost half of the patients showed DNA hypomethylation at the H19/IGF2 imprinted domain, and approximately7%–10% of SRS patients have maternal uniparental disomy of chromosome 7(UPD(7) mat); the rest of the SRS patients shows unknown etiology. In this study, we investigate whether there are further DNA methylation defects in SRS patients. We measured DNA methylation in seven SRS patients and five controls at more than 485,000 CpG sites using DNA methylation microarrays. We analyzed methylation changes genome-wide and identified the differentially methylated regions(DMRs) using bisulfite sequencing and digital PCR. Our analysis identifies epimutations at the previously characterized domains of H19/IGF2,providing proof of principle that our methodology can detect the changes in DNA methylation at imprinted loci. In addition,our results showed a novel SRS associated imprinted gene OSBPL5 located on chromosome 11p14 with the probe cg25963939,which is hypomethylated in 4/7 patients(P=0.023, β=.0.243). We also report DMRs in other genes including TGFβ3, HSF1,GAP43, NOTCH4 and MYH14. These DMRs were found to be associated with SRS using GO pathway analysis. In this study,we identified the probe cg25963939, located at the 5′UTR of imprinted gene OSBPL5, as a novel DMR that is associated with SRS. This finding provides new insights into the mechanism of SRS etiology and aid the further stratification of SRS patients by molecular phenotypes.

Clonal and drug resistance dynamics of methicillin-resistant Staphylococcus aureus in pediatric populations in China

Importance:Regional clonal replacements of methicillin-resistant Staphylococcus aureus (MRSA) are common.It is necessary to understand the clonal and drug resistance changes in specific areas.Objective:To evaluate the clonal and drug resistance dynamics of MRSA in Chinese children from 2010 to 2017.Methods:MRSA was isolated from patients in Beijing Children's Hospital from 2010 to 2013 and from 2016 to 2017.The molecular characteristics and antibiotic resistance were determined,Results:In total,211 MRSA isolates were collected,and 104 isolates were classified as community-associated MRSA (CA-MRSA).ST59-SCCmec Ⅳ was the most prevalent type in both CA-MRSA (65.4%) and healthcare-associated-MRSA (HA-MRSA) (46.7%).ST239-SCCmec Ⅲ accounted for 21.5% of all HA-MRSA,which were not detected in 2016,and only three isolates were detected in 2017.The pvl gene carrying rate of CA-MRSA was significantly higher than that of HA-MRSA (42.3% vs.29.0%,P =0.0456).Among CA-MRSA,resistance rate to all tested antibiotics excluding chloramphenicol remained stable over the periods of 2010-2013 and 2016-2017.HA-MRSA displayed an overall trend of decreased resistance to oxacillin,gentamicin,tetracycline,ciprofloxacin,and rifampin,and increased resistance to chloramphenicol,consistent with the difference of antibiotic resistance patterns between ST59-SCCmec Ⅳ and ST239-SCCmec Ⅲ isolates.Vancomycin minimal inhibitory concentration (MIC) creep was found in the study period in all MRSA and ST59-SCCmec Ⅳ isolates.Interpretation:ST59-SCCmec Ⅳ has spread to hospitals and replaced the traditional ST239-SCCmec Ⅲ clone,accompanied by changes in drug resistance.Furthermore,vancomycin MIC creep indicated that the rational use of antibiotics should be seriously considered.

Treatment outcome in children with central nervous system-positive Burkitt lymphoma using only intrathecal and systemic chemotherapy combined with rituximab

Background:With current chemotherapy treatment,>90%of survival has been obtained for Burkitt lymphoma(BL).In this study,the demographic characteristics and treatment outcomes are presented for 78 children in China with central nervous system-positive(CNS+)BL.Methods:This retrospective study consecutively enrolled 78 CNS+BL patients in Beijing Children’s Hospital(BCH)from 2007 to 2019 who received the BCH B-cell non-Hodgkin’s lymphoma regimen(modified by French-American-British mature lymphoma B-cell 96[FAB/LMB96]C1 arm±rituximab).Clinical characteristics,methods of disease detection in the CNS,and outcomes were evaluated.Univariate and multivariate analyses were used to assess prognostic factors.Results:The median age of 65 boys and 13 girls at the time of diagnosis was 5.7 years(ranging from 1 to 14 years).Patients were followed up for a median time of 34 months(ranging from 1 to 72 months).Bone marrow invasion was found in 38(48.7%)patients.There were 48(61.5%),44(56.4%),and 25(32%)patients with cranial nerve palsy,intracerebral mass(ICM),and parameningeal extension,respectively.Abnormal cerebrospinal fluid(CSF)morphology and CSF immunophenotype appeared in 15(19.2%)and 15(19.2%)patients,respectively.There were 69(88.5%)patients treated with chemotherapy combined with rituximab,and nine patients were treated solely with chemotherapy.Finally,five patients died of treatment-related infection,recurrence occurred for 13,and one developed a second tumor.The 3-year overall survival and event-free survival rates were 78.9%±4.7%and 71.4%±6.0%,respectively.Treatment with chemotherapy only,ICM positivity,and>4 organs involved at diagnosis were independent risk factors.Conclusions:Rituximab combined with a modified LMB96 regimen has greatly increased the efficacy of treatment for Chinese children with CNS+BL,and with the continuous collection of outcome data,treatment-related complications are decreasing.For further verification,a large sample multicentre randomized controlled study should be performed to explore a treatment scheme for Chinese children with even greater efficacy.

The effectiveness of sound-processing strategies on tonal language cochlear implant users:A systematic review

Importance:Contemporary cochlear implants(CIs)are well established as a technology for people with severe-to-profound sensorineural hearing loss,with their effectiveness having been widely reported.However,for tonal language CI recipients,speech perception remains a challenge:Conventional signal processing strategies have been demonstrated to possibly provide insufficient information to encode tonal cues,and CI recipients have exhibited considerable deficits in tone perception.Thus,some tonal language-oriented sound-processing strategies have been introduced.The effects of available tonal language-oriented strategies on tone perception are reviewed and evaluated in this study.The results may aid in designing and improving tonal language-appropriate sound-processing strategies for CI recipients.Objective:The objective of this systematic review was to investigate the effects of tonal-language-oriented signal processing strategies on tone perception,music perception,word and sentence recognition.Methods:To evaluate the effects of tonal language-oriented strategies on tone perception,we conducted a systematic review.We searched for relevant reports dated from January 1979 to July 2017 using PubMed,Cochrane Library,EBSCO,Web of Science,EMBASE,and 4 Chinese periodical databases(CBMdisc,CNKI,VIP,andWanfang Data).Results:According to our search strategy,672 potentially eligible studies were retrieved from the databases,with 12 of these studies included in the final review after a 4-stage selection process.The majority of sound-processing strategies designed for tonal language were HiResolution with Fidelity 120(HiRes 120),fine structure processing,temporal fine structure(TFS),and C-tone.Generally,acute or short-term comparisons between the tonal language-oriented strategies and the conventional strategy did not reveal statistically significant differences in speech perception(or show a small improvement).However,a tendency toward improved tone perception and subjectively reported overall preferred sound quality was observed with the tonal language-oriented strategies.Interpretation:Conventional signal processing strategies typically provided very limited F0 information via temporal envelopes delivered to the stimulating electrodes.In contrast,tonal language-oriented coding strategies attempted to present more spectral information and TFS cues required for tone perception.Thus,a tendency of improved performance in tonal language perception in CI users was shown.

Progresses in clinical studies on antiviral therapies for COVID-19—Experience and lessons in design of clinical trials

Antiviral therapy with antiviral agents is a very important component of treatment for the 2019 novel coronavirus disease(COVID-19)caused by the severe acute respiratory syndrome coronavirus-2(SARS-CoV-2).It is important to clarify how to evaluate efficacy and safety of antiviral agents in treatment of COVID-19 during the pandemic of this disease.We need to answer the following questions:do we still need to use rigorously designed randomized controlled clinical trials(RCTs)?Or,will it be enough if we use loosened criteria,observational studies or even retrospective case series and case reports?The answer is"No,we still need to use the strictly designed preferably blinded multicenter RCTs to evaluate the antiviral agents."In this article,we reviewed almost all the RCT reports on monotherapies and combined therapies with antiviral agents for COVID-19,and found that among the reports on monotherapies,only remdesivir,and among combined antiviral agents,only the combined regimen with interferon-β1b,lopinavir-ritonavir and ribavirin were effective and safe based on evidences from RCTs.The results of five RCTs for chloroquine or hydroxychloroquine consistently showed that they were ineffective and unsafe in the treatment of COVID-19,especially at larger doses.Many aspects in the design of the clinical trials may be related to success or failure of a trial and the relevant factors need to be analyzed,discussed and emphasized from the specific requirements and considerations of antiviral therapies.We hope such discussions be of certain use in designing clinical trials for pediatric antiviral therapies.

Detection of FOXO1 break-apart status by fluorescence in situ hybridization in atypical alveolar rhabdomyosarcoma

The morphologies of alveolar rhabdomyosarcoma(ARMS) are various. Some cases entirely lack an alveolar pattern and instead display a histological pattern that overlaps with embryonal rhabdomyosarcoma(ERMS). The method of pathological diagnosis of ARMS and ERMS has been updated in the 4th edition of the World Health Organization's guidelines for classification of skeletal muscle tumors. Under the new guidelines, there is still no molecular test to distinguish between these two subtypes of rhabdomyosarcoma(RMS). In the present study, we applied fluorescent in situ hybridization(FISH) and found that the Forkhead box O1(FOXO1) gene broke apart, amplified, and displayed an aneuploid signal that was related to the RMS pathological subtype.Aside from the fact that FOXO1 break-apart and its amplification were correlated with atypical ARMS, aneuploidies were usually found in atypical ERMS. In conclusion, our results detail a potential biomarker to improve the accuracy of pathological diagnosis by discriminating between atypical ARMS and atypical ERMS.

Treatment of malignant rhabdoid tumors of the head and neck with combined chemotherapy and 125I particle implantation

INTRODUCTION The malignant rhabdoid tumor (MRT) was originally described as a highly malignant variant of Wilms' tumor in 1978 and was designated as a distinct entity in 1981.1 This highly aggressive tumor is characterized by its rhabdoid feature and biallelic loss of SMARCB1/INI1/hSNF5.2 The prognosis is very poor with only 31％ of patients surviving to 1 year,3 and there are no standardized treatment strategies available.

Newborn screening with targeted sequencing:a multicenter investigation and a pilot clinical study in China

Different newborn screening(NBS) programs have been practiced in many countries since the 1960 s. It is of considerable interest whether next-generation sequencing is applicable in NBS. We have developed a panel of 465 causative genes for 596 early-onset, relatively high incidence, and potentially actionable severe inherited diseases in our Newborn Screening with Targeted Sequencing(NESTS) program to screen 11,484 babies in 8 Women and Children’s hospitals nationwide in China retrospectively. The positive rate from preliminary screening of NESTS was 7.85%(902/11,484). With 45.89%(414/902) follow-up of preliminary positive cases, the overall clinically confirmative diagnosis rate of monogenic disorders was 12.07%(50/414), estimating an average of 0.95%(7.85% × 12.07%) clinical diagnosis rate, suggesting that monogenic disorders account for a considerable proportion of birth defects. The disease/gene spectrum varied in different regions of China. NESTS was implemented in a hospital by screening 3923 newborns to evaluate its clinical application. The turn-around time of a primary report, including the sequencing period of < 7 days, was within 11 days by our automatic interpretation pipeline. Our results suggest that NESTS is feasible and cost-effective as a first-tier NBS program, which will change the status of current clinical practice of NBS in China.

Chromosome band 11q23 deletion predicts poor prognosis in bone marrow metastatic neuroblastoma patients without MYCN amplification

Background:Interphase fluorescence in situ hybridization(FISH)of bone marrow cells has been confirmed to be a direct and valid method to assess the v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog(MYCN)amplification in patients with bone marrow metastatic neuroblastoma.MYCN amplification alone,however,is insufficient for pretreatment risk stratification.Chromosome band 11q23 deletion has recently been included in the risk stratification of neuroblastoma.In the present study,we aimed to evaluate the biological characteristics and prog-nostic impact of 11q23 deletion and MYCN amplification in patients with bone marrow metastatic neuroblastoma.Methods:We analyzed the MYCN and 11q23 statuses of 101 patients with bone marrow metastatic neuroblastoma using interphase FISH of bone marrow cells.We specifically compared the biological characteristics and prognostic impact of both aberrations.Results:MYCN amplification and 11q23 deletion were seen in 12(11.9%)and 40(39.6%)patients.The two mark-ers were mutually exclusive.MYCN amplification occurred mainly in patients with high lactate dehydrogenase(LDH)and high neuron-specific enolase(NSE)levels(both P<0.001),and MYCN-amplified patients had more events(tumor relapse,progression,or death)than MYCN-normal patients(P=0.004).11q23 deletion was associated only with age(P=0.001).Patients with MYCN amplification had poorer outcomes than those with normal MYCN(3-year event-free survival[EFS]rate:8.3±8.0%vs.43.8±8.5%,P<0.001;3-year overall survival[OS]rate:10.4±9.7%vs.63.5%±5.7%,P<0.001).11q23 deletion reflected a poor prognosis only for patients with normal MYCN(3-year EFS rate:34.3±9.5%vs.53.4±10.3%,P=0.037;3-year OS rate:42.9±10.4%vs.75.9±6.1%,P=0.048).Those with both MYCN amplification and 11q23 deletion had the worst outcome(P<0.001).Conclusions:Chromosome band 11q23 deletion predicts poor prognosis only in bone marrow metastatic neuroblastoma patients without MYCN amplification.Combined assessment of the two markers was much superior to single-marker assessment in recognizing the patients at a high risk of disease progression.

Whole-exome sequencing reveals twovariants in thegene in two Chinese patients with left ventricular non-compaction cardiomyopathy

Importance:Pathogenic variants in theRBM20 gene are associated with aggressive dilated cardiomyopathy(DCM).Recently,RBM20 was found to be associated with left ventricular non-compaction cardiomyopathy(LVNC).Thus far,only five families with LVNC have been reported to carry variants inRBM20.It remains unknown whether the variants inRBM20 associated with DCM can also cause LVNC.Objective:To elucidate the causativeRBM20 variant in two unrelated patients with both LVNC and DCM,and to identify the clinical characteristics associated with variants inRBM20.Methods:Trio whole-exome sequencing(WES)was performed.Variants were filtered and classified in accordance with the guidelines of the American College of Medical Genetics and Genomics(ACMG).Results:We identified two distinctde novo variants inRBM20(one per patient)in these two patients with LVNC.Both variants have been reported in patients with DCM,without the LVNC phenotype.Patient 1 was an 11-year-old girl who had DCM,LVNC,and heart failure;the ratio of noncompacted-to-compacted myocardium was 2.7:1.Ade novo heterozygous variant c.1907G>A(p.Arg636His)in exon 9 was identified in this patient.Patient 2 was a 13-year-old boy who had clinical phenotypes identical to those of Patient 1;the ratio of noncompacted-to-compacted myocardium was 3.2:1 in this patient.WES revealed ade novo heterozygous variant c.1909A>G(p.Ser637Gly)in exon 9.Both variants were previously characterized as pathogenic,and our study classified them as pathogenic variants based on the ACMG guidelines.Interpretation:We found that two patients with LVNC had variants inRBM20.Our results extended the clinical spectrum of the twoRBM20 variants and illustrated that the same variant inRBM20 can cause DCM,with or without the LVNC phenotype.

4SCAR-GD2-modified T-cell therapy in neuroblastoma withamplification: A case report with over 4-year follow-up data

Introduction: Neuroblastoma (NB) is the most common extracranial solid tumor among children. The 5-year event-free survival rate for high-risk (HR) NB is still poor, especially for patients with advanced NB withMYCN gene amplification. Chimeric antigen receptor T (CAR-T) cell therapy is a new treatment for HR-NB.Case presentation: A 55-month-old boy with stage IV HR-NB received 4th-generation CAR-T cells that target disialoganglioside GD2, as consolidation maintenance treatment after intensive chemotherapy, surgery, and autologous stem-cell transplantation. As of February 2019, his CAR-T follow-up time was 37.5 months, indicating prolonged survival. Cranial MRI and ultrasound showed no mass;123I-metaiodobenzylguanidine (123I-MIBG) scan was negative.Conclusion: GD2-CAR-T cells may be an effective treatment option for NB patients withMYCN amplification.

Acute myeloid leukemia following a primary mediastinal germ cell tumor

Introduction:There is a known association between primary mediastinal germ cell tumor(PMGCT)and hematologic malignancy that is not linked to treatment.They are exceptionally rare entities with a low morbidity and a poor prognosis.Case presentation:An 11-year-old boy presented with an anterior mediastinal mass diagnosed as a malignant germ cell tumor on the basis of an excisional biopsy.He was found to have acute myeloid leukemia(AML)two years after the chemotherapy for his germ cell tumor.The clinical course was very aggressive with a survival time of only 1 week after diagnosis of AML associated with PMGCT.Conclusion:AML associated with PMGCT needs to be diagnosed correctly.Relevant examinations should be carried out in patients with PMGCTs during and after chemotherapy,and long-term follow-up is still necessary to reduce the risk of morbidity and mortality.