Shanghai Children's Medical Center Research Articles

Analysis of immunity markers related to nosocomial infection in children with sepsis

Objective: To investigate the immunity markers related to nosocomial infection in children with sepsis. Methods: A retrospective study including 155 cases diagnosed as sepsis from September 2015 to June 2020 in children's intensive care unit (PICU) of Shanghai Children's Medical Center was conducted. According to the presence of nosocomial infection occurred in PICU, septic children were divided into two groups: no nosocomial infection and nosocomial infection group. The differences about helper T-cells 1 and 2 cytokines, T cells subgroup absolute count, the proportion of CD14+ human leukocyte antigen DR (CD14+HLA-DR), the proportion of regulatory T cells, pediatric risk of mortality Ⅲ (PRISM-Ⅲ), the treatment and outcome between the two groups were compared. Through propensity score matching (PSM), the disease severity and treatment of the two groups were matched to analyze the differences between the above indicators. Chi-square test or U test was used for comparison between groups. Receiver operating characteristic (ROC) curve was used to predict the occurrence of nosocomial infection. Results: There were 104 cases in no nosocomial infection group and 51 cases in nosocomial infection group. The first PICU-acquired infections occurred at (12±7) days after PICU admission. The most common PICU-acquired infections were pneumonia (26 cases, 51.0%) and bloodstream infections (15 cases, 29.4%). PRISM-Ⅲ of nosocomial infection group was significantly higher than that in no nosocomial infection group (8 (0-31) vs. 4 (0-17), Z=3 913.00, P<0.01).The proportion of using vasoactive drugs and invasive mechanical ventilation of nosocomial infection group was significantly higher (35.3% (18/51) vs. 10.6% (11/104), χ²=13.77, P<0.01; 86.3% (44/51) vs. 38.5% (40/104), χ²=31.51, P<0.01).The PICU length of stay of nosocomial infection group was significantly longer (20 (3-94) vs.7 (2-41) days, Z=4 585.50, P<0.01). The mortality of the nosocomial infection group was significantly higher than that of the group without nosocomial infection (29.4% (15/51) vs. 6.7% (7/104), χ²=14.45, P<0.01). Interleukin-6 and interleukin-10 of the nosocomial infection group were significantly higher than that in no nosocomial infection group (37.83 (2.23-7 209.99) vs. 13.45 (0.80~50 580.64) ng/L, Z=3 390.50, P=0.01; 10.42 (1.11-6 052.21) vs.4.10 (0.16-409.28) ng/L, Z=3 212.00, P=0.03). CD4+/CD8+ and the percentage of CD14+HLA-DR were significantly lower in the nosocomial infection group compared with the no nosocomial infection group (1.16 (0.44-4.96) vs. 1.61 (0.15-6.37), Z=1 955.00, P=0.01; 0.48 (0.08-0.99) vs. 0.67 (0.09-0.98), Z=1 915.50, P<0.01). After PSM, the percentage of CD14+HLA-DR of nosocomial infection group was significantly lower than that in no nosocomial infection group (0.44 (0.08-0.99) vs. 0.64 (0.09-0.98), Z=758.00, P=0.02). The ROC curve analysis of the percentage of CD14+HLA-DR in predicting nosocomial infection showed that the area under the curve was 0.642, the cut-off value was 0.39, and the 95%CI was 0.528-0.755. Conclusion: The level of the percentage of CD14+HLA-DR maybe is related to the occurrence of nosocomial infection in children with sepsis.

Preliminary practice of multidisciplinary cooperative vaccination management model for pediatric patients with hematological and oncological diseases

Objective: To preliminarily establish the multidisciplinary cooperative vaccination management model for pediatric patients with hematological and oncological diseases, and to explore its feasibility. Methods: In this prospective study a total of 150 children with hematological and oncological diseases visited immunization clinic of Shanghai Children's Medical Center from March 2017 to August 2018 were enrolled in this study. After establishing the multidisciplinary team, designing vaccination plan, staff training, implementation and quality control, a multidisciplinary immunization clinic was set up and the vaccination plan were implemented. The implementation rate of vaccination immunization, the HBsAb level and serum hepatitis B surface antibody (HBsAb) level before and after treatment, the HBsAb level and serum immunoglobulin G antibody (IgG) levels of measles, mumps, rubella (MMR) before and 6 months after immunization, the vaccine-related adverse reactions were assessed prospectively. Chi-square test or Fisher exact test was used to compare the differences of antibody level. Results: A total of 124 cases had been vaccinated as planned, with a coverage rate of 82.7%. Among these cases, the difference of HBsAb positive rate before and after treatment was significant (62.9% (78/124) vs.13.7% (17/124), χ²= 63.489, P<0.01). In 64 cases that completed three doses of hepatitis B immunization, there was a significant difference in HBsAb positive rate before and 6 months after immunization (6.3% (4/64) vs. 98.4% (63/64), P<0.01). In 40 cases that completed MMR immunization, the IgG antibody positive rate for measles (22.5% (9/40) vs. 82.5% (33/40), χ²=31.746,P<0.01), mumps (22.5% (9/40) vs.82.5% (33/40), χ²=28.872,P<0.01), rubella (25.0% (10/40) vs.62.5% (25/40), χ²=11.429, P<0.01) before and 6 months after immunization were significantly different. Of the 421 doses of immunization, 25 (5.9%) doses reported controlled systemic or local adverse event. Conclusions: The immunization of pediatric patients with hematological and oncological diseases is of great importance. The newly-developed multidisciplinary cooperation immunization model for Chinese children with hematological and oncological diseases is feasible, and the immunization protocol is safe and has a certain effect.

Adequate asparaginase is important to prevent central nervous system and testicular relapse of pediatric Philadelphia chromosome‐negative B‐cell acute lymphoblastic leukemia

Asparaginase (Asp) is one of the most important drugs for treating acute lymphoblastic leukemia (ALL). However, off-protocol Asp administration (OPAA) or hypersensitivity may disturb its pharmacokinetic profile. In this retrospective study, we sought to determine whether OPAA and hypersensitivity to Escherichia coli asparaginase (E. coli Asp) impaired extramedullary relapse prevention in a pediatric ALL cohort treated according to SCMC-ALL-2005 protocol from 2005 to 2014 at the Shanghai Children's Medical Center (SCMC). In total, 676 patients were enrolled in this study, including 369 with OPAA and 60 exhibiting hypersensitivity to E. coli Asp. At the end of the most recent follow-up, 58 patients had extramedullary relapse. The 5-year cumulative extramedullary relapse incidence in patients with OPAA was 11.01%, whereas that in patients without OPAA was 5.28% (P=.0036). Moreover, the 5-year cumulative extramedullary relapse incidence in patients that exhibited hypersensitivity to E. coli Asp was 16.48%, whereas that in patients without hypersensitivity was 7.59% (P=.0195). Concerning the relapse site, OPAA not only increased central nervous system (CNS) relapse but testicular relapse as well. Based on Fine and Gray multivariate analysis, OPAA and hypersensitivity to Asp were independent risk factors for extramedullary relapse. In conclusion, to prevent extramedullary relapse of ALL, adequate duration to administrate Asp was more important than the total dosage, and more attention should be paid to Asp inadequate due to hypersensitivity. This article is protected by copyright. All rights reserved.

Real-World Verification of Artificial Intelligence Algorithm-Assisted Auscultation of Breath Sounds in Children

Objective: Lung auscultation plays an important role in the diagnosis of pulmonary diseases in children. The objective of this study was to evaluate the use of an artificial intelligence (AI) algorithm for the detection of breath sounds in a real clinical environment among children with pulmonary diseases.Method: The auscultations of breath sounds were collected in the respiratory department of Shanghai Children's Medical Center (SCMC) by using an electronic stethoscope. The discrimination results for all chest locations with respect to a gold standard (GS) established by 2 experienced pediatric pulmonologists from SCMC and 6 general pediatricians were recorded. The accuracy, sensitivity, specificity, precision, and F1-score of the AI algorithm and general pediatricians with respect to the GS were evaluated. Meanwhile, the performance of the AI algorithm for different patient ages and recording locations was evaluated.Result: A total of 112 hospitalized children with pulmonary diseases were recruited for the study from May to December 2019. A total of 672 breath sounds were collected, and 627 (93.3%) breath sounds, including 159 crackles (23.1%), 264 wheeze (38.4%), and 264 normal breath sounds (38.4%), were fully analyzed by the AI algorithm. The accuracy of the detection of adventitious breath sounds by the AI algorithm and general pediatricians with respect to the GS were 77.7% and 59.9% (p < 0.001), respectively. The sensitivity, specificity, and F1-score in the detection of crackles and wheeze from the AI algorithm were higher than those from the general pediatricians (crackles 81.1 vs. 47.8%, 94.1 vs. 77.1%, and 80.9 vs. 42.74%, respectively; wheeze 86.4 vs. 82.2%, 83.0 vs. 72.1%, and 80.9 vs. 72.5%, respectively; p < 0.001). Performance varied according to the age of the patient, with patients younger than 12 months yielding the highest accuracy (81.3%, p < 0.001) among the age groups.Conclusion: In a real clinical environment, children's breath sounds were collected and transmitted remotely by an electronic stethoscope; these breath sounds could be recognized by both pediatricians and an AI algorithm. The ability of the AI algorithm to analyze adventitious breath sounds was better than that of the general pediatricians.

Effects of repairing ventricular septal defects with right vertical infra-axillary mini-incision on lung function and postoperative analgosedation.

The present study aimed to assess the effects of repairing ventricular septal defects (VSDs) with right vertical infra-axillary mini-incision (RVAI). A total of 116 patients with VSDs were prospectively enrolled and underwent cardiac surgery between June 2017 and December 2018 at the cardiac intensive care unit of Shanghai Children's Medical Center (Shanghai, China). Of these, 58 patients underwent the RVAI procedure and 58 patients matched 1:1 underwent the standard median sternotomy incision (MSI) procedure and were designated as the control group. The demographic data and clinical outcomes intra- and postoperatively were compared. A bedside lung ultrasound was performed to evaluate the degree of lung injury and the number of B-lines was quantified and compared between the two groups. The sedation and analgesia levels were also assessed after the operation. No significant difference was identified between the two groups regarding the overall cardiopulmonary bypass or aortic cross-clamp time. All patients were extubated within 8 h. The RVAI group had shorter incision lengths (median, 4.6 cm) and less drainage (median, 15 ml) than the MSI group. Furthermore, compared to the MSI group, the RVAI group had a significantly higher number of B-lines in the right lung regions immediately after surgery and at 12 h postsurgery (24.1 and 5.2%, respectively) but eventually exhibited no differences at 24 and 36 h postsurgery; by contrast, there were no differences in the left lung regions. The bedside bispectral index score and the Face, Legs, Activity, Cry, Consolability scale score exhibited no significant differences after the operation. In conclusion, the RVAI procedure appears to be a safe alternative for repairing VSDs in addition to satisfactory cosmetic results and the incision does not interfere with postoperative analgosedation.

Risk Factors of Venoarterial Extracorporeal Membrane Oxygenation-Related Intracranial Hemorrhage in Children with Congenital Heart Disease.

To analyze the risk factors for intracranial hemorrhage (ICH) in congenital heart disease (CHD) patients supported with venoarterial extracorporeal membrane oxygenation (VA-ECMO). We performed a retrospective analysis of VA ECMO patients after open heart surgery in Shanghai Children's Medical Center from February 2017 to December 2018, with a total of 50 patients: 14 patients in the ICH group and 36 patients in the control group. Clinical data were analyzed and compared between groups to search for risk factors for ICH. The overall incidence of ICH was 28% (14/50). The in-hospital mortality rate of the ICH group was 57.1% (8/14) vs. 58.3% (21/36) in the control group. The proportion of neonates in the ICH group was 64.3% (9/14) vs. 25% in the control group (9/36) (p = 0.009), and the ICH incidence in extracorporeal cardiopulmonary resuscitation (ECPR) patients was 64.3% (9/14) vs. 13.9% (5/36) (p = 0.000). The percentage of selective cerebral perfusion in the ICH group was 64.3% (9/14) vs. 16.7% (6/36) (p = 0.001) in the control group, and the maximum procalcitonin (PCT) was 43.70 ± 30.48 ng/ml in the ICH group versus 26.92 ± 23.28 ng/ml (p = 0.050) in the control group. Multivariate analysis showed that neonates (odds ratio [OR] = 6.47 [1.09-38.46]), ECPR use (OR = 7.48 [1.26-44.41]), and maximum PCT values (OR = 1.04 [1.001-1.070]) were independent risk factors for ICH. The probability of ICH remains high in children supported with VA-ECMO after cardiac surgery. Neonatal patients, ECPR use, and PCT peak values are independent risk factors for ICH.

Nutrition risk profile of 62 408 inpatients based on electronic health records in a tertiary children's hospital

ObjectivesThis study aimed to evaluate the nutrition risk profile of hospitalized children with electronic health record–based nutrition risk screening. Additionally, this study analyzed the association between high nutrition risk and clinical outcomes. MethodsChildren discharged from Shanghai Children's Medical Center between 2017 and 2018 were enrolled and nutritionally screened. Nutrition risk scores using the Screening Tool for Assessment of Malnutrition in Pediatrics (STAMP), length of stay (LOS), and costs of hospitalization were recorded. Enrolled patients were categorized into two groups: the low and medium nutrition risk (LMNR) group, with scores ranging from 0 to 3, and the high nutrition risk (HNR) group, with scores ≥4. ResultsOut of 62 408 subjects, 17.4% were at HNR. Patients with congenital heart diseases (83.9%), hematology-oncology diseases (26.0%) and gastroenterological diseases (21.4%) were affected most. Infants had the highest HNR rates (35.5%) of any age group. Surgical patients (20.7%) had a higher rate of HNR than non-surgical patients (9.5%). The HNR group had longer LOS (10.0 d versus 3.0 d, P < 0.001), higher total hospital costs (53 680.1 Chinese yuan [CNY] versus 8810.1 CNY, P < 0.001), and higher costs of antibiotics (441.0 CNY versus 0.0 CNY, P < 0.001) compared to the LMNR group. As STAMP score values increased, growing LOS and costs of hospitalization, medications, and antibiotics were observed. ConclusionsA high prevalence of HNR was found in patients of Shanghai Children's Medical Center. Surgeries, specific disease, and infancy were important HNR risk factors. HNR scores using STAMP might predict prolonged LOS and higher medical costs.

Artificial intelligence-assisted auscultation in detecting congenital heart disease.

Computer-assisted auscultation has become available to assist clinicians with physical examinations to detect congenital heart disease (CHD). However, its accuracy and effectiveness remain to be evaluated. This study seeks to evaluate the accuracy of auscultations of abnormal heart sounds of an artificial intelligence-assisted auscultation (AI-AA) platform we create. Initially, 1397 patients with CHD were enrolled in the study. The samples of their heart sounds were recorded and uploaded to the platform using a digital stethoscope. By the platform, both remote auscultation by a team of experienced cardiologists from Shanghai Children's Medical Center and automatic auscultation of the heart sound samples were conducted. Samples of 35 patients were deemed unsuitable for the analysis; therefore, the remaining samples from 1362 patients (mean age-2.4 ± 3.1 years and 46% female) were analysed. Sensitivity, specificity, and accuracy were calculated for remote auscultation compared to experts' face-to-face auscultation and for artificial intelligence automatic auscultation compared to experts' face-to-face auscultation. Kappa coefficients were measured. Compared to face-to-face auscultation, remote auscultation detected abnormal heart sound with 98% sensitivity, 91% specificity, 97% accuracy, and kappa coefficient 0.87. AI-AA demonstrated 97% sensitivity, 89% specificity, 96% accuracy, and kappa coefficient 0.84. The remote auscultations and automatic auscultations, using the AI-AA platform, reported high auscultation accuracy in detecting abnormal heart sound and showed excellent concordance to experts' face-to-face auscultation. Hence, the platform may provide a feasible way to screen and detect CHD.

Role of gut microbiota in children with allergic rhinitis with high serum total IgE level

Objective:To study the role of gut microbiota in children with allergic rhinitis with high serum total IgE level. Method:A total of 17 cases of children in Shanghai Children's Medical Center of Shanghai Jiao Tong University School of Medicine, who suffered from perennial allergic rhinitis of grade 5-6, were enrolled in this study. Baseline information were collected from all participants. Peripheral blood was collected to test the level of serum total IgE and specific IgE. Fecal samples were collected for bacterial DNA extraction and sequenced by 16S rDNA high-throughput sequencing. R, Mother and LEfSe softwares were used for diversity analysis, relative abundance calculation and differential species detection. Result:Twenty-three fecal samples were collected in total, including thirteen in attack period（attack group） and ten in control period（control group）. In the attack group, six cases were serum total IgE positive（positive group） and seven were negative（negative group）. Compared with the control group, there was no significant difference in either Alpha diversity or Beta diversity of Weighted Unifrac in the attack group（P>0.05）. The relative abundance of odoribacteraceae and odoribacter were significantly increased in the attack group（LDA score>2）. The relative abundance of Porphyromonadaceae in positive group were significantly lower than that in negative group, while family Dethiosulfovibrionaceae genus Pyramidobacter was definitely higher on the contrast（LDA score>2）. Conclusion:Children with allergic rhinitis have different characteristics of intestinal flora during the attack and control period. Gut microbiota is associated with high serum total IgE level in children with allergic rhinitis. Specific microbial alterations play a potential role in disease pathophysiology.

Clinical characteristics of connective tissue disease associated interstitial lung disease in children

Objective: To elucidate the clinical features of connective tissue disease associated interstitial lung disease (CTD-ILD) in children. Methods: A total of 24 children diagnosed with CTD-ILD and treated in Department of Rheumatology and Immunology, Shanghai Children's Medical Center from January 2010 to December 2019 were included in the study. Their medical data including clinical features, lab test, imaging, pulmonary function test, treatment and outcome were analyzed statistically. Results: In these 24 patients, 4 were males and 20 females. Their main clinical presentations were cough (10/24, 42%), shortness of breath (10/24, 42%), tachycardia in quiet state (8/24, 33%), fatigue with activity (7/24, 29%), and fever (6/24, 25%). The main abnormal physical examination findings were moist rales (4/24, 17%) and acropachy (2/24, 8%). There were various abnormal findings in the patients' lab test. All the patients (100%) had pulmonary interstitial changes on chest CT. Eight patients had spirometry test, and all (100%) showed decreased diffusion capacity. After immunosuppressive treatment, 15 cases (63%) improved, 4 cases (17%) gave up or died, while 5 cases (21%) had no significant improvement on the imaging examination. Conclusions: The onset of pediatric CTD-ILD could be insidious. Early diagnosis and aggressive treatment may change the prognosis, but are both difficult and need further studies.

Prediction of Fluid Responsiveness by Stroke Volume Variation in Children Undergoing Fontan Operation.

Background Fontan operation is a palliative medical procedure performed on children with single-ventricle defects. As postoperative success of the procedure largely depends on the preload volume, it is necessary to maintain an appropriate pressure gradient between the systemic vein and the left atrium to ensure the effective volume of systemic circulation. However, there is a lack of effective indexes to evaluate fluid responsiveness in Fontan patients. Stroke volume variation (SVV) is a dynamic hemodynamic parameter based on cardiopulmonary interaction in mechanical ventilation. This study is aimed at validating the sensitivity and specificity of SVV and central venous pressure (CVP) in assessing the fluid responsiveness of Fontan patients. Method Sixty-four children with single ventricle who underwent modified Fontan operation between May 2018 and January 2020 were included in this study. Patients were administered 10 ml·kg−1 albumin for fluid challenge within 10 min after cardiopulmonary bypass. Before and after fluid challenge, the invasive arterial pressure module was connected to MostCare™ equipment to collect the cardiac index (CI) and SVV dynamically in a time window of 30 s at a frequency of 1000 Hz. According to the range of CI change, patients with ΔCI ≥ 15% were classified into the responder (R) group and those with ΔCI < 15% into the nonresponder (NR) group. Using SVV and CVP as indicators, the receiver operating characteristic (ROC) curve of the patients was established, and the area under curve (AUC), diagnostic threshold, sensitivity, and specificity were calculated. Results The SVV values were 16.28% (25th and 75th percentiles 14.17%-19.24%) and 13.68% (25th and 75th percentiles 12.90%-15.89%) before and after fluid challenge treatment in responders, respectively, and the values were 18.60 ± 1.83 mmHg before and 20.20 ± 2.39 mmHg for CVP after treatment. The AUC of SVV was 0.74 (95% confidence interval (CI) 0.54-0.94, P < 0.05), and the cutoff value was 16%, offering a sensitivity of 50% and a specificity of 91.7%. Meanwhile, the AUC of CVP was 0.70 (95% CI 0.50-0.92, P > 0.05), and the cutoff value was 19.5 mmHg, offering a sensitivity of 58% and a specificity of 76%. Conclusion SVV exhibited a good predictive value for fluid responsiveness in pediatric Fontan patients. Appropriate fluid therapy according to SVV could improve the cardiac function of such patients. Trial registration. This study was registered in Chinese Clinical Trail Registry on Jan 26, 2018. Registration number is ChiCTR1800014654. Registry URL is http://www.chictr.org.cn/showproj.aspx?proj=25019. This observational prospective study was approved by the Local Ethics Committee of Shanghai Children's Medical Center affiliated to Shanghai Jiao Tong University (SCMCIRB-K2017035).

Distinct Genomic Landscape of Chinese Pediatric Acute Myeloid Leukemia

Although comprehensive genomic studies have revealed key genomic aberrations in pediatric acute myeloid leukemia (AML), knowledge about Chinese patients remains lacking. Here we report the genomic landscape of Chinese pediatric AML by analyzing the sequence mutations and fusions from transcriptome sequencing (RNA-seq) of 292 cases diagnosed through 2009 to 2018 in Shanghai Children's Medical Center. Informed consents were obtained from parents for all patients. A total of 1831 non-synonymous mutations that were predicted somatic and/or associated to pediatric cancer were identified in 972 genes, including 1597 single nucleotide variants (SNV), 210 insertion/deletion (indels) and 24 internal tandem duplications (ITD), with a median of 6 mutations per case (ranging 0 to 15). Among these abnormalities, 7 aberrations occurred in more than 5% of cases in current cohort, including mutations in KIT (n=54, 18.5%), FLT3 (n=46, 15.8%), NRAS (n=28, 9.6%), CEBPA (n=23, 7.9%), ASXL2 (n=20, 6.8%), KRAS (n=16, 5.5%) and CSF3R (n=15, 5.1%). 444 potential driver variations were identified affecting 66 genes by a combined strategy of mutation pathogenicity and hotspot analysis. Each patient carried a median of one driver mutations per case (ranging 0 to 7). In addition, RNA-seq identified 227 fusions involving 99 genes in 203 out of 292 patients (69.5%), and CBL exon8/9 deletion in 12 patients (4.1%). The most prevalent fusions detected in current cohort included RUNX1-RUNX1T1 (n=82, 28.1%), KMT2A rearrangements (n=45, 15.4%) and NUP98 rearrangements (n=17, 5.8%). Furthermore, novel gene rearrangements were identified in current study, including PTPRA-FUS, ZEB2-ATIC, MSI2-UBE3C (n=1 each). Distinct genomic aberration profile was revealed while comparing our results to the mutation profile characterized in Children's Oncology Group (COG)-National Cancer Institute (NCI) TARGET AML initiative representing the Western pediatric AML cohort. A total of 16 recurrently mutated genes were identified with significantly (two-sided fisher exact test) different mutation frequency. Among these, 7 genes mutated more frequently in Chinese patients, including KIT (18.5% vs 12.8% in Chinese and Western cohort, respectively. p=0.027), ASXL2 (6.8% vs 3.6%, p=0.043), CSF3R (5.1% vs 2.4%, p=0.044), JAK2 (3.4% vs 0.0%, p&amp;lt;0.001), DNM2 (2.7% vs 0.0%, p&amp;lt;0.001), KDM6A (2.1% vs 0.0%, p&amp;lt;0.001) and KMT2C (1.7% vs 0.0%, p=0.003). On the other hand, mutations in FLT3 (15.8% vs 33.0%, p&amp;lt;0.001), NRAS (9.6 vs 30.9%, p&amp;lt;0.001), KRAS (5.5% vs 12.8%, p&amp;lt;0.001), WT1 (2.4% vs 13.6%, p&amp;lt;0.001), NPM1 (2.4% vs 10.3%, p&amp;lt;0.001), PTPN11 (3.8% vs 8.1%, p=0.016), TET2 (1.0% vs 5.2%, p=0.001), CBL sequence mutation (0.0% vs 3.0%, p&amp;lt;0.001) and IKZF1 (0.3% vs 2.7%, p=0.018) were occurred less frequently in Chinese patients. Notably, the RAS signaling pathway as a whole was significantly less frequently mutated in Chinese patients (35.6% vs 71.0%, p&amp;lt;0.001). Furthermore, distinct associations between mutations and FAB subtypes were also observed. For example, NF1 mutations were significantly enriched with subtype M5 in Chinese patients (p=0.003), which was previously reported as co-mutated with CBFB-MYH11 fusion with associated with subtype M4. Survival analysis revealed key genomic aberrations associated with patient prognosis. Variants significantly (log-rank test) associated with better event free survival rate included mutations in CEBPA (p=0.023), NPM1 (p=0.026) and GATA2 (p=0.016). On the other hand, CBFA2T3-GLIS2 (p=0.028), nucleoporin gene family related fusions (including NUP98, NUP214 and NUP153, p&amp;lt;0.001), FUS related fusions (p=0.030), mutations in RUNX1 (p&amp;lt;0.001) and FLT3 (p=0.003) were associated with worse prognosis. A revised risk stratification model was proposed based on these associations observed. Characterized a first comprehensive genomic landscape of Chinese pediatric AML, our results reveal a distinct mutation profile as compared to the Western cohort, in terms of both mutation frequency and patterns of mutation co-occurrence. These findings further reveal the complexity of pediatric AML and highlight the importance of tailored risk stratification for Chinese patients in clinical management. Disclosures No relevant conflicts of interest to declare.

Efficacy and safety of implantable cardioverter-defibrillator implantation in pediatric tachycardia cases

Objective: To analyze the indication, efficacy and complications of implantable cardioverter-defibrillator (ICD) implantation in children with severe tachycardia. Methods: The retrospective study collected the clinical data of 6 patients who accepted ICD implantation in Shanghai Children's Medical Center from January 2009 to January 2020. The etiologies of tachycardia, procedure of the ICD implantation and the operation associated complications were analyzed. Results: The 6 patients aged from 6 years and 5 months to 16 years and 2 months, and their weight were from 15.4 kg to 49.8 kg. Three patients were diagnosed with long QT syndrome, and the remaining three with catecholaminergic polymorphic ventricular tachycardia, hypertrophic cardiomyopathy and lethal cardiac channelopathy, respectively. All the patients suffered from drug-resistant ventricular tachycardia or ventricular vibration before the operation. After the ICD implantation, 3 patients had electric storm, which was alleviated after analgesics-sedatives treatment with chlorpromazine, dexmedetomidine or midazolam combined with fentanyl, as well as reset of the ICD parameters and support from psychological consultation. The other 3 patients did not undergo any complications as the above comprehensive strategies were given after the operation prophylactically. All patients continued anti-arrhythmic medicine after the operation and all survived at the end of the follow-up period lasted from 1 month to 7 years. Two patients had ventricular tachycardia (VT) and ventricular vibration, which were successfully recognized and defibrillated by ICD. Conclusions: ICD implantation is safe and effective in children and adolescent patients. The electric storm may happen after operation, which could be prevented by the comprehensive strategies including appropriate ICD parameter-setting, analgesics-sedatives treatment and psychological support.

Efficacy and safety of hepatitis B re-vaccination in children after completion of chemotherapy and(or) hematopoietic stem cell transplantation

Objective: To assess the anti-hepatitis B surface antibody (HBsAb) titers in children after completion of chemotherapy and (or) hematopoietic stem cell transplantation (HSCT), evaluate the efficacy and safety of the current hepatitis B re-vaccination schedule. Methods: A total of 239 children who completed their chemotherapy and (or) HSCT and visited the vaccination clinic of Shanghai Children's Medical Center from March 2017 to July 2019 were enrolled in this study. According to the previous diseases, patients were divided into leukemia group (85 cases), lymphoma group (30 cases), solid tumor group (49 cases) and non-malignant hematological disease group (75 cases). According to the treatment of previous diseases, the patients were divided into chemotherapy group (126 cases), HSCT group (89 cases) and chemotherapy plus HSCT group (24 cases). HBsAb titers were assessed both at the time of diagnosis and after completion of treatment and some children who were HBsAb seronegative were re-vaccinated with 3 doses of hepatitis B vaccine, the vaccine-related adverse reactions were monitored. HBsAb titers were measured again one month after the completion of inoculation. HBsAb titers were defined as negative at levels <10 U/L and positive at ≥ 10 U/L. Chi-square test or Fisher exact test was used to compare the difference of negative conversion rate of hepatitis B antibody between groups, and Logistic regression was used to explore the risk factors of hepatitis B antibody negative conversion. Results: Among 239 patients, there were 143 males and 96 females. At the time of diagnosis, 179 patients (74.9%) were HBsAb seropositive and 60 patients (25.1%) were HBsAb seronegative. After completion of chemotherapy and (or) HSCT, 133 of 179 children with HBsAb seropositive (74.3%) at diagnosis became HBsAb seronegative. Univariate analysis showed significant differences at the negative conversion rates of HBsAb between different disease groups (χ²=10.211，P=0.015), different treatments groups (χ²=14.899，P<0.01) and different HBsAb titers groups before treatment (χ²=32.117，P<0.01). Logistic regression showed that HSCT (chemotherapy group as the reference, odds ratio (OR）=2.999, 95% confidence interval (CI) 1.276-7.050，P=0.012) and HBsAb titers<328.2 U/L before treatment (HBsAb titers≥328.2 U/L group as the reference, OR=6.397， 95% CI3.159-12.954，P<0.01) were risk factors for negative conversion of HBsAb. Among 48 patients whose HBsAb was seronegative after completion of chemotherapy and (or) HSCT and re-vaccinated with hepatitis B vaccine, 47 (97.9%) cases became HBsAb seropositivie. No serious adverse effects or complications were reported among these patients. Conclusions: After completion of chemotherapy and (or) HSCT, most children completely lose their protective humoral immunity against hepatitis B. Hepatitis B re-vaccination schedule can be efficiently and safely applied in those patients.

Periconceptional use of cod liver oil, a vitamin D source, could decrease the risk of CHD in offspring.

To explore if there is association between vitamin D supplementation through cod liver oil ingestion around the periconceptional period and the risk of developing severe CHD in offspring. Furthermore, we would examine the interaction between vitamin D and folic acid supplementation in the association. A case-control study was conducted in Shanghai Children's Medical Center, in which, a total of 262 severe CHD cases versus 262 controls were recruited through June 2016 to December 2017. All children were younger than 2 years. To reduce potential selection bias and to minimise confounding effects, propensity score matching was applied. After propensity score matching, vitamin D supplementation seemed to be associated with decreased odds ratio of severe CHD (odds ratio = 0.666; 95% confidence intervals: 0.449-0.990) in the multivariable conditional logistic analysis. Furthermore, we found an additive interaction between vitamin D and folic acid supplementation (relative excess risk due to interaction = 0.810, 95% confidence intervals: 0.386-1.235) in the association. The results suggested that maternal vitamin D supplementation could decrease the risk of offspring severe CHD; moreover, it could strengthen the protective effect of folic acid. The significance of this study lies in providing epidemiological evidence that vitamin D supplementation around the periconceptional period could be a potential nutritional intervention strategy to meet the challenge of increasing CHD.

Clinical analysis of 26 children with postoperative residual or recurrent fibrosarcoma

Objective: To evaluate the long-term outcomes and prognostic factors of postoperative residual or recurrent fibrosarcoma in children. Methods: Clinical data of 26 patients continually admitted to Shanghai Children's Medical Center between April 2004 and February 2019 with postoperative residual or recurrent fibrosarcoma were analyzed retrospectively. All patients were treated with Shanghai Children's Medical Center-rhabdomyosarcoma-1999 (SCMC-RS-99) regimen and timely radical tumor resection. Before chemotherapy, according to the surgery and imaging examination, 26 patients were divided into 2 groups: postoperative residual group and postoperative recurrent group. Clinical features and long-term follow-up results of patients were summarized. Kaplan-Meier analysis was used to evaluate the overall survival (OS) and event-free survival (EFS) rates, Log-Rank test and Cox proportional hazards models were used for univariate and multivariate prognostic analysis of factors including age (<3 years or 3-18 years old), gender, primary tumor site, postoperative stage, disease status, ETS variant 6 (ETV6) gene and chemotherapy drugs. Results: Among 26 cases, 13 were male and 13 were female, 17 cases were in postoperative residual group and 9 cases were in postoperative recurrent group. Until the last follow-up at December 31, 2019, the median follow-up time was 73 months (ranged from 10 to 188 months).The 5-year OS and EFS rates were (86±7)% and (77±9)%. Univariate analysis showed that, the 5-year EFS rate of postoperative residual group was significantly higher than that of the postoperative recurrent group ((94±5)% vs.(63±16)%,χ(2)=5.106,P=0.024), the 5-year EFS rate of patients <3 years old was significantly higher than that of patients 3-18 years old ((94±5)% vs. (62±17)%, χ(2)=6.507, P=0.011). Gender (χ(2)=0.445), primary tumor site (χ(2)=0.258), postoperative stage (χ(2)=3.046), ETV6 gene (χ(2)=1.496), and whether doxorubicin-containing drugs in chemotherapy (χ(2)=1.692) did not exhibit significant impact on 5-EFS rate (all P>0.05). Age, postoperative stage and disease status were included in COX proportional risk model for multivariate analysis, which showed that age >3 years old (HR=8.95, 95%CI 0.73-109.50, P=0.086), stage Ⅲ-Ⅳ (HR=16.50, 95%CI 0.84-321.40, P=0.065) and postoperative recurrence (HR=10.60, 95%CI 0.84-134.30, P=0.068) had no significant impact on EFS rate. Conclusion: Children with postoperative residual or postoperative recurrent fibrosarcoma still had good remission rate and long-term survival, especially young children without recurrence have a significant survival advantage.

Long-term follow-up of acute lymphoblastic leukemia in young children treated by the SCMC-ALL-2009 protocol

This study evaluated the long-term therapeutic effect and prognostic factors of acute lymphoblastic leukemia (ALL) in 100 young Chinese children (<2 years old) who were enrolled in the Shanghai Children's Medical Center (SCMC)-ALL-2009 study in five pediatric hematological disease centers based on collaboration. The 5-year and 10-year event-free survivals (EFS) were 74.7 ± 3.2% and 73.3 ± 3.4%. The 10-year EFS rates for low risk, intermediate-risk, and high-risk patients were 81.9 ± 5.0%, 71.3 ± 4.3%, and 22.2 ± 13.9%, respectively. Relapse occurred in 19 patients. MRD results on day 55, good or poor response to prednisolone, and age at diagnosis were shown to have important prognostic and therapeutic implications. Compared with the SCMC-ALL-2005 protocol, showed that the 10-year-EFS and 10-year-overall survival of the SCMC-ALL-2009 protocol were better than that of the −2005 protocol. Notably, the intermediate-risk group was improved after the chemotherapy intensity was strengthened.

Differences in the bone marrow histopathology between pediatric acquired aplastic anemia and refractory cytopenia of childhood

Objective: To study the differences in the bone marrow histopathology between acquired aplastic anemia (AAA) in children and refractory cytopenia of childhood (RCC) to facilitate their diagnoses and differential diagnosis. Methods: The clinical data and bone marrow biopsies of the RCC and AAA cases diagnosed from January 2008 to December 2018 in Xinhua Hospital, Shanghai Jiaotong University School of Medicine and Shanghai Children's Medical Center affiliated to Shanghai Jiaotong University School of Medicine were analyzed. Results: A total of 71 AAA and 79 RCC cases were analyzed. There were 52 males and 19 females, age ranged 1.0-15.0 years (median, 8.9 years) in the AAA group, and 53 males and 26 females, age ranged 0.5-16.0 years (median, 5.0 years) in the RCC group. All the biopsy specimens of AAA patients had severe hypocellularity; the cellularity of 88.7% (63/71) specimens was under 5.0%, and 11.3%(8/71) was 5%-24%. None of the AAA specimens showed any dysplastic change. All the biopsy specimens of RCC patients had hypocellularity, including 94.9%(75/79) of the specimens with a cellularity of 5%-50%. All of the RCC specimens showed a patchy distribution of hematopoiesis. A dysplastic change of erythroid cells and micromegakaryocytes was found in 40.5% (32/79) and in 60.8% (48/79) of the RCC cases, respectively. Conclusions: The degree of hypocellularity, the distribution pattern of hematopoiesis, the cell composition and localization of erythroid cell clusters and the appearance of micromegaryocytes could help the diagnosis and differential diagnosis of AAA and RCC.

Clinicopathological characteristics of NTRK-rearranged mesenchymal tumors in childhood

Objective: To investigate the clinical and pathological features of pediatric NTRK-rearranged tumors. Methods: Four NTRK-rearranged soft tissue tumors and one renal tumor at Shanghai Children's Medical Center, Shanghai Jiaotong University and Singapore KK Women's and Children's Hospital from January 2017 to September 2019 were identified. Pan-TRK immunohistochemistry, and the ALK and ETV6 gene break-apart fluorescence in situ hybridizations (FISH) were performed. NTRK gene rearrangement was detected using sequencing-based methods. Results: There were 3 males and 2 females in this study. The patients were between 3 months and 13 years of age. Histologically, the tumors were infiltrative spindle cell tumors with variable accompanying inflammatory cells. Immunohistochemistry showed positive reactivity for pan-TRK in all tumors, with nuclear staining for NTRK3 fusion, and cytoplasmic staining for NTRK1 fusion. The molecular testing revealed NTRK gene fusions (one each of TPM3-NTRK1, ETV6-NTRK3 and DCTN1-NTRK1, and two cases of LMNA-NTRK1). Two patients were receiving larotrectinib. The others were are well without disease, with follow-up durations of 9 to 29 months. Conclusions: NTRK-rearranged mesenchymal tumors from soft tissue sites and kidney are identified. A novel DCTN1-NTRK1 fusion is described. Pan-TRK immunohistochemistry is useful for diagnosis. NTRK-targeted therapy may be an option for unresectable, recurrent or metastatic cases.

Application of penile index in the diagnosis and therapeutic evaluation of concealed penis in children

Objective: To explore the significance of penile index in the diagnosis of concealed penis and the evaluation of therapeutic efficacy. Methods: A retrospective study was conducted on 221 children with phimosis and 113 children with concealed penis aged 6-10, all of whom had undergone circumcision or phalloplasty respectively in Shanghai Children's Medical Center from January 2014 to December 2017. Penile index was measured before and after surgery. The values of phimosis and concealed penis were tested by group t test. Self -control test was performed for values of concealed penis before and after operations. Results: Penile index was 0.78±0.08 in children with phimosis. It was 0.23±0.10 in concealed penis before operation and changed to 0.84±0.11 postoperatively. In children with phimosis and concealed penile, the difference of penile index was statistically significant (P<0.001). The difference of penile index before and after operation was statistically significant (P<0.001) in children with concealed penis. Conclusion: Penile index is an effective index to evaluate the degree of penis exposure.