Shanghai Children's Medical Research Articles

Efficacy of domestic single-hole robotic surgery system in the treatment of pediatric urological diseases

To explore the efficacy of domestic single-hole robotic surgery system in the treatment of pediatric urological diseases. A prospective review of clinical data of children who underwent laparoscopic surgery in the Department of Urology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, was conducted from July to November 2023. All surgeries were performed using the sharp single-port serpentine arm robotic surgery system, with an umbilical access route. All surgeries are performed by the same chief physician. Operative time, intraoperative blood loss, incision size, and postoperative complications were recorded. A total of 12 patients were included, consisting of 8 males and 4 females, aged 8.0-17.0 (13.5±2.7) years. The procedures included 5 pyeloplasties (1 case of bilateral pyeloplasty), with a unilateral operative time [M (Q1, Q3) ]of 180 (145, 200) minutes and a blood loss of 5 (5, 10) ml. Oral mucosa ureteroplasty was performed in 1 patient, taking 3 hours and 52 minutes with a blood loss of 10 ml. Renal cyst decortication was conducted in 1 case in 85 minutes with a blood loss of 20 ml. High ligation of the spermatic vein was conducted in 3 patients, with an average operative time of 97 minutes and no intraoperative blood loss. Bilateral gonadectomy was completed in 80 minutes with a blood loss of 5 ml. Ovarian cystectomy (1 case) was performed in 69 minutes with a blood loss of 5 ml. All surgeries were successfully completed without conversion to open surgery. Except for the oral mucosa ureteroplasty, which required an additional 5 mm auxiliary port, all procedures were performed through a 3 cm umbilical incision. Among the patients who underwent pyeloplasty, 1 case of urinary leak was identified and successfully treated conservatively with adequate drainage over 25 days. Re-stenosis was experienced by 1 patient with a long segment ureteral stricture postoperatively, while no Clavien-Dindo grade≥2 complications were observed in other patients. All umbilical wounds were concealed, and satisfactory postoperative appearances were noted. The domestic single-hole robotic surgery system is effective in treating pediatric urological diseases.

Effects of asparaginase-associated pancreatitis in children with haematological tumours.

Asparaginase-associated pancreatitis (AAP) is a major challenge for continuing asparaginase therapy. We aimed to investigate the acute and long-term complications and survival rates related to first and second AAP episodes in Chinese children with haematological malignancies. We retrospectively analysed clinical data of children with pancreatitis who received asparaginase chemotherapy for acute lymphoblastic leukaemia (ALL), acute mixed cell leukaemia, and non-Hodgkin's lymphoma at Shanghai Children's Medical Center from November 2013 to November 2023. Of the 76 children included in the study, 12 had local complications (15.79%), with no deaths recorded. Systemic complications manifested in 28 patients (36.84%), resulting in 3 deaths (3.95%). Four patients (5.26%) developed long-term complications (chronic pancreatitis or insulin-dependent diabetes mellitus). No significant differences in local or long-term complications were recorded between children in the asparaginase re-exposed (n=39) and non-re-exposed (n=45) groups. Among the re-exposed patients, eight (25.81%) experienced a second attack without fatalities or complications. Survival analysis of intermediate- to high-risk patients revealed a significantly higher event-free survival (EFS) rate for the re-exposed group than for the non-re-exposed group. The second AAP episode's occurrence and severity had no relation to the first AAP episode's severity, and the second AAP episode was significantly less severe than the first (p<0.001). The second AAP episode's occurrence is unrelated to the first AAP episode's severity, and the second AAP episode's severity is significantly lower than that of the first. Further, asparaginase therapy could improve EFS in children with intermediate and high-risk ALL.

Exploring the prevalence and chest CT predictors of Long COVID in children: a comprehensive study from Shanghai and Linyi.

COVID-19 constitutes a pandemic of significant detriment to human health. This study aimed to investigate the prevalence of Long COVID following SARS-CoV-2 infection, analyze the potential predictors of chest CT for the development of Long COVID in children. A cohort of children who visited the respiratory outpatient clinics at Shanghai Children's Medical Center or Linyi Maternal and Child Health Care Hospital from December 2022 to February 2023 and underwent chest CT scans within 1 week was followed up. Data on clinical characteristics, Long COVID symptoms, and chest CT manifestations were collected and analyzed. Multivariate logistic regression models and decision tree models were employed to identify factors associated with Long COVID. A total of 416 children were included in the study. Among 277 children who completed the follow-up, the prevalence of Long COVID was 23.1%. Chronic cough, fatigue, brain fog, and post-exertional malaise were the most commonly reported symptoms. In the decision tree model for Long COVID, the presence of increased vascular markings, the absence of normal CT findings, and younger age were identified as predictors associated with a higher likelihood of developing Long COVID in children. However, no significant correlation was found between chest CT abnormality and the occurrence of Long COVID. Long COVID in children presents a complex challenge with a significant prevalence rate of 23.1%. Chest CT scans of children post-SARS-CoV-2 infection, identified as abnormal with increased vascular markings, indicate a higher risk of developing Long COVID.

Comparison of the effects of child-centered playful companionship and pharmacological sedation in alleviating preoperative anxiety in preschool children

Objective: To investigate the effectiveness of child-centered playful companionship and sedative medication in alleviating preoperative anxiety in preschool children. Methods: A retrospective analysis was conducted on 3 825 preschool children (3-6 years) who underwent elective surgery at Shanghai Children's Medical Center from April 2021 to March 2022. The children were divided into three groups based on the preoperative anxiolytic intervention: child-centered playful companionship group (n=2 198), pharmacological sedation group (n=1 281), and no intervention group (n=346). The pharmacological sedation group received intranasal dexmedetomidine at 2 μg/kg or oral midazolam syrup at 0.5 mg/kg. The child-centered playful companionship group received care from certified preoperative sedation nurses using a child-centered playful nursing model. The no intervention group did not receive any anti-anxiety measures due to various subjective and objective reasons. Preoperative separation anxiety scores (PSAS), sedation medication usage, and Ramsay sedation scores were recorded for all children. The primary outcome was the success rate of separation based on PSAS scores across different anxiolytic intervention groups, while the secondary outcome was the Ramsay sedation score. Results: The child-centered playful companionship group included 1 462 boys and 736 girls, with a median age [M (Q1, Q3)]of 59 (49, 69) months. The pharmacological sedation group included 824 boys and 457 girls, with a median age of 52 (42, 61) months; and the no intervention group included 212 boys and 134 girls, with a median age of 57 (48, 69) months. The success rate of separation in the child-centered playful companionship group was 95.6% (2 102/2 198), and in the pharmacological sedation group was 93.8% (1 202/1 281), both significantly higher than the 43.6% (151/346) of the no intervention group (all P<0.05). Among the 1 281 children in the pharmacological sedation group, 785 received oral midazolam and 496 received intranasal dexmedetomidine. Compared to the intranasal dexmedetomidine group, the oral midazolam group was younger, had a lower body weight and a higher proportion of American Society of Anesthesiologists (ASA) class Ⅲ (all P<0.05). The success rate of separation was 93.4% (733/785) in the oral midazolam group and 94.6% (469/496) in the intranasal dexmedetomidine group, with no statistically significant difference (P=0.392). The Ramsay sedation score was 2 (2, 2) in the intranasal dexmedetomidine group, better than the 2 (2, 2) of the oral midazolam group (P=0.024). Conclusion: Both child-centered playful companionship and pharmacological sedation effectively alleviate preoperative anxiety in preschool children.

Establishment of Cephalic Index by Computed Tomography in Sampled Chinese Children.

Cephalic Index (CI), the ratio of head width to length, is one of the indexes reflecting cranial morphological characteristics. Current norms were established by European and American countries. The purpose of the study was to study anthropometry of cranial parameters using computed tomography scans to establish the CI of the sampled Chinese Children. The cross-sectional study was carried out on patients of age younger than 14 years old at Shanghai Children's Medical Center. The measurement of maximum cranial breadth and maximum cranial length were taken on a computed tomography scan machine and recorded for analysis. Cephalic Index was calculated for each age and sex group and compared with previously established norms. Five hundred eighteen patients met the inclusion criteria, including 301 males and 217 females. The means for boys and girls were 87.1 (SD: 4.3) and 85.8 (SD: 4.3), respectively. There was a significant difference between boys and girls (P < 0.01). Cephalic Index in different ages and on applying the 1-way analysis of variance association was statistically insignificant (P = 0.19). Chinese head shape was brachycephalic. A statistically significant correlation was seen between the CI and sex, while not age.

Clinical analysis of 18 children with aggressive mature B-cell lymphoma after liver transplantation

Objective: To summarize the clinical characteristics, prognostic factors and treatment outcomes of childhood aggressive mature B-cell lymphoma after liver transplantation. Methods: This retrospective study included 18 children with newly diagnosed aggressive mature B-cell lymphoma after liver transplantation and treated from June 2018 to June 2022 in the Department of Hematology and Oncology of Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine. Clinical characteristics, treatment and outcomes of patients at last evaluation were analyzed. Overall survival (OS) and event free survival (EFS) rates were calculated by Kaplan-Meier method and Log-Rank analysis was performed to find factors of poor prognosis. Results: Among all 18 patients, there were 6 males and 12 females, and the age of onset was 40 (35, 54) months. The interval from transplant to tumor diagnosis was 21 (17, 35) months and 5 patients had early onset disease (<1 year since transplant). Seventeen patients had abdominal lesions. Diarrhea, vomiting and abdominal masses were the main clinical manifestations. All patients were Epstein-Barr virus (EBV) related posttransplant lymphoproliferative disorders (PTLD). One patient received individualized therapy due to critical sick at diagnosis, and the remaining 17 patients received CP (cyclophosphamide, methylprednisolone plus rituximab) and/or modified EPOCH (prednisone, etoposide, doxorubicin, vincristine, cyclophosphamide plus rituximab) regimens. Of all 18 patients, 15 cases got complete response, 2 cases got partial response, 1 patient died of severe infection. The 2-year OS and EFS rates of 18 patients were (94±5)% and (83±8)%, respectively. None of age, gender or early onset disease had effect on OS and EFS rates in univariate analysis (all P>0.05). Conclusions: The symptoms of PTLD were atypical. Close surveillance of EBV-DNA for patients after liver transplantation was crucial to early stage PTLD diagnosis. CP or modified EPOCH regimen was efficient for pediatric patients with aggressive mature B cell lymphoma after liver transplantation.

Treatment of ornithine transcarbamylase deficiency in a child with glyceryl phenylbutyrate

Glyceryl phenylbutyrate (GPB) serves as a long-term management medication for Ornithine transcarbamylase deficiency (OTCD), effectively controlling hyperammonemia, but there is a lack of experience in using this medicine in China. This article retrospectively analyzes the case of a child diagnosed with OTCD at Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, including a review of related literature. After diagnosis, the patient was treated with GPB, followed by efficacy follow-up and pharmacological monitoring. The 6-year and 6-month-old male patient exhibited poor speech development, disobedience, temper tantrums, and aggressive behavior. Blood ammonia levels peaked at 327 μmol/L; urine organic acid analysis indicated elevated uracil levels; cranial MRI showed extensive abnormal signals in both cerebral hemispheres. Genetic testing revealed de novo mutation in the OTC gene (c.241T>C, p.S81P). Blood ammonia levels were approximately 43, 80, and 56 μmol/L at 1, 2, and 3 months after starting GPB treatment, respectively. During treatment, blood ammonia was well-controlled without drug-related adverse effects. The patient showed improvement in developmental delays, obedience, temperament, and absence of aggressive behavior.

Analysis of 41 cases of non-metastatic Ewing's sarcoma in children

To summarize the clinical characteristics, treatment outcomes, and prognostic factors of children with non-metastatic Ewing's sarcoma (ES). A retrospective analysis was conducted on the clinical data of 41 children with non-metastatic ES diagnosed and treated at the Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine from January 2010 to December 2018. All patients underwent chemotherapy based on the RMS-2009 protocol of the center, and local treatment such as surgery and/or radiotherapy was performed according to risk grouping. The Kaplan-Meier method was used to calculate the overall survival (OS) and event-free survival (EFS) rates. Univariate prognostic analysis was performed using the log-rank test, and multivariate analysis was conducted with Cox regression. Of the 41 children, 21 were male and 20 were female. The median age at diagnosis was 7.7 years (range: 1.2-14.6 years). The median follow-up time for patients with event-free survival was 68.1 months (range: 8.1-151.7 months). As of the last follow-up, 33 patients were in complete remission, and the overall 5-year EFS and OS rates were (78±6)% and (82±6)%, respectively. Univariate analysis by the log-rank test showed that a tumor diameter ≥8 cm, time from diagnosis to start of local treatment ≥16 weeks, and incomplete surgical resection were associated with poor prognosis (P<0.05). Multivariate Cox regression analysis indicated that incomplete surgical resection (HR=8.381, 95%CI: 1.681-41.801, P=0.010) was an independent risk factor for poor prognosis in children with ES. Secondary tumors occurred in 2 cases. A comprehensive treatment strategy incorporating chemotherapy, surgery, and radiotherapy can improve the prognosis of children with ES. Poor prognosis is associated with an initial tumor diameter ≥8 cm, while complete surgical resection and early initiation of local treatment can improve outcomes.

Sex-specific difference in phenotype of Kabuki syndrome type 2 patients: a matched case-control study.

Kabuki syndrome (KS) is a monogenic disorder leading to special facial features, mental retardation, and multiple system malformations. Lysine demethylase 6A, (KDM6A, MIM*300128) is the pathogenic gene of Kabuki syndrome type 2 (KS2, MIM#300867), which accounts for only 5%-8% of KS. Previous studies suggested that female patients with KS2 may have a milder phenotype. We summarized the phenotype and genotype of KS2 patients who were diagnosed in Shanghai Children's Medical Center since July 2017 and conducted a 1:3 matched case-control study according to age and sex to investigate sex-specific differences between patients with and without KS2. There were 12 KS2 cases in this study, and 8 of them matched with 24 controls. The intelligence quotient (IQ) score of the case group was significantly lower than that of the control group (P < 0.001). In addition, both the incidence of intellectual disability (ID) (IQ < 70) and moderate-to-severe ID (IQ < 55) were significantly higher in the case group than those in the control group. No sex-specific difference was found in the incidence of ID or moderate-to-severe ID between the female cases and female controls, whereas there was a significant difference between male cases and male controls. Furthermore, the rate of moderate-to-severe ID and congenital heart disease (CHD) was significantly higher in the male group than that in the female group. Our results showed that a sex-specific difference was exhibited in the clinical phenotypes of KS2 patients. The incidence of CHD was higher in male patients, and mental retardation was significantly impaired. However, the female patients' phenotype was mild.

Factors influencing delayed high-dose methotrexate excretion and its correlation with adverse reactions after treatment in children with malignant hematological tumors.

High-dose methotrexate (HDMTX) is crucial in treating pediatric malignant hematological tumors. However, its use is often complicated by delayed excretion and associated adverse reactions, which can significantly affect treatment outcomes and patient safety. Identifying risk factors is essential for safer, more effective therapy. This study aimed to investigate the influencing factors for delayed excretion and their correlation with adverse reactions in children with malignant hematological tumors after receiving HDMTX chemotherapy. From April to October 2021, the clinical information of children who had undergone HDMTX chemotherapy and had their blood tested for drug concentration was gathered by the Department of Hematology and Oncology at Shanghai Children's Medical Center. Via univariate and multivariate logistic regression, the factors affecting the delayed excretion of HDMTX were examined, and the relationship between delayed excretion and unfavorable effects in children was determined. This study included 99 patients comprising 199 courses of HDMTX. The occurrence rate of HDMTX delayed excretion was 20.1%. Age ≥9 years and a 24-hour methotrexate (MTX) concentration of 64 µmol/L were independent risk factors for delayed MTX excretion according to multivariate logistic regression analysis (P<0.05). Negative side effects, such as fever, infection, mucositis, gastrointestinal response, and decreased platelet count in children with delayed excretion were statistically significant when compared to those of children with normal excretion. White blood cell reduction, hemoglobin levels below 65 g/L, MTX excretion delay, and concomitant etoposide treatment were all independent risk factors for infection in children. To estimate the risk of delayed MTX excretion during HDMTX therapy, patient laboratory data should be scrutinized, especially for patients ≥9 years or those with a 24-hour MTX concentration of greater than 64 µmol/L.

Imaging features and clinical evaluation of pulmonary nodules in children.

With the widespread use of computed tomography (CT), the detection rate of pulmonary nodules in children has gradually increased. Due to the lack of epidemiological evidence and clinical guideline on pulmonary nodule treatment in children, we aimed to provide a reference for the clinical diagnosis and management of pediatirc pulmonary nodules. This retrospective study collected consecutive cases from April 2012 to July 2021 in the Shanghai Children's Medical Center. The sample included children with pulmonary nodules on chest CT scans and met the inclusion criteria. All patients were categorized into tumor and non-tumor groups by pre-CT clinical diagnosis. Nodule characteristics between groups were analyzed. To establish a clinical assessment model for the benign versus malignant pulmonary nodules, patients who have been followed-up for three months were detected and a decision tree model for nodule malignancy prediction was constructed and validated. The sample comprised 1341 patients with an average age of 7.2 ± 4.6 years. More than half of them (51.7%) were diagnosed with malignancies before CT scan. 48.3% were diagnosed with non-tumor diseases or healthy. Compared to non-tumor group, children with tumor were more likely to have multiple nodules in both lungs, with larger size and often be accompanied by osteolytic or mass lesions. Based on the decision tree model, patients' history of malignancies, nodules diameter size≥5mm, and specific nodule distribution (multiple in both lungs, multiple in the right lung or solitary in the upper or middle right lobe) were important potential predictors for malignity. In the validation set, sensitivity, specificity and AUC were 0.855, 0.833 and 0.828 (95%CI: 0.712-0.909), respectively. This study conducted a clinical assessment model to differentiate benignity and malignancy of pediatric pulmonary nodules. We suggested that a nodule's diameter, distribution and patient's history of malignancies are predictable factors in benign or malignant determination.

Long-term outcome of hematopoietic stem cell transplantation in two children with Mucopolysaccharidosis

To explore the long-term efficacy of allogeneic hematopoietic stem cell transplantation (alloHSCT) in patients with Mucopolysaccharidosis (MPS), which has rarely been reported in China. A 18-month-old boy and a 23-month-old girl undergoing alloHSCT for MPS VI and MPS IH Shanghai Children's Medical Center on March 30, 2006 and September 6, 2006 were selected as the study subjects. A busulfan-based myeloablative regimen was used as the conditioning regimen. Peripheral stem cells were respectively collected from a human leucocyte antigen (HLA) matched sibling carrier donor and a HLA 9/10 matched unrelated donor. Both patients were followed up for more than 15 years. The functions of internal organs before and after the transplantation were compared, and child 1 was also compared with his untreated brother and healthy brother. Both children have achieved full donor chimerism after the transplantation, and their enzymatic activities have remained stable. The enzymatic activity of the child 1 was slightly lower than normal but similar to that of his carrier donor, whilst that of the child 2 was normal. Both children have attended schools with good academic performance. Compared with his untreated brother, the respiratory function and hearing of child 1 have significantly improved. However, his orthopedic and cardiac disorders have still remained and required medical intervention. For child 2, her obstructive pulmonary disease was resolved and cognitive development was well preserved after the HSCT. Her heart disease has become stabilized and even improved with time, though her corneal clouding and skeletal malformation still required surgery. MPS patients can sustain long-term and stable enzymatic activities after successful alloHSCT. Compared with untreated patients, their health can be significantly improved, along with considerably prolonged survival, though the long-term efficacy of HSCT for different organs may vary to a certain extent.

Autosomal dominant neurodevelopmental disorders associated with KIF1A gene variants in 6 pediatric patients.

To analyze the clinical and genetic characteristics of children with autosomal dominant neurodevelopmental disorders caused by kinesin family member 1A (KIF1A) gene variation. Clinical and genetic testing data of 6 children with KIF1A gene de novo heterozygous variation diagnosed in Shanghai Children's Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine from the year 2018 to 2020 were retrospectively analyzed. Pathogenic variants were identified based on whole exome sequencing, and verified by Sanger sequencing. Moreover, the effect of variants on three-dimensional structure and stability of protein was analyzed by bioinformatics. Among 6 patients there were 4 males and 2 females, and the age of consultation varied from 7 months to 18 years. All cases had varying degrees of motor developmental delay since childhood, and 4 of them had gait abnormalities or fell easily. In addition, 2 children were accompanied by delayed mental development, epilepsy and abnormal eye development. Genetic tests showed that all 6 cases had heterozygous de novo variations of KIF1A gene, including 4 missense mutations c.296C>T (p.T99M), c.761G>A (p.R254Q), c.326G>T (p.G109V), c.745C>G (p.L249V) and one splicing mutation c.798+1G>A, among which the last three variants have not been previously reported. Bioinformatics analysis showed that G109V and L249V may impair their interaction with the neighboring amino acid residues, thereby impacting protein function and reducing protein stability, and were assessed as "likely pathogenic". Meanwhile, c.798+1G>A may damage an alpha helix in the motor domain of the KIF1A protein, and was assessed as "likely pathogenic". KIF1A-associated neurological diseases are clinically heterogeneous, with motor developmental delay and abnormal gait often being the most common clinical features. The clinical symptoms in T99M carriers are more severe, while those in R254Q carriers are relatively mild.

Vaccination Recommendations and Clinical Characteristics of Children after Allogeneic Hematopoietic Stem Cell Transplantation

To investigate the clinical characteristics, the risk factors related to antibody-negative conversion, and the effectiveness and safety of revaccination in children who underwent allogeneic hematopoietic stem cell transplantation (Allo-HSCT). The clinical characteristics of 516 children after Allo-HSCT who were eligible for revaccination in the Vaccination Evaluation Clinic of Shanghai Children's Medical Center from March 2017 to March 2023 were analyzed. Of the 516 patients enrolled, 464 (89.9%) had started revaccination, with a median time of 2.1 (IQR, 1.8-2.6) years after transplantation and 1.1 (IQR, 0.7-1.5) years after cessation of immunosuppressive therapy. There were 418 cases of hepatitis B surface antibody (HBsAb) seropositive before transplantation, and 339 cases (81.1%) became negative at the time of evaluation after transplantation. The visit time for children with persistently HBsAb seropositive was 1.9 (IQR, 1.3-2.3) years after transplantation, which was shorter than the time for children with HBsAb seronegative (2.2 [IQR, 1.9-2.8] years, P&amp;lt;0.001). HBsAb negative conversion was related to the HBsAb titers pre-transplantation, with a lower proportion of high titers in the negative conversion group (4.7% vs. 17.7%, P&amp;lt;0.001). Both univariate and multivariate analyses suggested that HBsAb seroconversion was statistically related to uncompleted three doses of the hepatitis B vaccine before transplantation, low pre-transplantation antibody titers, and ≥2 years after transplantation. Among 40 patients with HBsAb seronegative who received hepatitis B vaccination, 39 (97.5%) had HBsAb titers converted to seropositive. The immune response rates of measles, mumps, and rubella (MMR) were 96.6% (28/29), 69.0% (20/29,) and 88.5% (23/26), respectively. There were no serious adverse side effects after revaccination.After Allo-HSCT, standard evaluation procedures for revaccination are highly recommended. The immune response rates after hepatitis B and MMR revaccination were highly recommended. No severe adverse side effects were observed.

Genomic Landscape of Pediatric Non-Down's Syndrome Acute Megakaryoblastic Leukemia in China

Acute megakaryoblastic leukemia (AMKL) accounts for 4% to 15% of newly diagnosed pediatric acute myeloid leukemia (AML), and different from Down's syndrome AMKL (DS-AMKL) and non-AMKL, clinical outcomes of non-DS-AMKL are characterized by an inferior prognosis. Although comprehensive genomic studies have revealed key genomic aberrations of non-DS-AMKL in Western cohort, there is still no reports about Chinese patients. Here we report a comprehensive transcriptomic study on 100 Chinese pediatric non-DS-AMKL cases through 2009 to 2022 in Shanghai Children's Medical Center. A total of 133 rearrangements were detected involving 78 patients, including previously reported recurrent fusion events which defining subgroups of AMKL, namely CBFA2T3-GLIS2 (n=20, 20%), NUP98-KDM5A (n=16,16%), rearrangements of HOX cluster genes (HOXr, n=11, 11%), RBM15-MKL1 (n=5, 5%) and MLLr (n=3, 3%). Two new recurrent gene translocations, XPO1-TRNC18 and STAG2 rearrangements (STAG2r) were detected in 5 (5%) and 11 (11%) cases, respectively. Further unsupervised clustering analysis was done with the most variant coding genes defined by standard deviation, the results showed that cases carrying STAG2r and XPO1-TNRC18 fusion exhibited distinguishable gene expression pattern from other subgroups and were clustered together respectively. It suggested these two rearrangements as potential driver genomic alterations in AMKL. By introducing XPO1-TNRC18 fusion and three STAG2 aberrations (STAG2 knock-out, STAG2-GNA12 and STAG2-OCRL) into 32D cell line, we proved these gene alterations promoted cell proliferation and colonies formation, suggesting potential function in tumor transformation. Based on these evidences, we defined XPO1-TNRC18 and STAG2r as two new subgroups of AMKL. We identified 222 nonsynonymous sequency mutations affecting 137 genes totally, including 202 single-nucleotide variants and 20 insertion/deletion, with a median of two mutations for per case (range 0-6). Among driver abnormalities, 7 aberrations occurred in more than 3% of cases in current cohort, including JAK2 (n=15, 15%), MPL (n=13, 13%), PTPN11 (n=7, 7%), NRAS (n=5, 5%), GATA1 (n=4, 4%), CTCF (n=4, 4%) and JAK3 (n=3, 3%). All the mutations could be clustered into 8 pathways, and the most frequently mutated pathways were JAK signaling (30%), transcription regulation (29%) and RAS signaling (14%). Mutation frequency varied across different subgroups. For example, JAK/STAT lesions were enriched in STAG2r subgroup (p&amp;lt;0.05). Distinct genomic aberration profile was revealed while comparing results of this non-DS-AMKL cohort to the mutation profile of non-AMKL cohort which we have published before. CBFA2T3-GLIS2, NUP98-KDM5A, STAG2r, XPO1-TNRC18 and RBM15-MKL1 subgroups were merely detected in AMKL, while driver aberrations like FLT3-ITD, CBFB-MYH1 and so on were not detected in AMKL. For driver mutations, JAK2 (15% vs 3.7%, p&amp;lt;0.0001), MPL (13% vs 0%, p&amp;lt;0.0001 ) and CTCF (4% vs 0%, p=0.007) were detected more frequently in non-DS-AML, while NRAS (5% vs 18.8%, p&amp;lt;0.001), KRAS (2% vs 10.6%, p=0.008), KIT (1% vs 21.6%, p&amp;lt;0.001), CSF3R (1% vs 6.1%, p=0.047), FLT3 (0% vs 22.5%, p&amp;lt;0.001), CEBPA (0% vs 9.8%, p&amp;lt;0.001), AXSL2 (0% vs 8.6%, p&amp;lt;0.001), GATA2 (0% vs 6.1%, p=0.007) and DHX15 (0% vs 4.5%, p=0.038) occurred less frequently in non-DS-AMKL cohort. Survival analysis revealed association between key aberrations and clinical outcomes. Carrying CBFA2T3-GLIS2 (p=0.018), NUP98-KDM5A (p&amp;lt;0.001) and FUS-ERG (p=0.018) was associated with unfavorable prognosis. Driver mutations in JAK2 (p=0.03) and RAS pathway (p=0.01) were associated with shorter overall survival. Among the two new subgroups, the new XPO1-TNRC18 subgroup demonstrated similar clinical outcomes to MLLr cases, with 5-year EFS and OS of 50%, and STAG2r was characterized by a favorable clinical outcome, with 5-year EFS and OS over 75%. As the first comprehensive genomic landscape of Chinese pediatric non-DS-AMKL, our results defined two new subgroups with distinct expression patterns and prognosis characteristics. We further revealed a distinct mutation profile between AMKL and non-AMKL and shed light on association between driver aberrations and clinical outcomes. These findings revealed non-DS-AMKL as a heterogenous disease, and suggested the importance of exploration of risk-stratification and targeted therapy in different mutations driven cases.

One Tube 23 Color Full Spectral Flow Cytometry Panel in Detecting Minimal Residual Disease in Pediatric B-Cell Acute Lymphoblastic Leukemia

Introduction Minimal residual disease (MRD) is a normalized tool for risk stratification in the treatment of pediatric acute lymphoblastic leukemia (ALL) and has been introduced into many standardized chemotherapy regimens. Flow cytometry (FC) plays an important role in the monitoring of MRD. However, FC-MRD can't reliably detect residual leukemic cells below level of 0.01% in real clinical scenarios and some patients with negative MRD relapsed, suggesting the current used set of markers are not sensitive enough or specific enough. Published studies has shown that more markers with more reliable combination of antibodies may help improve the sensitivity and specificity of FC-MRD. Spectral multicolor flow cytometry (SMFC) has shown an advantage over traditional FC that more fluorescent markers could be applied simultaneously and more complex marker combinations could be exploited to distinguish leukemic blasts from normal B cell precursors with high specificity. Here we designed a SMFC-based panel of 26 markers with 23 fluorescent colors in one tube to monitor B-ALL MRD. Method The one-tube 23-color panels was designed according to previously published studies and our clinical experience based on standardized EuroFlow 8-color MRD panel. All the leukemia-associated immunophenotypes (LAIPs) were defined based on its deviation from hematogones. For CD10, CD19, CD22, CD34, CD58, CD73, CD86, CD123, CD200and CD304, the overexpression was considered as LAIP, while the under-expression was considered as LAIP for CD24, CD38, CD45 and CD81. Asynchronous co-expression of CD34 and CD20, CD34 and CD21 were also included. The aberrant cross-lineage expression was taken as LAIP for CD2, CD56, CD65, CD15, CD13, CD33, CD66c, NG2 and CD133. For CD44, under-expression or overexpression can both be considered as LAIP. To verify the effectiveness of the panel, 317 bone marrow samples from 317 patients with B-ALL diagnosed between 2009 to 2014 at the Shanghai Children's Medical Center (SCMC) were included. These samples were collected at day 19 to 283 (median: day 35), with 213 (67.19%) collected at around day 35, which was a regular time point to monitor MRD and to readjust the risk stratification. The results were compared with those of conventional 8-color FC-MRD. Results The limit of blank (LOB), limit of detection (LOD), and lower limit of quantitation (LLOQ) were firstly determined, the results showed reproducible sensitivity up to 0.001% (1-in-10 5) after acquisition of 4.8 million cells for 23-color panel. The 8-color and 23-color MRD panels showed high correlation of the quantitation of MRD (r 2=0.80, p&amp;lt;0.0001). Among cases of discordant between 8-color MRD negative (with cutoff &amp;lt;0.01%) and 23-color MRD negative (with cutoff &amp;lt;0.001%), relapse only occurred in patients with 23-color MRD positive and 8-color MRD negative, rather than patients with 23-color MRD negative and 8-color MRD positive, suggesting a higher sensitivity and specificity for 23-color MRD assay (See Figure). Patients with detectable MRD by either 8-color or 23-color had a significantly higher incidence of relapse (CIR, p&amp;lt;0.05) and shorter event free survival (EFS, p&amp;lt;0.05). Positive 23-color MRD seemed to be an even stronger factor impacting CIR and EFS. Compared to patients with 8-color MRD negative and 23-color MRD positive, patients with 8-color MRD positive and 23-color MRD negative had a significantly lower CIR (p&amp;lt;0.05) and a better EFS (p=0.068). Patients with positive 23-color MRD lower than 0.01% showed a trend towards poorer EFS and OS (p=0.083% and p=0.061%, respectively) compared to patients with 23-color MRD negative. Conclusion Based on these evidences, SMFC-based one-tube 23-color MRD panel for B-ALL was convenient and maneuverable with higher sensitivity and specificity compared to conventional 8-color FC-MRD panel. It would be a promising method to improve the risk stratification.

Nosocomial dissemination of blaIMP-4 among Klebsiella pneumoniae by horizontal gene transfer and clonal spread: the epidemic IncN plasmids and the emerging high-risk IMP-4-producing ST101 clone.

To determine the genomic features of IMP-4-producing Klebsiella pneumoniae isolates recovered from paediatric patients and the transmission dynamics of blaIMP-4. IMP-producing K. pneumoniae isolates were collected from paediatric patients in Shanghai Children's Medical Center from 2013 to 2020. WGS was performed for all isolates, and the complete genomes of three IMP-4-producing isolates were generated. The distribution of blaIMP-4-harbouring plasmids was determined, and a conjugation assay was employed to investigate the horizontal transfer of blaIMP-4-harbouring plasmids. We collected 21 blaIMP-carrying K. pneumoniae isolates, with IMP-4 (16/21, 76.2%) as the predominant subtype, followed by IMP-8 (n = 3) and IMP-26 (n = 2). IMP-4-producing isolates displayed a diverse population structure and all blaIMP-4 genes were located on plasmids, including IncN (n = 9), IncHI5 (n = 5), IncFII(K) (n = 1) and IncFII(pKP91) (n = 1), although only IncN plasmids were conjugative. Clonal transmission of ST101 strains carrying IncHI5 blaIMP-4-harbouring plasmids was observed, and the acquisition of blaIMP-4 by the international high-risk ST101 clone constituted a novel combination of ST101 clone and carbapenemase genes. Plasmid analysis demonstrated that the conjugal transfer of the IncHI5 blaIMP-4-harbouring plasmid might be blocked by the ST101 bacterial host. The horizontal transfer of IncN plasmids and clonal spread of the international high-risk ST101 clone facilitated the nosocomial dissemination of blaIMP-4 among K. pneumoniae. The emerging IMP-4-producing ST101 clone displays diverse combinations of carbapenemase genes, and this clone could be a continually evolving threat and warrants prospective monitoring.

Risk Factors and Nomogram Model of Postoperative Delirium in Children with Congenital Heart Disease: A Single-Center Prospective Study.

Delirium is a common postoperative complication in children with congenital heart disease, which affects their postoperative recovery. The purpose of this study is to explore the risk factors of delirium and construct a nomogram model to provide novel references for the prevention and management of postoperative delirium in children with congenital heart disease. 470 children after congenital heart surgery treated in the cardiac intensive care unit (CICU) of Shanghai Children's Medical Center were divided into a model and a validation cohort according to the principle of 7:3 distribution temporally. Then, the delirium-related influencing factors of 330 children in the training cohort were analyzed, and the nomogram model was established by a combination of Lasso regression and logistic regression. The data of 140 children in the validation cohort were used to verify the effectiveness of the model. Multivariable logistic regression analysis showed that age, disease severity, non-invasive ventilation after extubation, delayed chest closure, phenobarbital dosage, promethazine dosage, mannitol usage, and elevated temperature were independent risk factors for postoperative delirium. The area under the receiver operating characteristic curve (AUC) of the nomogram model was 0.864 and the Brier value was 0.121. Regarding the validation of the model's effect, our results showed that 51 cases were predicted by the model and 34 cases actually occurred, including 4 cases of false negative and 21 cases of false positive. The positive predictive value of the model was 58.8%, and its negative predictive value was 95.5%. The nomogram model established in this study showed acceptable performance in predicting postoperative delirium in children with congenital heart disease.

Risk factors of gastrointestinal bleeding after cardiopulmonary bypass in children: a retrospective study.

During cardiac surgery that involved cardiopulmonary bypass (CPB) procedure, gastrointestinal (GI) system was known to be vulnerable to complications such as GI bleeding. Our study aimed to determine the incidence and risk factors associated with GI bleeding in children who received CPB as part of cardiac surgery. This retrospective study enrolled patients aged <18 years who underwent cardiac surgery with CPB from 2013 to 2019 at Shanghai Children's Medical Center. The primary outcome was the incidence of postoperative GI bleeding in children, and the associated risk factors with postoperative GI bleeding episodes were evaluated. A total of 21,893 children who underwent cardiac surgery with CPB from 2013 to 2019 were included in this study. For age distribution, 636 (2.9%) were neonates, 10,984 (50.2%) were infants, and 10,273 (46.9%) were children. Among the 410 (1.9%) patients with GI bleeding, 345 (84.2%) survived to hospital discharge. Incidence of GI bleeding in neonates, infants and children were 22.6% (144/636), 2.0% (217/10,984) and 0.5% (49/10,273), respectively. The neonates (22.6%) group was associated with highest risk of GI bleeding. Patients with GI bleeding showed longer length of hospital stays (25.8 ± 15.9 vs. 12.5 ± 8.9, P < 0.001) and higher mortality (15.9% vs. 1.8%, P < 0.001). Multivariate logistic regression analysis showed that age, weight, complicated surgery, operation time, use of extracorporeal membrane oxygenation (ECMO), low cardiac output syndrome (LCOS), hepatic injury, artery lactate level, and postoperative platelet counts were significantly associated with increased risk of GI bleeding in children with congenital heart disease (CHD) pediatric patients that underwent CPB procedure during cardiac surgery. The study results suggest that young age, low weight, long operation time, complicated surgery, use of ECMO, LCOS, hepatic injury, high arterial lactate level, and low postoperative platelet counts are independently associated with GI bleeding after CPB in children.

Cost-effectiveness analysis of dinutuximab β for the treatment of high-risk neuroblastoma in China.

Dinutuximab β can be used to treat children with high-risk neuroblastoma (NB). Due to its high price, whether dinutuximab β is cost-effective for the treatment of high-risk NB remains uncertain. Therefore, assessing the cost-effectiveness of dinutuximab β in children with high-risk NB is of high importance. The health utilities and economic outcomes in children with high-risk NB were projected using a partitioned survival model. The individual patient data (IPD) of add-on treatment with dinutuximab β (GD2 group) were derived from the literature, while the IPD of traditional therapy (TT group) were obtained from retrospective data of Shanghai Children's Medical Center. Treatment costs included drugs, adverse event-related expenses, and medical resource use. Utility values were obtained from the literature. Costs and quality-adjusted life-years (QALYs) were measured over a 10-year time horizon. Deterministic sensitivity analyses (DSA) and probabilistic sensitivity analyses (PSA) were also conducted. Compared with the TT group, QALY increased in the GD2 group by 0.72 with an increased cost of $171,269.70, leading to an incremental cost-effectiveness ratio of 236,462.75$/QALY. DSA showed that the price of dinutuximab β was the main factor on the results than other parameters. Compared with the TT group, the GD2 group could not be cost-effective in the PSA at the $37,920/QALY threshold. Results found that dinutuximab β is not a cost-effective treatment option for children with high-risk NB unless its price is significantly reduced.