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Dasatinib, an orally administered Src-family kinase inhibitor, is combined with the standard chemotherapeutic regimen to enhance antineoplastic activity against core-binding factor acute myeloid leukemia (CBF-AML) in adults; however, limited data are available for use in children. In the present study, we studied the pharmacokinetics and safety of dasatinib in children. Dasatinib (60 or 80 mg/m2 once daily) was administered to 20 children with CBF-AML. Blood samples were collected and drug concentrations were quantified by high-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS). Population pharmacokinetic analysis and Monte-Carlo simulations were performed using NONMEM software, and safety analyses were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 (NCT03844360). Twenty pediatric patients (3.3–14.4 years of age) were included, and a total of 40 dasatinib concentrations were available for population pharmacokinetic analysis. The mean (standard deviation) of the estimated area under the concentration-time curve extrapolated to steady state (AUCss) of dasatinib 60 and 80 mg/m2 was 366.1 (146.6) ng·h/mL and 425.3 (150.7) ng·h/mL, respectively. The majority of adverse events were grade 1/2 in severity, including thrombocytopenia, rash, and pain in the extremities. The estimated cumulative incidence of complete remission and complete molecular response were 95.0% and 75.5%, respectively. The population pharmacokinetics of orally administered dasatinib were evaluated in pediatric CBF-AML patients. The AUCss of dasatinib (80 mg/m2) in CBF-AML pediatric patients was similar to those of dasatinib (100 mg) in adult patients. Dasatinib is well-tolerated in pediatric patients with CBF-AML.

Ovarian cancer (OV) is the most lethal gynecologic malignancy. One major reason of the high mortality of the disease is due to platinum-based chemotherapy resistance. Increasing evidence reveal the important biological functions and clinical significance of zinc finger proteins (ZNFs) in OV. In the present study, the relationship between the zinc finger protein 76 (ZNF76) and clinical outcome and platinum resistance in patients with OV was explored. We further analyzed ZNF76 expression via multiple gene expression databases and identified its functional networks using cBioPortal. RT-qPCR and IHC assay shown that the ZNF76 mRNA and protein expression were significantly lower in OV tumor than that in normal ovary tissues. A strong relationship between ZNF76 expression and platinum resistance was determined in patients with OV. The low expression of ZNF76 was associated with worse survival in OV. Multivariable analysis showed that the low expression of ZNF76 was an independent factor predicting poor outcome in OV. The prognosis value of ZNF76 in pan-cancer was validated from multiple cohorts using the PrognoScan database and GEPIA 2. A gene-clinical nomogram was constructed by multivariate cox regression analysis, combined with clinical characterization and ZNF76 expression in TCGA. Functional network analysis suggested that ZNF76 was involved in several biology progressions which associated with OV. Ten hub genes (CDC5L, DHX16, SNRPC, LSM2, CUL7, PFDN6, VARS, HSD17B8, PPIL1, and RGL2) were identified as positively associated with the expression of ZNF76 in OV. In conclusion, ZNF76 may serve as a promising prognostic-related biomarker and predict the response to platinum in OV patients.

Background Children with acute lymphoblastic leukemia (ALL) undergoing chemotherapy experience a relatively high risk of infection. And the disturbance of gut microbiota is generally believed to impair intestinal barrier function and may induce bacterial infections and inflammation. The study aimed to investigate the alterations in the gut microbiota and assess its relationship with chemotherapy-induced pneumonia in pediatric ALL patients. Methods We conducted a case–control study with 14 cases affected by pneumonia and 44 unaffected subjects and characterized the physiological parameters and gut microbiota by microarray-based technique. Results There were significant differences in α- and β-diversity in the affected group compared with the control group. At species level, the LEfSe analysis revealed that Enterococcus malodoratus, Ochrobactrum anthropi and Actinomyces cardiffensis were significantly abundant in the affected subjects. A receiver operating characteristic (ROC) curve yielded the area under the curve (AUC) of 0.773 for classification between the two groups. In addition, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways involved in the bacterial secretion system were more enriched in the affected group than in the control group. Conclusions Gut microbiota alteration was associated with chemotherapy-induced pneumonia in pediatric ALL patients, which provided a new perspective on the personalized clinical care of pediatric ALL.

Li Zhang,1,* Xin-Mei Yang,2,* Jing Chen,3 Lei Hu,4 Fan Yang,5 Yue Zhou,5 Bei-Bei Zhao,1 Wei Zhao,2,5,* Xiao-Fan Zhu1,* 1Department of Pediatric, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, People’s Republic of China; 2Department of Clinical Pharmacy, Clinical Trial Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, People’s Republic of China; 3Pediatric Hematology & Oncology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 4Tianjin Institute of Pharmaceutical Research (TIPR), Tianjin, People’s Republic of China; 5Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiao-Fan ZhuDepartment of Pediatric, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, People’s Republic of ChinaTel/Fax +86 22 2390 9001Email xfzhu@ihcams.ac.cnWei ZhaoDepartment of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, No. 44, Wenhua West Road, Jinan, Shandong Province, People’s Republic of ChinaTel/Fax +86 531 8838 3308Email zhao4wei2@hotmail.comBackground: An oral tetra-arsenic tetra-sulfide (AS4S4) formula has been recommended as an outpatient post-remission treatment for Chinese adults with acute promyelocytic leukemia (APL) but limited data are available for children. In this exploratory study, we aimed to evaluate the pharmacokinetics and safety of the AS4S4 formula in children.Methods: Eleven newly diagnosed and one relapsed pediatric patient (4– 14 years of age) treated with the AS4S4 formula were included. Blood samples were collected from 12 children, and drug concentrations were quantified by ICP-MS. Population pharmacokinetic analysis and Monte-Carlo simulation were performed using NONMEM software. Toxic effects were graded according to the NCI-CTCAE, Version 3.Results: A total of 107 arsenic concentrations (0.1– 75.0 μg L− 1) were used for population pharmacokinetic analysis. The median (range) of estimated weight-normalized CL and volume distribution at steady-state were 45.26 (35.63– 82.18) L h− 1 kg− 1 and 230.37 (85.96– 495.68) L kg− 1, respectively. No patients discontinued AS4S4 treatment owing to adverse events, and there were no drug-related adverse events over grades 3– 4. All newly diagnosed APL patients were in MCR with a median follow-up of 28 months (range, 23 to 37 months). Both the estimated 3-year EFS and OS rates were 100%.Conclusion: The pharmacokinetics and safety oral AS4S4 formula was evaluated for the first time in pediatric APL. The pharmacokinetic assessment demonstrated that the dosing regimen of 60 mg/kg/d TID resulted in a higher steady-state through concentration in children than that which was achieved in adults. The results of this study indicate that the AS4S4 formula is safe in newly diagnosed pediatric APL patients.Keywords: acute promyelocytic leukemia, Realgar-Indigo Naturalis Formula, pediatric, safety, population pharmacokinetics

The first two authors contributed equally * The last two authors contributed equally Background: Realgar-Indigo Naturalis Formula (RIF), the only commercially oral arsenic agent, was launched in China from 2009. It has been recommended as consolidation or maintenance therapy in adults with acute promyelocytic leukemia (APL). Recently, RIF had been off-label used in pediatric APL in China. However, the knowledge of efficacy and dosage of RIF in pediatric was limited until now. Objective: The purpose of this pilot study was to evaluate effectiveness and pharmacokinetics of RIF as consolidation or maintenance therapy for newly diagnosed and relapsed APL in pediatric after induction therapy with intravenous arsenic trioxide. Meanwhile, modeling and simulation techniques were used to evaluate and optimize RIF dosing regimen in pediatric population. Patients and Methods: A total of 11 newly diagnosed APL and 1 relapsed patient (4-14years of age) were included from July 2016 to August 2017.The one relapsed and six newly diagnosed patients were treated with RIF (60 mg/kg/day TID) as maintenance therapy. Five newly diagnosed patients were treated with RIF (60 mg/kg/day TID) as consolidation and maintenance therapy. The treatment protocol and MRD results are shown in Figure 1. Event-free survival and overall survival were used to evaluate the efficacy. The plasma concentration of arsenic was quantified by inductively coupled plasma mass spectrometry (ICP-MS). Population pharmacokinetic analysis was carried out using the nonlinear mixed effects modeling program NONMEM V 7.2 (Icon Development Solutions, USA). Results: All newly diagnosed APL patients were alive as of July 1, 2019 and were in MCR with a median follow-up of 28 months (range, 23 to 37 months). Both the estimated 3-year EFS and OS rates were 100%. Of note, all the patients completed the postremission therapy containing RIF on an outpatient basis. A total of 107 arsenic concentrations were used for population pharmacokinetic model building. The arsenic concentrations of the blood samples ranged from 0.1 to 75.0 µg/L. The steady-state trough plasma arsenic concentration during the RIF treatment was 47.43μg/L (range, 25.74 to 62.97μg/L).A one-compartment model with first-order elimination fitted the data. Body weight was the only significant covariate of CL for the final model development. The developmental pharmacokinetic model was evaluated by goodness-of-fit plots and bootstrap analysis. The mean and variance of NPDE were -0.118 and 0.93, respectively. Conclusions: The effectiveness and pharmacokinetics were evaluated for the first time in pediatricAPL.The developmental population pharmacokinetic model for RIF in children revealed that one-compartment model with first-order elimination fitted the data.The current dosing regimen of 60 mg/kg/day TID resulted higher steady-state through concentration than that in adults (24.4μg/L, range:11.5 to 64μg/L). Disclosures:No relevant conflicts of interest to declare. This trial was conducted in accordance with the Declaration of Helsinki. OffLabel Disclosure: The combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) has become the front-line treatment for patients with acute promyelocytic leukemia (APL). Realgar-Indigo Naturalis Formula (RIF), the only commercially oral arsenic agent, was launched in China from 2009. Since then, RIF had been used for over 5000 adults with acute promyelocytic leukemia (APL). One pill of RIF is 270 mg which contains 30 mg of Realgar, 125 mg of Indigo naturalis, 50 mg of Radix salviae miltiorrhizae, 45 mg of Radix pseudostellariae, and 20mg of garment film. However, the pharmacokinetics of RIF in children has not been studied.

The Electronic Flight Bag (EFB) provides pilots real-time or existing data by converting the papery documents into electronic books. Consequently the efficiency and the security have been improved, which reduce pilots’ ground communication time and the paperweight. As a key factor of what influences the takeoff process, the takeoff performance undoubtedly has been an essential research task of EFB, while many factors may affect the takeoff performance, such as flap position, anti-ice and the external temperature. By means of interpolation, this paper integrates those factors and gets Maximum Take-off Weight (TOW), Take-off Decision Speed (V1), Take-off Rotation Speed (VR) and Take-off Safety Speed (V2). And then implants the result into the EFB based on the iOS.

Fetus in fetu (FIF) is a very rare congenital malformation with an incidence of 1/500,000 live births. These children are often hospitalized because of vomiting, abdominal distension or abdominal mass found by their parents. The most common position for the parasitic fetus is the retroperitoneum but other position such as the scrotal sac, cranial cavity, sacrococcygeal region, back , oral cavity has been reported. FIF is often misdiagnosed as a mature teratoma. Ultrasound, CT, MRI are of great significance in distinguishing between FIF and teratoma. The postoperative pathological examination may reveal axial skeleton which can make a definitive diagnosis of FIF. In this report, we present a case of FIF in an 8-month-old girl.

Soft tissue expansion is a technique useful in reconstruction when a shortage of tissue exists. This study presents an investigation on using chronic balloon expansion in the urethral and vaginal reconstruction of high persistent cloaca. The common channel was expanded by a balloon, which was progressively inflated over 3–4 weeks at a pressure of 30–50 mmHg until an adequate amount of tissue was obtained. The expanded channel was longitudinally split into anterior and posterior segments: the former was approximated to form a neourethra in continuity with the reconstructed bladder neck and the latter was tubularized to form a vagina. Twenty-one patients underwent primary posterior sagittal urethro-vaginoplasty using the expanded urogenital sinus. Histologic examination demonstrated that the expanded tissue consisted of a dense fibrous wall lined with a stratified squamous non-cornified epithelium, which was characterized by active cell mitosis and angiogenesis. The patients were followed-up for 0.6–9 year (mean 5.69 ± 2.43 years). All reconstructed urethras, vaginas, and vulvas were satisfactory in color, texture match, and sensation. Urinary continence (grades I and II) was observed in all patients without intermittent catheterization. Two complications were encountered in our study. One patient showed a distal urethral dehiscence and a secondary urethroplasty was performed 6 months after the operation. Another patient developed a redundant urethra upon reaching puberty and urethroplasty was needed. Chronic balloon expansion allows the formation of adequate tissue similar in appearance and type to the vagina and urethra. It also provides a valuable surgical alternative for the management of high persistent cloaca.