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This retrospective single-center study was to evaluate the expression of TCF3 protein in pediatric Burkitt lymphomas (pBLs) and analyze its relations with clinical characteristics and prognosis. A total of 58 pBLs and 30 reactive hyperplastic lymphadenites (RH) were recruited. The high expression rate of TCF3 was 67.24% in pBLs, significantly higher than that in the RHs (36.67%,ip/i = .01), which was consistent with the findings in biopsy specimens from mRNA and protein level, respectively. The expression of TCF3 was significantly associated with tumor localization and size. A total of 54 patients having received short-intensive chemotherapy had a median follow-up of 54.15 months (range: 1-111 months). Log-rank test of Kaplan-Meier survival curves indicated an inverse correlation of TCF3 expression with the overall survival (OS) and event-free survival (EFS). Univariate analysis showed that high TCF3 expression was significantly associated with poor EFS. The result of multivariate COX regression analysis indicated that the TCF3 expression was an independent prognostic factor for EFS.

Purpose Pediatric patients with inborn errors of immunity (IEI) undergoing umbilical cord blood transplantation (UCBT) are at risk of early mortality. Our aim was to develop and validate a prediction model for early mortality after UCBT in pediatric IEI patients based on pretransplant factors. Methods Data from 230 pediatric IEI patients who received their first UCBT between 2014 and 2021 at a single center were analyzed retrospectively. Data from 2014–2019 and 2020–2021 were used as training and validation sets, respectively. The primary outcome of interest was early mortality. Machine learning algorithms were used to identify risk factors associated with early mortality and to build predictive models. The model with the best performance was visualized using a nomogram. Discriminative ability was measured using the area under the curve (AUC) and decision curve analysis. Results Fifty days was determined as the cutoff for distinguishing early mortality in pediatric IEI patients undergoing UCBT. Of the 230 patients, 43 (18.7%) suffered early mortality. Multivariate logistic regression with pretransplant albumin, CD4 (absolute count), elevated C-reactive protein, and medical history of sepsis showed good discriminant AUC values of 0.7385 (95% CI, 0.5824–0.8945) and 0.827 (95% CI, 0.7409–0.9132) in predicting early mortality in the validation and training sets, respectively. The sensitivity and specificity were 0.5385 and 0.8154 for validation and 0.7667 and 0.7705 for training, respectively. The final model yielded net benefits across a reasonable range of risk thresholds. Conclusion The developed nomogram can predict early mortality in pediatric IEI patients undergoing UCBT.

ObjectiveTo analyze the efficiency of unrelated umbilical cord blood transplantation (UCBT) in the treatment of hereditary leukodystrophy following busulfan- and cyclophosphamide-based myeloablative chemotherapy.MethodsA retrospective study was performed in patients with hereditary leukodystrophy who underwent UCBT after myeloablative chemotherapy between April 2015 and March 2020.ResultsThe study cohort included 12 pediatric patients (ten males), nine with cerebral adrenoleukodystrophy (ALD) and three with juvenile globoid cell leukodystrophy (GLD). All received HLA-matched or partially mismatched unrelated UCBT. There were no cases of graft rejection. Median neutrophil engraftment time was 20 days [12–33 days] and median platelet engraftment time was 29 days [14–65 days]. Median follow-up was 36 months [1–86 months], and the overall survival rate for patients with cerebral ALD and juvenile GLD after UCBT was 77.8% (7/9) and 100% (3/3), respectively. In patients with ALD, although lipid profiles (serum very-long-chain fatty acid) were improved post-UCBT, six patients demonstrated worse neurologic function score and performance status post-UCBT, and six patients had higher Loes scores at last follow-up compared with baseline. In patients with juvenile GLD, all patients showed stable neurologic function score and performance status despite the Loes score of one patient increased slightly after transplantation.ConclusionIn patients with cerebral ALD, patients with no or mild neurological symptoms can benefit from UCBT, while UCBT cannot reverse advanced disease. In patients with juvenile GLD, UCBT is safe and contributes to stabilize neurological function.

Yang Fu, Xiaohua Zhu, Ping Cao, Chen Shen, Xiaowen Qian, Hui Miao, Yi Yu, Hongsheng Wang, Xiaowen Zhai Department of Hematology, National Children’s Medical Center Children’s Hospital of Fudan University, Shanghai, People’s Republic of ChinaCorrespondence: Hongsheng Wang; Xiaowen Zhai, Department of Hematology, National Children’s Medical Center Children’s Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, People’s Republic of China, Tel +86 21 64931123, Fax +86 21 64931901, Email honswang@hotmail.com; xwzhai@fudan.edu.cnPurpose: To analyze the contribution of metagenomic next-generation sequencing (mNGS) in the guidance of clinical treatment and outcomes of infection during myelosuppression among children with hematological and neoplastic diseases.Patients and Methods: The clinical data and results of mNGS assay of febrile patients suspected of infection were retrospectively collected. The characteristics of pathogenic microorganisms and clinical course of myelosuppressed children with hematological diseases were summarized.Results: Our study included 70 patients (45 males) with a median age of 5 years (range: 0.5 to 13 y). During the study period, there were 96 events of suspected infection. According to comprehensive clinical diagnosis, 73 blood infections, 43 pneumonia and 2 urinary tract infections occurred. The positive rate of mNGS was significantly higher than that of traditional microbial detection (83.3% vs 17.7%). The main pathogens detected by mNGS were Pseudomonas aeruginosa, Acinetobacter, human herpesvirus, Candida and Aspergillus. The average duration of fever was 4.9 days and 11.6 days (P < 0.05), and the average cost of anti-infection treatment was RMB ¥ 28,077 and 39,898 (P < 0.05) among children received mNGS within 48 hours and more than 48 hours after the onset of infection symptoms.Conclusion: mNGS contributes to clinical management of children with infection during myelosuppression, especially among patients with negative traditional microbial detection. Early implementation of mNGS in children with symptoms has a tendency to reduce the time of infection, fever and the cost of treatment.Keywords: metagene, pathogenic microorganism, child, hematology and oncology

To identify prognostic factors that can be used to further improve outcome, we studied 384 patients with this genotype treated on Chinese Children’s Cancer Group acute lymphoblastic leukemia (ALL) -2015 protocol between 1 January 2015 and 31 December 2019. All patients provisionally received intensified chemotherapy in the intermediate-risk. The overall 5-year event-free survival (EFS) was 84.4% (95% confidence interval [CI], 80.6-88.3). Independent factors associated with lower 5-year EFS were male sex (80.4%, [95% CI, 74.8-86.4] vs. 88.9%, [95% CI, 84.1-93.9] in female, p = 0.033) and positive Day 46 minimal residual disease (MRD) (≥ 0.01%) (62.1%, [95% CI, 44.2-87.4] vs. 87.1%, [95% CI, 83.4-90.9] in patients with negative MRD, p < 0.001). The presence of testicular leukemia at diagnosis (n=10) was associated with particularly poorer 5-year EFS (33.3% [95% CI, 11.6-96.1] vs. 83.0% [95% CI, 77.5-88.9] in the other 192 male patients, P < 0.001) and was an independent risk factor (HR, 5.7, [95% CI, 2.2-14.5], p < 0.001). These data suggest that the presence of positive MRD after intensive remission induction and testicular leukemia at diagnosis are indications for new molecular therapeutics or immunotherapy in patients with TCF3-PBX1 ALL.

Postoperative recurrence of liver cancer is the main obstacle to improving the survival rate of patients with liver cancer. We established an mRNA-based model to predict the risk of recurrence after hepatectomy for liver cancer and explored the relationship between immune infiltration and the risk of recurrence after hepatectomy for liver cancer. We performed a series of bioinformatics analyses on the gene expression profiles of patients with liver cancer, and selected 18 mRNAs as biomarkers for predicting the risk of recurrence of liver cancer using a machine learning method. At the same time, we evaluated the immune infiltration of the samples and conducted a joint analysis of the recurrence risk of liver cancer and found that B cell, B cell naive, T cell CD4+ memory resting, and T cell CD4+ were significantly correlated with the risk of postoperative recurrence of liver cancer. These results are helpful for early detection, intervention, and the individualized treatment of patients with liver cancer after surgical resection, and help to reveal the potential mechanism of liver cancer recurrence.

Background Hereditary leukodystrophies are diverse metabolic diseases caused by gene mutations that result in the abnormal development or degeneration of myelin. Transplantation of matched sibling donor umbilical cord blood (UCB) can slow progression and prolong survival in some cases. For patients without siblings, however, UCB transplantation from unrelated donors may be the only option. Methods This retrospective study assessed unrelated UCB transplantation (UCBT) efficacy following busulfan- and cyclophosphamide-based myeloablative chemotherapy. Results The study cohort included 12 pediatric patients (ten males), nine with adrenoleukodystrophy (ALD) and three with globoid cell leukodystrophy (GLD), treated between April 2015 and March 2020. All received HLA-matched or partially mismatched UCBT. Median age at UCBT was 7.2 years (range, [0.8–12.9 years]). There were no cases of graft rejection. Median neutrophil engraftment time was 20 days [12–33 days] and median platelet engraftment time was 29 days [14–65 days]. Median follow-up was 28 months [1–73 months], and overall survival rate was 83.3% (10/12). Seven patients had higher Loes scores post-transplantation, and two patients died of infection. Four patients with rapid neurological deterioration pre-UCBT exhibited worse neurological symptoms post-UCBT. In contrast, four patients with stable neurological symptoms pre-UCBT demonstrated symptom stability post-UCBT, and two with no neurological symptoms pre-UCBT were also symptom-free post-UCBT. Further, lipid profiles of surviving ALD patients were improved post-treatment. Conclusions Hereditary leukodystrophy patients with mild neurological symptoms can benefit from UCBT, while UCBT cannot reverse advanced disease.

Background Acute lymphoblastic leukemia (ALL), the most common childhood malignancy, is characterized by recurring structural chromosomal alterations and genetic alterations, whose detection is critical in diagnosis, risk stratification and prognostication. However, the genetic mechanisms that give rise to ALL remain poorly understood. Methods Using next-generation sequencing (NGS) in matched germline and tumor samples from 140 pediatric Chinese patients with ALL, we landscaped the gene mutations and estimated the mutation frequencies in this disease. Results Our results showed that the top driver oncogenes having a mutation prevalence over 5% in childhood ALL included KRAS (8.76%), NRAS (6.4%), FLT3 (5.7%) and KMT2D (5.0%). While the most frequently mutated genes were KRAS, NRAS and FLT3 in B cell ALL (B-ALL), the most common mutations were enriched in NOTCH1 (23.1%), FBXW7 (23.1%) and PHF6 (11.5%) in T cell ALL (T-ALL). These mutant genes are involved in key molecular processes, including the Ras pathway, the Notch pathway, epigenetic modification, and cell-cycle regulation. Strikingly, more than 50% of mutations occurred in the high-hyperdiploid (HeH) ALL existed in Ras pathway, especially FLT3 (20%). We also found that the epigenetic regulator gene KMT2D, which is frequently mutated in ALL, may be involved in driving leukemia transformation, as evidenced by an in vitro functional assay. Conclusion Overall, this study provides further insights into the genetic basis of ALL and shows that Ras mutations are predominant in childhood ALL, especially in the high-hyperdiploid subtype in our research.

BACKGROUND: This study aims to investigate the efficacy and safety of umbilical cord blood transplantation (UCBT) without serotherapy for treating children with leukocyte adhesion deficiency type I (LAD-I). METHODS: Clinical characteristics and data of five children with LAD-I who underwent UCBT at our hospital between September 2016 and September 2018 were retrospectively analyzed. RESULTS: Five (two boys and three girls) patients with LAD-I were included. The median age at UCBT was 9 months (range, 8 to 32 months). The same myeloablative conditioning regimen was administered for each patient and included busulfan, fludarabine, and cyclophosphamide. HLA matching of patients and umbilical cord blood was 8/10 to 10/10. The median dose of total nucleated cells (TNC) infused was 10.2×10(7)/kg (range, 4.5×10(7) to 20.6×10(7)/kg) and the median dose of CD34+ cells was 3.2×10(5)/kg (range, 1.9×10(5) to 5.7×10(5)/kg). The median time of neutrophil engraftment was 20 days (range, 13 to 28 days). The median time of platelet engraftment was 36 days (range, 32 to 56 days). All patients received complete donor chimerism (CDC). Four of the five patients developed grade II–IV acute graft-versus-host disease (GvHD). The median follow-up time after transplantation was 19 months (range, 8 to 38 months). Four of the patients survived and achieved complete clinical remission. The other patient died of bronchiolitis obliterans 8 months after UCBT. CONCLUSIONS: UCBT is an effective treatment method for LAD-I patients. Also, severe LAD-I patients should undergo stem cell transplantation as early as possible.

Purpose With the wide application of immunologic reconstitution treatment, such as hematopoietic stem-cell transplantation (HSCT), most patients of inflammatory bowel disease (IBD) with immunodeficiency owing to monogenic abnormalities need surgical intervention during the course of treatment, which is quite different from traditional IBD surgery. The aim of this study was to generalize the surgical strategies as a part of comprehensive therapy for these rare diseases. Methods A retrospective study was conducted based on the clinical data of children with immunodeficiency-derived IBD who underwent surgical treatment in Children's Hospital of Fudan University between January 2015 and December 2017. Results A total of 18 patients with monogenic abnormalities were enrolled. The major surgical indications included 11 cases of acute or chronic intestinal obstructions, 4 refractory intestinal infections, and 3 pneumoperitoneum, while 12 cases had perforations noted during intraoperative exploration. All of the patients underwent varieties of enterostomies to divert the affected or obstructed intestine during the primary surgery. Wound infections or dehiscence occurred in 7 patients, and 2 patients underwent reoperations for adhesive intestinal obstruction and prolapse. Postoperatively, 15 patients survived, 13 of which achieved immune reconstitution through subsequent HSCT or immunoglobulin supplementation. In the second-stage surgery, a posterior sagittal approach rectal resection was performed in 5 patients with complex anorectal complications. Twelve patients had undergone stoma closure procedures. Conclusion Surgical intervention should be performed earlier because the perforations are usually insidious in monogenic IBD. Preventative enterostomies are suggested in preparation for HSCT among patients with severe anorectal complications. Wound infections are the most common complication after the primary operation. Posterior sagittal rectal resection is a good option for patients with complex anorectal complications. Type of study Clinical research paper. Level of evidence Level IV.

In this study we evaluated children with newly diagnosed advanced (stage III and stage IV) mature B-cell non-Hodgkin lymphoma (B-NHL) or mature B-cell acute leukemia (B-AL), who were treated with Berlin-Frankfurt-Munster (BFM)95-based protocol combined with rituximab (R+BFM95). Our study recruited 46 patients who were treated with BFM95 protocol combined with rituximab. There are 23 patients as the historical control treated with BFM90 protocol. Compared with patients treated with BFM90 protocol, the 5-year event-free survival (EFS) rate of patients under R+BFM95 was higher (83.7%±5.7% vs. 69.6%±9.6%; P=0.1062). Among subgroups of our patients, the 5-year EFS of patients with stage III was 87.3%±6.1% vs. 77.8%±9.8% (P=0.2998), stage IV/B-AL was 72.7%±13.4% versus 40.0%±21.9% (P=0.0878) between patients treated with R+BFM95 and BFM90, respectively. Among patients whose lactate dehydrogenase (LDH) level were

Pancreatic cancer is a highly malignant and metastatic tumor of the digestive system. Even after surgical removal of the tumor, most patients are still at risk of metastasis. Therefore, screening for metastatic biomarkers can identify precise therapeutic intervention targets. In this study, we analyzed 96 pancreatic cancer samples from The Cancer Genome Atlas (TCGA) without metastasis or with metastasis after R0 resection. We also retrieved data from metastatic pancreatic cancer cell lines from Gene Expression Omnibus (GEO), as well as collected sequencing data from our own cell lines, BxPC-3 and BxPC-3-M8. Finally, we analyzed the expression of metastasis-related genes in different datasets by the Limma and edgeR packages in R software, and enrichment analysis of differential gene expression was used to gain insight into the mechanism of pancreatic cancer metastasis. Our analysis identified six genes as risk factors for predicting metastatic status by LASSO regression, including zinc finger BED-Type Containing 2 (ZBED2), S100 calcium-binding protein A2 (S100A2), Jagged canonical Notch ligand 1 (JAG1), laminin subunit gamma 2 (LAMC2), transglutaminase 2 (TGM2), and the transcription factor hepatic leukemia factor (HLF). We used these six EMT-related genes to construct a risk-scoring model. The receiver operating characteristic (ROC) curve showed that the risk score could better predict the risk of metastasis. Univariate and multivariate Cox regression analyses revealed that the risk score was also an important predictor of pancreatic cancer. In conclusion, 6-mRNA expression is a potentially valuable method for predicting pancreatic cancer metastasis, assessing clinical outcomes, and facilitating future personalized treatment for patients with ductal adenocarcinoma of the pancreas (PDAC).

Infantile-onset inflammatory bowel disease can be caused by defects in interleukin-10 signalling. The natural history and clinical outcomes of allogeneic haematopoietic stem cell transplantation, medical treatment and surgery have not been thoroughly described.This study evaluates disease progression and clinical outcome in patients with interleukin-10 signalling deficiency.One hundred and nine patients with interleukin-10 signalling deficiency were retrospectively reviewed from a single tertiary centre. The Kaplan-Meier method was applied to calculate probabilities of survival and interval between transplant and stoma closure.One hundred and nine patients were reviewed, and 102 patients were included in the survival analysis. One hundred and eight patients were identified with IL10RA mutations, and one patient harboured IL10RB mutation. Seventy-three patients received haematopoietic stem cell transplantation. The overall survival after transplantation was 64.2% (95% confidence interval, 52.8 to 75.6), and without transplantation, it was 47.5% (95% confidence interval, 14.8 to 80.2, P = 0.47). The median timeframe between transplant and stoma closure was 19.6 months. The probability of survival was significantly lower in patients with perforation (P 0.001), ileus (P = 0.038) and without thalidomide treatment (P 0.001) among patients who did not receive haematopoietic stem cell transplantation. The survival probability was not associated with timeframe between transplant and onset, graft source and genotypes.The survival probability was not significantly different between patients with transplantation and the non-transplanted patients.

High-dose methotrexate (HD-MTX) is widely used in pediatric acute lymphoblastic leukemia (ALL) treatment regimens. In this study, we aimed to develop a population pharmacokinetic (PK) model of HD-MTX in Chinese pediatric patients with ALL for designing personalized dosage regimens. In total, 4,517 MTX serum concentration data for 311 pediatric patients with ALL, aged 0.75–15.2 years and under HD-MTX treatment, were retrospectively collected at a tertiary Children’s Hospital in China. The non-linear mixed-effect model was used to establish the population PK model, using NONMEM software. The potential covariate effects of age, body weight, and biochemical measurements (renal and liver function) on MTX PK disposition were investigated. The model was then evaluated using goodness-of-fit, visual predictive check. MTX PK disposition was described using a three-compartment model reasonable well. Body weight, implemented as a fixed allometric function on all clearance and volume of distribution parameters, showed a substantial improvement in model fit. The final population model demonstrated that the MTX clearance estimate in a typical child with body weight of 19 kg was 6.9 L/h and the central distribution of volume estimate was 20.7 L. The serum creatinine significantly affected the MTX clearance, with a 0.97% decrease in clearance per 1 μmol/L of serum creatinine. Other covariates (e.g., age, sex, bilirubin, albumin, aspartate transaminase, concomitant medication) did not significantly affect PK properties of MTX. The proposed population PK model could describe the MTX concentration data in Chinese pediatric patients with ALL. This population PK model combined with a maximum a posteriori Bayesian approach could be used to estimate individual PK parameters, and optimize personalized MTX therapy in target patients, thus aiming to reduce toxicity and improve treatment outcomes.

HLA-B*46:85 differs from HLA-B*46:01:01:01 in exon 3 at position 560 by a single non-synonymous mutation.

BackgroundSubcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a malignant primary T-cell lymphoma that is challenging to distinguish from autoimmune disorders and reactive panniculitides. Delay in diagnosis and a high misdiagnosis rate affect the prognosis and survival of patients. The difficulty of diagnosis is mainly due to an incomplete understanding of disease pathogenesis.MethodsWe performed single-cell RNA sequencing of matched subcutaneous lesion tissue, peripheral blood, and bone marrow from a patient with SPTCL, as well as peripheral blood, bone marrow, lymph node, and lung tissue samples from healthy donors as normal controls. We conducted cell clustering, gene expression program identification, gene differential expression analysis, and cell-cell interaction analysis to investigate the ecosystem of SPTCL.ResultsBased on gene expression profiles in a single-cell resolution, we identified and characterized the malignant cells and immune subsets from a patient with SPTCL. Our analysis showed that SPTCL malignant cells expressed a distinct gene signature, including chemokines families, cytotoxic proteins, T cell immune checkpoint molecules, and the immunoglobulin family. By comparing with normal T cells, we identified potential novel markers for SPTCL (e.g., CYTOR, CXCL13, VCAM1, and TIMD4) specifically differentially expressed in the malignant cells. We also found that macrophages and fibroblasts dominated the cell-cell communication landscape with the SPTCL malignant cells.ConclusionsThis work offers insight into the heterogeneity of subcutaneous panniculitis-like T-cell lymphoma, providing a better understanding of the transcription characteristics and immune microenvironment of this rare tumor.

Objectives Umbilical cord blood transplantation (UCBT) is associated with a relatively high rate of engraftment failure. This study aimed at exploring whether any fecal microbiota could be associated with engraftment failure following UCBT in Crohn's disease patients with IL10RA deficiency. Methods Thirteen patients were recruited and their 230 fecal samples were collected longitudinally from immediately before conditioning chemotherapy to 8 weeks post the UCBT. The V3-V4 regions of the bacterial 16S rRNA gene were amplified by PCR and sequenced, followed by bioinformatics analyses. Results Following the UCBT, 7 out of 13 patients achieved neutrophil and platelet engraftment with a median of 21 and 28 days, respectively (S group), while 6 patients failed to achieve engraftment (F group). In comparison with that in the S group, significantly lower Shannon diversity values on the UCBT day (P = 0.0176) and less abundance of Bifidobacterium longum, Bifidobacterium pseudolongum, Enterobacteriaceae_538000, and one taxon of Lachnospiraceae family was detected in the F group, accompanied by significantly higher abundances of four taxa including Lautropia, Pseudomonas, and species Microvirgula aerodenitrificans during the chemotherapy period as well as UCBT. The abundances of thirty OTUs were correlated significantly with clinical indices. Conclusions Microbial indicators of reduced diversity of microbiota and signatures of specific bacterial abundances, such as a lower abundance of Bifidobacterium longum, for engraftment failure would require validation. These indicators may help for the risk stratification in patients with IL10RA deficiency undergoing UCBT.

Objectives Umbilical cord blood transplantation (UCBT) is associated with a relatively high rate of engraftment failure. This study aimed at exploring whether any fecal microbiota could be associated with engraftment failure following UCBT in Crohn’s disease patients with IL10RA deficiency. Methods Thirteen patients were recruited and their 230 fecal samples were collected longitudinally from immediately before conditioning chemotherapy to 8 weeks post the UCBT. The V3-V4 regions of the bacterial 16S rRNA gene were amplified by PCR and sequenced, followed by bioinformatics analyses. Results Following the UCBT, 7 out of 13 patients achieved neutrophil and platelet engraftment with a median of 21 and 28 days, respectively (S group), while 6 patients failed to achieve engraftment (F group). In comparison with that in the S group, significantly lower Shannon diversity values on the UCBT day (P = 0.0176) and less abundance of Bifidobacterium longum, Bifidobacterium pseudolongum, Enterobacteriaceae_538000, and one taxon of Lachnospiraceae family was detected in the F group, accompanied by significantly higher abundances of four taxa including Lautropia, Pseudomonas, and species Microvirgula aerodenitrificans during the chemotherapy period as well as UCBT. The abundances of thirty OTUs were correlated significantly with clinical indices. Conclusions Microbial indicators of reduced diversity of microbiota and signatures of specific bacterial abundances, such as a lower abundance of Bifidobacterium longum, for engraftment failure would require validation. These indicators may help for the risk stratification in patients with IL10RA deficiency undergoing UCBT.

BACKGROUND Interleukin-10 (IL10)/interleukin-10 receptor (IL10R) deficiency is a rare disease with life-threatening infantile-onset colitis. We sought to accurately phenotype this disorder based on a large cohort of patients with a proven defect of IL10 signaling and to clarify the effects of allogeneic hematopoietic stem cell transplantation (HSCT). METHODS We analyzed the phenotypes of our 61 patients and reviewed 78 other previously reported cases with identified mutations in the genes encoding IL10 or IL10R. We also compared the clinical features of patients with interleukin-10 receptor B (IL10RB), interleukin-10 receptor A (IL10RA), and IL10 mutations. The therapeutic effects of allogeneic HSCT were evaluated. RESULTS We found that the disease onset time was extremely early: 70.3% within 30 days postnatal and 94.9% within the first 6 months of life. In addition, 94.2% of patients typically presented with perianal lesions. Oral ulcers and skin rash were common extra-intestinal manifestations (33.8% and 51.8%, respectively). There was no statistically significant difference in disease onset time, perianal lesion involvement, or mortality rate among patients with IL10RB, IL10RA, or IL10 deficiency. However, the surgery rate was higher in patients with IL10RB mutations than in those with IL10 or IL10RA mutations (P < 0.05). Compared with those with IL10RA deficiency, a higher percentage (32%, 9 of 28) of patients with IL10RB mutations developed B-cell lymphoma (P < 0.01). Compared with other regions, a higher percentage (98.7%) of IL10RA mutations was detected among patients in East Asia countries (P < 0.01), with hot-spot mutation sites of c.C301T and c.G537A. Allogeneic HSCT is efficacious but has a high mortality rate (17.5%, 7 of 40). CONCLUSIONS Our study expands the current knowledge on the genotype-correlated phenotypes with a defect of IL10 signaling. B-cell lymphoma was more frequent than would be expected in patients with IL10RB mutations. There may be a unique genetic architecture among Eastern Asia compared with other populations. Although allogeneic HSCT represents a causal therapeutic approach for IL10-and IL10R-deficient patients, a word of caution is warranted.

To detect pathological variant in two patients with Chediak-Higashi syndrome (CHS) from a consanguineous family and to explore its genotype-phenotype correlation.Clinical data was collected for this pedigree. Genomic DNA was prepared from probands' peripheral leukocytes and their relatives' fingernail. Whole exome sequencing and Sanger sequencing were carried out to detect potential variant of the LYST gene.The proband presented with partial oculocutaneous albinism, immunodeficiency and acidophilic inclusion body in bone marrow and blood smears. A novel homozygous nonsense variant c.8782CT (p.Gln2928*) was identified in exon 34 of the LYST gene in the sib pair. The same variant was found to be in heterozygous status in 6 unaffected individuals from the pedigree.Above result enriched the mutational spectrum of CHS and provided a basis for genetic counseling and prenatal diagnosis for this pedigree.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common malignancy in children, while relapse and refractory ALL remains a leading cause of death in children. However, paired ALL samples of initial diagnosis and relapse subjected to next-generation sequencing (NGS) could construct clonal lineage changes, and help to explore the key issues in the evolutionary process of tumor clones. Therefore, we aim to analyze gene alterations during the initial diagnosis and relapse of ALL patients and to explore the underlying mechanism. METHODS: Targeted exome sequencing technology was used to detect molecular characteristic of initial diagnosis and relapse of ALL in 12 pediatric patients. Clinical features, treatment response, prognostic factors and genetic features were analyzed. RESULTS: In our 12 paired samples, 75% of pre-B-cell acute lymphoblastic leukemia (B-ALL) patients had alterations in the Ras pathway (NRAS, KRAS, NF1, and EPOR), and Ras mutation are very common in patients with ALL relapse. TP53 mutations mainly existed in the primary clones and occurred at the initial diagnosis and relapse of ALL. Relapse-associated genes such as NT5C2 and CREBBP were observed in patients with ALL relapse; however, all patients included in this study had gene abnormalities in the Ras pathway, and NT5C2 and CREBBP genes may collaboratively promote ALL relapse. CONCLUSIONS: Among the 12 ALL patients, Ras pathway mutations are common in ALL relapse and may be associated with other recurrence-related genes alterations. The study with paired samples could improve the understanding of ALL relapse.

Additional file 1: Table S1. 950 Genes screened in the exon sequencing. Table S2. Sequences of shRNA used in this study. Table S3. Sequences of real-time PCR primers used in this study. Table S4. Clinical characteristics and genetic types of patient cohorts. Table S5. Other mutations occurring in our ALL cohort. Figure S1. Somatic mutations in acute lymphoblastic leukemia (ALL). A, Boxplots showed the median depth of coverage depth in tumor samples and the control samples (matched germline samples). B, Boxplots showed the median number of somatic mutations detected in B-ALL and T-ALL. C, Pattern of single base substitution in B-ALL and T-ALL patients. D, Density plots of the allele fraction (AF) of single nucleotide variants (SNVs) in the B-ALL and T-ALL patients. The main clones with a maximum AF close to 0.4 and subclonal mutations with a maximum AF below 0.25. Figure S2. Recurrent mutations in epigenetic regulations. Schematic diagrams of protein structures involving gene mutations in PHF6, EZH2, SUZ12.

Background: Acute lymphoblastic leukemia (ALL), the most common childhood malignancy, is characterized by molecular aberrations. Recently, genetic profiling has been fully investigated on ALL; however, the interaction between its genetic alterations and clinical features is still unclear. Therefore, we investigated the effects of genetic variants on ALL phenotypes and clinical outcomes. Methods: Targeted exome sequencing technology was used to detect molecular profiling of 140 Chinese pediatric patients with ALL. Correlation of genetic features and clinical outcomes was analyzed. Results: T-cell ALL (T-ALL) patients had higher initial white blood cell (WBC) count (34.8×10 9 /L), higher incidence of mediastinal mass (26.9%), more relapse (23.1%), and enriched NOTCH1 (23.1%), FBXW7 (23.1%) and PHF6 (11.5%) mutations. Among the 18 recurrently mutated genes, SETD2 and TP53 mutations occurred more in female patients (P=0.041), NOTCH1 and SETD2 mutants were with higher initial WBC counts (≥50×10 9 /L) (P=0.047 and P=0.041), JAK1 mutants were with higher minimal residual disease (MRD) level both on day 19 and day 46 (day 19 MRD ≥1%, P=0.039; day 46 MRD ≥0.01%, P=0.031) after induction chemotherapy. Multivariate analysis revealed that initial WBC counts (≥50×10 9 /L), MLLr , and TP53 mutations were independent risk factors for 3-year relapse free survival (RFS) in ALL. Furthermore, TP53 mutations, age ( MLLr were independently associated with adverse outcome in B-cell ALL (B-ALL). Conclusions: MLLr and TP53 mutations are powerful predictors for adverse outcome in pediatric B-ALL and ALL. Genetic profiling can contribute to the improvement of prognostication and management in ALL patients.

Background: Disseminated Bacillus Calmette-Guérin disease (D-BCG) in children with chronic granulomatous disease (CGD) can be fatal, while its clinical characteristics remain unclear because both diseases are extremely rare. The patients with CGD receive BCG vaccination, because BCG vaccination is usually performed within 24 h after delivery in China.Methods: We prospectively followed-up Chinese patients with CGD who developed D-BCG to characterize their clinical and genetic characteristics. The diagnoses were based on the patients' clinical, genetic, and microbiological characteristics.Results: Between September 2009 and September 2016, we identified 23 patients with CGD who developed D-BCG. Their overall 10-year survival rate was 34%. We created a simple dissemination score to evaluate the number of infected organ systems and the survival probabilities after 8 years were 62 and 17% among patients with simple dissemination scores of ≤3 and >3, respectively (p = 0.0424). Survival was not significantly associated with the CGD stimulation index or interferon-γ treatment. Eight patients underwent umbilical cord blood transplantation and 5 of them were successfully treated. The genetic analyses found mutations in CYBB (19 patients), CYBA (1 patient), NCF1 (1 patient), and NCF2 (1 patient). We identified 6 novel highly likely pathogenic mutations, including 4 mutations in CYBB and 2 mutations in NCF1.Conclusions: D-BCG is a deadly complication of CGD. The extent of BCG spreading is strongly associated with clinical outcomes, and hematopoietic stem cell transplantation may be a therapeutic option for this condition.

To explore the underlying molecular mechanisms of childhood B-precursor acute lymphoblastic leukemia (ALL) by bioinformatics analysis and find potential targets for childhood ALL diagnosis and treatment.Gene expression profile GSE28460 was downloaded from the Gene Expression Omnibus, including 49 diagnostic and relapse bone marrow samples with childhood B-precursor ALL. The differentially expressed genes (DEGs) were identified by paired t-test. Pathway enrichment analysis of DEGs and transcription factors (TFs) enrichment analysis were performed, followed by construction of co-expressed, DEGs, and susceptibility gene protein-protein interaction (PPI) network. Based on these three networks, relevant regulatory network modules and the important DEGs in the modules were identified.Total of 947 DEGs were identified. Up-regulated DEGs enriched 20 pathways including cell cycle, and down-regulated DEGs significantly enriched Jak-STAT signaling pathways. CDK1 and BRCA1 were found to have more hubs in both co-expressed network and PPI network. Besides, total of five modules in INTS10, MCM, BRCA1, GYPA, and VCAN1 families were identified and a pathway of INTS10-INTS6-POLR2A-MAGI2 was selected.Cell cycle and Jak-STAT signaling pathway were closely associated with relapse of childhood B-precursor ALL. The DEGs, such as PTTG1, PIK3CA, CDK1, and BRCA1 may be the potential targets for childhood ALL diagnosis and treatment.

Background This retrospective cohort study analysed the clinical characteristics and outcomes of patients with childhood lymphoblastic lymphoma (LBL) treated in Shanghai, China. Procedure From 2001 to 2010, 108 evaluable patients ≤16 years of age who were newly diagnosed with biopsy-proven LBL were treated with one of three treatment protocols: CCCG-99, SCMC-T-NHL-2002, or LBL-CHOF-2006. Results Two patients had Stage I disease, 5 had Stage II, 55 had Stage III, and 46 had Stage IV. The immunophenotype was T-cell LBL in 92 patients (85.2%) and precursor B-cell LBL in 16 (14.8%). The abandonment rate was 11.5%. Twenty-five patients (23.2%) suffered from resistant disease, including 1 with isolated central nervous system (CNS) relapse. At a median follow-up of 40.4 months (range, 0–114 months), the 5-year probability of event-free survival (pEFS) was 63.9 ± 4.6% in all patients. The 5-year pEFS for patients with pB-LBL was better than for patients with T-LBL (100% vs. 61.3 ± 5.1%, P = 0.007). Patients who had achieved complete remission on day 33 of induction had significantly better pEFS than those who had not (78.8 ± 4.6% vs. 28.2 ± 9.0%, P = 0.000). Three of 25 patients who experienced resistant disease were alive at the end of the study period. Conclusions The abandonment rate was lower for patients with LBL than for patients with acute lymphoblastic leukemia. Prophylactic cranial radiation can be omitted for patients with LBL even when advanced-stage disease is present, as intensive systemic chemotherapy with intrathecal therapy is sufficient to prevent CNS relapse. The survival of patients with resistant disease was very poor. Pediatr Blood Cancer 2014;61:659–663. © 2013 Wiley Periodicals, Inc.

BACKGROUND The aim of this study was to investigate the diagnostic and prognostic value of microRNA (miRNA)-21, miRNA-23a, and miRNA-125b in Burkitt lymphoma (BL) in children. MATERIAL AND METHODS We recruited 41 children with BL for the case group, 56 children with lymph node inflammation for the positive control group, and 60 healthy children for the negative control group. Real-time fluorescent quantitative polymerase chain reaction (RT-qPCR) was conducted for detection of circulating miRNA-21, miRNA-23a, and miRNA-125b. A receiver operating characteristic (ROC) curve was drawn to compare the diagnostic value of miRNA-21, miRNA-23a, and miRNA-125b. Kaplan-Meier method and log-rank test were used for prognostic analyses. RESULTS MiRNA-21 and miRNA-23a had significantly higher expression in cases than in positive and negative controls (all P

Summary We report the outcome of 92 non-high risk children with acute lymphoblastic leukaemia (ALL) following a Berlin-Frankfurt-Munster (BFM) Intercontinental ALL -based protocol. Compared with a matched historical control group, we found a lower incidence of treatment-related early death (1·2% vs. 10·9%, P = 0·015), a higher 6-year event-free survival (75·4 ± 4·9% vs. 58·2 ± 6·7%, P = 0·02), reduced total in-hospital costs per person (US $) (10267·0 vs. 18331·0, P

Introduction: Genetic variability affects clinical outcome in pediatric acute lym- phocytic leukemia (ALL) patients. Evaluating gene polymorphisms in ABC trans- porters could help identify relapse risk and predict outcome. Material and methods: The SNaPshot SNP technique was used to analyze sin- gle-nucleotide polymorphisms (SNPs) in the multidrug transporter 1 (MDR1), multidrug resistance associated proteins (MRP1, MRP2) and breast cancer resist- ance protein (BCRP) genes of 82 pediatric ALL patients. The association between the SNPs with risk of all events and death as well as with survival was evalu- ated by the univariate Cox proportional hazard model. Results: The BCRP G34A SNP was the only SNP significantly associated with ALL. Risk factors included pre-treatment WBC counts and post-treatment peripher- al and bone marrow leukemic cell counts. We found no association between MDR1 SNPs with these factors. The BCRP C421A C/A and C/C genotypes were significantly associated with low pre-treatment WBC counts while MRP2 G1249A G/G was significantly associated with low levels of post-treatment peripheral and bone marrow leukemic cells. A combination of C1236T, G1249A and/or G34A SNPs was significantly associated with lower EFS and OS. Conclusions: Polymorphisms associated with risk of ALL and clinical outcome may be potential biomarkers to predict clinical outcome and improve progno- sis in childhood ALL.

Autologous nonmyeloablative hematopoietic stem cell transplantation (AHST) in newly diagnosed and young adult type 1 diabetes mellitus (T1DM) was reported. We report our first year AHST experience in newly diagnosed childhood T1DM. 7 patients with T1DM (HbA1c 11.7%-14%, 4 with diabetic ketoacidosis, aged 5.0-13.7 years) diagnosed within the previous 3 months by clinical findings and hyperglycemia and confirmed with positive antibodies against GAD65, IA2, ICA or insulin. Hematopoietic stem cells were mobilized with cyclophosphamide and granulocyte colonystimulating factor and then collected from peripheral blood by leukapheresis and cryopreserved. The cells were injected intravenously after conditioning with cyclophosphamide and rabbit antithymocyte globulin. Major side effects, changes in exogenous insulin requirements, HbA1c, C-peptide levels are analyzed. During a 12- to 18-month follow-up, 6 (6/7, 85.7%) patients became insulin free 1-3 months after AHST, 1 patients failed (5 year old) to acquire insulin free, all the patients resumed normal school study. The preprandial, predormital blood glucose were ranged from 3.9-6.0 mmol/L with the HbA1c level between 4.6%-6.1% in insulin-independent patients. Vomiting, anorexia, short-term fever, hair loss occurred in all the patients during AHST, convulsion occurred in 1 patients due to severe sodium water retention, leukocytopenia was evident in the first 1-3 months after AHST, one patients suffered from acute bronchitis 2 months after AHST. No other systemic organ lesions were found in all the patients. High-dose immunosuppression and AHST were performed with acceptable toxicity in 7 patients with newly diagnosed childhood T1DM. With AHST, beta cell function was improved and induced insulin independence in the majority of the patients.