Prognostic significance of multiparametric flow cytometry minimal residual disease at two time points after induction in pediatric acute myeloid leukemia.

BACKGROUND: Prompt response to induction chemotherapy is a prognostic factor in pediatric acute myeloid leukemia. In this study, we aimed to evaluate the prognostic significance of multiparametric flow cytometry-minimal residual disease (MFC-MRD), assessed at the end of the first and second induction courses. METHODS: MFC-MRD was performed at the end of the first induction (TP1) in 524 patients and second induction (TP2) in 467 patients who were treated according to the modified Medical Research Council (UK) acute myeloid leukemia 15 protocol. RESULTS: Using a 0.1% cutoff level, patients with MFC-MRD at the two time points had lower event-free survival and overall survival. Only the TP2 MFC-MRD level could predict the outcome in a separate analysis of high and intermediate risks based on European LeukemiaNet risk stratification and KMT2A rearrangement. The TP2 MFC-MRD level could further differentiate the prognosis of patients into complete remission or non-complete remission based on morphological evaluation. Multivariate analysis indicated the TP2 MFC-MRD level as an independent adverse prognostic factor for event-free survival and overall survival. When comparing patients with MFC-MRD ≥ 0.1%, those who underwent hematopoietic stem cell transplant during the first complete remission had significantly higher 5-year event-free survival and overall survival and lower cumulative incidence of relapse than those who only received consolidation chemotherapy. CONCLUSIONS: The TP2 MFC-MRD level can predict the outcomes in pediatric patients with acute myeloid leukemia and help stratify post-remission treatment.

Long Non-coding RNA RP11-252C15.1 is a Potential Biomarker of Prognosis and Hallmark for Leukemogenesis in Children with B-cell Precursor Acute Lymphoblastic Leukemia.

INTRODUCTION: Improved understanding of the prognostic biomarkers associated with childhood acute lymphoblastic leukemia (ALL) is needed for accurate risk group stratification. This study aimed to identify potential long-non coding RNA (lncRNA) markers and evaluate their prognostic value in children with ALL. METHODS: We selected 50 children with newly diagnosed ALL and 20 age-matched patients with idiopathic immune thrombocytopenia (controls). RNA sequencing was performed to identify differentially expressed lncRNAs between the ALL and control groups. Correlation analysis was performed to determine the relationships between candidate lncRNAs, clinical features, and the risk of leukemogenesis. RESULTS: A total of 1,019 differentially expressed lncRNAs were identified between the ALL and control groups. Reverse-transcriptase (RT-qPCR) revealed that lncRNA RP11-252C15.1 and lncRNA RP11-701P16.2 were significantly upregulated in patients with ALL. Furthermore correlation analysis showed that lncRNA RP11-252C15.1 and lncRNA RP11-701P16.2 represent potential predictors of leukemogenesis; however, only lncRNA RP11-252C15.1 was associated with clinical features and outcome in children with B-cell precursor ALL (BCP-ALL). In vitro experiments confirmed that lncRNA RP11-252C15.1 was significantly overexpressed in BCP-ALL cell lines and promoted proliferation, and repressed apoptosis in MHH-CALL-3 cells. CONCLUSION: LncRNA RP11-252C15.1 is a potential oncogene in BCP-ALL pathogenesis and a prognostic biomarker in children with BCP-ALL.

[Clinical features and prognosis of high hyperdiploid childhood acute lymphoblastic leukemia: a multicenter retrospective analysis in Fujian Province, China]. / é«˜è¶ äºŒå€ä½“æ ¸åž‹å„¿ç«¥æ€¥æ€§æ·‹å·´ç»†èƒžç™½è¡€ç— çš„ä¸´åºŠç‰¹å¾åŠé¢„åŽ.

OBJECTIVES: To study the clinical features and prognosis of high hyperdiploid (HHD) childhood acute lymphoblastic leukemia (ALL). METHODS: A retrospective analysis was performed on the medical data of 1 414 children who were newly diagnosed with ALL and were admitted to five hospitals in Fujian Province of China from April 2011 to December 2020. According to karyotype, they were divided into two groups: HHD (n=172) and non-HHD (n=1 242). The clinical features and treatment outcome were compared between the two groups, and the factors influencing the prognosis were further explored. RESULTS: Among the 1 414 children with ALL, 172 (12.16%) had HHD. Compared with the non-HHD group, the HHD group had significantly lower proportions of children with risk factors for poor prognosis at diagnosis (age of onset ≥10 years or <1 year, white blood cell count ≥50×109/L, and T-cell phenotype) or positive fusion genes (TEL-AML1, BCR-ABL1, E2A-PBX1, and MLL gene rearrangement) (P<0.05). The HHD group had a significantly higher proportion of children with minimal residual disease (MRD) <0.01% at the end of induction chemotherapy (P<0.05). The 10-year event-free survival (EFS) rate and overall survival (OS) rate in the HHD group were significantly higher than those in the non-HHD group (P<0.05). The univariate analysis showed that the number of chromosomes of 58-66, trisomy of chromosome 10, trisomy of chromosome 17, bone marrow MRD <1% on day 15 or 19 of induction chemotherapy, and bone marrow MRD <0.01% on day 33 or 46 of induction chemotherapy were associated with a higher EFS rate (P<0.05), and trisomy of chromosome 10 was associated with a higher OS rate (P<0.05). The multivariate Cox analysis showed that trisomy of chromosome 17 was closely associated with a high EFS rate (P<0.05). CONCLUSIONS: The ALL children with HHD have few risk factors for poor prognosis at diagnosis and often have good prognosis. The number of chromosomes and trisomy of specific chromosomes are associated with prognosis in these children.

Evaluating the prognostic value of CD56 in pediatric acute myeloid leukemia.

BACKGROUND: Many cytogenetic changes and gene mutations are associated with acute myeloid leukemia (AML) survival outcomes. CD56 is related to poor prognosis when expressed in adult AML patients. However, the prognostic value of CD56 in children with AML has rarely been reported. In this research, we aimed to evaluate the prognostic value of CD56 in childhood AML. METHODS: The present retrospective study included 145 newly diagnosed pediatric patients with de novo AML (excluding AML-M3) in two hospitals between January 2015 and April 2021. RESULTS: The total median (range) age was 75 (8-176) months, and the median follow-up time was 35 months. No significant difference in the 3-year overall survival rate was noted between the CD56-positive and CD56-negative groups (67.0% vs. 79.3%, P = 0.157) who received chemotherapy. However, among high-risk patients, the CD56-positive group had a worse overall survival rate and event-free survival rate (P < 0.05). Furthermore, among high-risk patients, the CD56-positive group had higher relapse and mortality rates than the CD56-negative group (P < 0.05). CONCLUSIONS: CD56 represents a potential factor of poor prognosis in specific groups of children with AML and should be considered in the risk stratification of the disease. Given the independent prognostic value of CD56 expression, we should consider integrating this marker with some immunophenotypic or cytogenetic abnormalities for comprehensive analysis.

[Effect of increasing the intensity of chemotherapy on the prognosis of acute lymphoblastic leukemia in children with IKZF1 deletion].

OBJECTIVE: To study the clinical features of acute lymphoblastic leukemia (ALL) in children with IKAROS family zinc finger 1 (IKZF1) deletion, and to observe the effect of increasing the intensity of chemotherapy on the prognosis of this disease. METHODS: A total of 278 children diagnosed with ALL between December 2015 and February 2018 were systematically treated according to the Chinese Children's Leukemia Group-ALL 2008 protocol (CCLG-ALL 2008). The patients were divided into an IKZF1-deleted group and a control group according to the presence or absence of IKZF1. The IKZF1-deleted group was treated with the regimen for high-risk group (HR) in the CCLG-ALL 2008 protocol, while the control group received different intensities of chemotherapy according to clinical risk classification. The clinical features and event-free survival rate (EFS) were compared between the two groups. RESULTS: A total of 24 (8.6%) cases of 278 children were found to have large deletions of exons of the IKZF1 gene. The IKZF1-deleted group had significantly higher proportions of cases with white blood cell count ≥50×109/L at initial diagnosis, BCR-ABL1 fusion gene positive, minimal residual disease ≥10% on the 15th day of induction remission treatment, minimal residual disease-high risk and clinical risk classification-high risk compared with the control group (P<0.05). The 3-year EFS rate (76%±10%) in the IKZF1-deleted group was lower than that in the control group (84%±4%), but with no significant difference between the two groups (P=0.282). The estimated 3-year EFS rate in the IKZF1-deleted-non-HR group (actually treated with the chemotherapy regimen for HR in the CCLG-ALL 2008 protocol) was 82%±12%, which was lower than that in the control-non-HR group (86%±5%), but there was no significant difference (P=0.436). CONCLUSIONS: ALL children with IKZF1 deletion have worse early treatment response, and increasing the intensity of chemotherapy might improve the prognosis.

[Clinical features and prognosis of children with mature B-cell non-Hodgkin's lymphoma: an analysis of 28 cases].

OBJECTIVE: To study the clinical features and treatment outcome of children with mature B-cell non-Hodgkin's lymphoma (B-NHL). METHODS: A total of 28 previously untreated children with mature B-NHL were enrolled and given the chemotherapy regimen of CCCG-B-NHL-2010. Among them, 20 were given rituximab in addition to chemotherapy. The children were followed up for 31 months (ranged 4-70 months). A retrospective analysis was performed for the clinical features of these children. The Kaplan-Meier method was used for survival analysis. A univariate analysis was performed to investigate the prognostic factors. RESULTS: Among the 28 children, 17 (61%) had Burkitt lymphoma, 8 (29%) had diffuse large B-cell lymphoma (DLBCL), and 3 (11%) had unclassifiable B-cell lymphoma. As for the initial symptom, 13 (46%) had cervical mass, 10 (36%) had maxillofacial mass, 9 (32%) had hepatosplenomegaly, 5 (18%) had abdominal mass, and 5 (18%) had exophthalmos. Of all children, 14 had a lactate dehydrogenase (LDH) level of <500 IU/L, 3 had a level of 500-1 000 IU/L, and 11 had a level of ≥ 1 000 IU/L. After two courses of chemotherapy, 21 children achieved complete remission and 7 achieved partial remission. At the end of follow-up, 24 achieved continuous complete remission and 4 experienced recurrence. The 2-year event-free survival rate was (85.7± 6.6)%. The children with bone marrow infiltration suggested by bone marrow biopsy, serum LDH ≥500 IU/L, and bone marrow tumor cells >25% had a low 2-year cumulative survival rate. CONCLUSIONS: The CCCG-B-NHL 2010 chemotherapy regimen combined with rituximab has a satisfactory effect in the treatment of children with B-NHL. Bone marrow infiltration on bone marrow biopsy is associated with poor prognosis.

High expression of SLC27A2 predicts unfavorable prognosis and promotes inhibitory immune infiltration in acute lymphoblastic leukemia.

Solute carrier family 27 member 2 (SLC27A2) is involved in fatty acid metabolism in tumors and represents a prospective target for cancer therapy. However, the role and mechanism of action of SLC27A2 in acute lymphoblastic leukemia (ALL) remain unclear. In this study, we aimed to explore the intrinsic associations between SLC27A2 and ALL and evaluate the prognostic significance, biological functions, and correlation with immune infiltration. We used the transcriptome and clinical data from the TARGET dataset. Differentially expressed genes (DEGs) in the SLC27A2 low- and high-expression groups were analyzed for prognostic implications and functional enrichment. Furthermore, we analyzed the relationship between SLC27A2 gene expression and immune cell infiltration using the ESTIMATE method, which was evaluated using the TIGER platform. Finally, we knocked down SLC27A2 in the Jurkat ALL cell line and conducted cell proliferation, western blotting, flow cytometry, and CCK-8 assays to elucidate the biological function of SLC27A2 in ALL. Patients with ALL who have higher expression levels of SLC27A2 have poorer overall survival and event-free survival. According to gene set enrichment analysis, the DEGs were primarily enriched with immune system processes and the PI3K-Akt signaling pathway. There was an inverse relationship between SLC27A2 expression and immune cell invasion, suggesting involvement of the former in tumor immune evasion. In vitro experiments showed that knockdown of SLC27A2 inhibited cell proliferation and protein expression and altered the Akt pathway, with a reduced proportion of B cells. In conclusion, SLC27A2 plays a vital role in the development of ALL.

Experience in improving treatment outcomes for childhood acute lymphoblastic leukemia: real-world results for a province in China, 2011-2020.

The present study aimed to investigate the real-world results of childhood acute lymphoblastic leukemia (cALL) cases in Fujian, China. The clinical data of 1414 patients with newly diagnosed cALL in Fujian were retrospectively analyzed. Patients were treated according to the Chinese Children Leukemia Group 2008 protocol (CCLG-ALL 2008 group) or Chinese Children's Cancer Group 2015 protocol (CCCG-ALL 2015 group). Cumulative incidence of treatment abandonment (TA) at 5 years was 4.2% ± 0.6% and significantly associated with treatment period and risk stratification. The 5-OS and EFS were significantly higher in the CCCG-ALL 2015 group than in the CCLG-ALL 2008 group. Patients treated with CCCG-ALL 2015 from Fujian Medical Union Hospital had a significantly higher 4-year OS and EFS than did those from the other four hospitals. Real-world TA of cALL greatly decreased, and its long-term survival significantly increased in Fujian, which may be related to optimizing programs, multi-center collaboration, and improving treatment compliance.

Genetic prediction of causal association between serum bilirubin and hematologic malignancies: a two-sample Mendelian randomized and bioinformatics study.

Introduction: An increasing number of cohort studies have shown a correlation between serum bilirubin and tumors, but no definitive causal relationship has been established between serum bilirubin and hematological malignancies.Therefore, the aim of the present study was to assess the causal relationship of serum bilirubin, including total bilirubin (TBIL) and direct bilirubin (DBIL), with hematological malignancies, including leukemia, lymphoma, and myeloma. Methods: We used a genome-wide association study (GWAS) collection of TBIL, DBIL, and hematological malignancies data. Using two-sample Mendelian randomization(MR), we assessed the impact of TBIL and DBIL on hematological malignancies. For this study, the inverse variance weighting method (IVW) was the primary method of MR analysis. In the sensitivity analysis, the weighted median method, MR Egger regression, and MR-PRESSO test were used. To understand the mechanisms behind TBIL and DBIL, we used three different approaches based on screening single nucleotide polymorphisms (SNPs) and their associated genes, followed by bioinformatics analysis. Results: The IVW test results showed evidence of effects of TBIL (odds ratio [OR]: 4.47, 95% confidence interval [CI]: 1.58-12.62) and DBIL (OR: 3.31, 95% CI: 1.08-10.18) on the risk of acute myeloid leukemia (AML).The findings from bioinformatics indicated that TBIL could potentially undergo xenobiotic metabolism through cytochrome P450 and contribute to chemical carcinogenesis. Discussion: In this study, two-sample MR analysis revealed a causal relationship between TBIL, DBIL, and AML.

[Clinical Features and Prognosis of Acute T-cell Lymphoblastic Leukemia in Children--Multi-Center Data Analysis in Fujian].

OBJECTIVE: To evaluate the efficacy of acute T-cell lymphoblastic leukemia (T-ALL) in children and explore the prognostic risk factors. METHODS: The clinical data of 127 newly diagnosed children with T-ALL admitted to five hospitals in Fujian province from April 2011 to December 2020 were retrospectively analyzed, and compared with children with newly diagnosed acute precursor B-cell lymphoblastic leukemia (B-ALL) in the same period. Kaplan-Meier analysis was used to evaluate the overall survival (OS) and event-free survival (EFS), and COX proportional hazard regression model was used to evaluate the prognostic factors. Among 116 children with T-ALL who received standard treatment, 78 cases received the Chinese Childhood Leukemia Collaborative Group (CCLG)-ALL 2008 protocol (CCLG-ALL 2008 group), and 38 cases received the China Childhood Cancer Collaborative Group (CCCG)-ALL 2015 protocol (CCCG-ALL 2015 group). The efficacy and serious adverse event (SAE) incidence of the two groups were compared. RESULTS: Proportion of male, age≥10 years old, white blood cell count (WBC)≥50×109/L, central nervous system leukemia, minimal residual disease (MRD)≥1% during induction therapy, and MRD≥0.01% at the end of induction in T-ALL children were significantly higher than those in B-ALL children (P <0.05). The expected 10-year EFS and OS of T-ALL were 59.7% and 66.0%, respectively, which were significantly lower than those of B-ALL (P <0.001). COX analysis showed that WBC≥100×109/L at initial diagnosis and failure to achieve complete remission (CR) after induction were independent risk factors for poor prognosis. Compared with CCLG-ALL 2008 group, CCCG-ALL 2015 group had lower incidence of infection-related SAE (15.8% vs 34.6%, P =0.042), but higher EFS and OS (73.9% vs 57.2%, P EFS=0.090; 86.5% vs 62.3%, P OS=0.023). CONCLUSIONS: The prognosis of children with T-ALL is worse than children with B-ALL. WBC≥100×109 /L at initial diagnosis and non-CR after induction (especially mediastinal mass has not disappeared) are the risk factors for poor prognosis. CCCG-ALL 2015 regimen may reduce infection-related SAE and improve efficacy.

[Clinical Characteristics and Prognosis of MLL Rearranged Childhood Acute Lymphocyte Leukemia].

AbstractObjective: To investigate the clinical characteristics and prognostic factors in childhood acute lymphoblastic leukemia with MLL gene-rearrangement-positive (MLL-r+ ALL). METHODS: The clinical data of 1 414 newly diagnosed children with ALL admitted to five hospital in Fujian province from April 2011 to December 2020 were retrospectively analyzed. The clinical characteristics and efficacy of MLL-r+ and MLL-r- subgroup were compared. The prognostic factors of MLL-r ALL were analyzed by COX regression model. RESULTS: Among all children with ALL, the proportion of patients aged less than 1 year old was 1.8%, and the detection rate of MLL-r+ was 3.4% (48/1 414). The positive detection rate of MLL-r in the age groups <1 year old, and ≥1 year old and ≤14 years old was 38.5% (10/26) and 2.7 (38/1 388), respectively, the difference was statistically significant (P<0.000). Compared with MLL-r- group, the MLL-r+ group had a higher proportion of patients with age <1 year, white blood cell (WBC) count ≥50×109/L, combined central nervous system leukemia (CNSL) and testicular leukemia(TL), while MRD <0.01% on d 33 or d 46 of induction chemotherapy was lower (all P<0.05). The expected 10-year event free survival(EFS) rate and overall survival(OS) rate of the MLL-r+ group were significantly lower than those of the MLL-r- group （EFS： 49.9% vs 77.0%； OS: 55.3% vs 82.9%， P<0.05). COX regression model analysis showed that age <1 year, minimal residual disease (MRD) ≥0.01% on d 33 or d 46 of induction chemotherapy were independent risk factors for worse OS and EFS in MLL-r+ ALL patients (all P<0.05). CONCLUSION: Age <1 year old, high WBC, concomitant CNSL and TL are more common in children with MLL-r+ ALL at initial diagnosis, with poor early treatment response and long-term prognosis. Age <1 year old at initial diagnosis and MRD positive after induction chemotherapy may be risk factors for poor prognosis.

Dose-Dependent Efficacy of Umbelliferone and Gelatin-Coated ZnO/ZnS Core-Shell Nanoparticles: A Novel Arthritis Agent for Severe Knee Arthritis.

Rheumatoid arthritis (RA) is a well-known autoimmune disorder that affects 1% of the global population. Zinc (Zn) is crucial for bone homeostasis, when compared with normal human bone, Zn level found to be decreased in RA patients and collagen-induced arthritis (CIA) rats. Notably, Zn-based medicinal products play a prominent role in reducing disease symptoms and acute side effects of patients with bone-related diseases. In this study, we report the clinical efficiency of gelatin- (Gel-) coated ZnO-ZnS core-shell nanoparticles (CSNPs) with umbelliferon (Uf) drug (Uf-Gel-ZnO-ZnS CSNPs) on the normal and CIA-induced Wistar rats. The formed ZnO-ZnS CSNPs are spherical in shape, with an average particle diameter of 150 ± 7 nm. It showed strong cytocompatibility when tested on L929 and foreskin fibroblasts (BJ) cells by MTT assay. While comparing with free Uf, various doses (2.5 and 5 mg) of Uf-Gel-ZnO-ZnS CSNPs showed strong inhibition of CIA by attenuated proinflammatory cytokines such as interleukin-1ß, IL-6, PEG2, and IL-17. The Uf-Gel-ZnO-ZnS CSNPs show more effectiveness in reducing joint swelling and also increase the level of antioxidant enzymes. In addition, CSNPs significantly reduced the infiltration of inflammatory cells in the knee joint. Thus, the current study concludes that Uf-Gel-ZnO-ZnS CSNPs feasibly reduce the incidence of arthritis in a dose-dependent manner by attenuation of inflammation.

[Comparison of the Early Efficacy and Serious Adverse Events between CCCG-ALL 2015 and CCLG-ALL 2008 in the Treatment of Pediatric Patients with Acute Lymphoblastic Leukemia].

OBJECTIVE: To evaluate the early efficacy and serious adverse events (SAE) related to chemotherapy of different protocols in the treatment of pediatric patients with acute lymphoblastic leukemia (ALL), so as to improve the overall survival rate. METHODS: A comparison of the early efficacy and SAE was performed between pediatric patients treated with Chinese Children Cancer Group-ALL 2015 (CCCG-ALL 2015) protocol from January 2019 to June 2020 and those treated with Chinese Children Leukemia Group-ALL 2008 (CCLG-ALL 2008) protocol from January 2017 to December 2018. RESULTS: The remission rate before consolidation chemotherapy between the two groups was not significantly different (P=0.198), but the negative conversion rate of minimal residual disease (MRD) in CCLG-ALL 2008 group was significantly higher than that in CCCG-ALL 2015 group (P=0.000). The incidence of SAE in CCCG-ALL 2015 group was significantly lower than that in CCLG-ALL 2008 group (P=0.021), and the incidence of infection-related SAE was significantly higher in the latter (P=0.001), while the difference of non-infection-related SAE was not statistically significant (P=0.623). In addition, the treatment-related mortality in CCCG-ALL 2015 group was significantly lower than that in CCLG-ALL 2008 group (P=0.003). CONCLUSION: CCCG-ALL 2015 regimen reduces the intensity of chemotherapy, which can significantly decrease the chemotherapy-related SAE (especially infection-related SAE), as well as treatment-related mortality. However, the MRD negative conversion rate is low before consolidation treatment, and the overall long-term efficacy remains to be further observed.

Association of Platelet Desialylation and Circulating Follicular Helper T Cells in Patients With Thrombocytopenia.

Thrombocytopenia is a multifactorial condition that frequently involves concomitant defects in platelet production and clearance. The physiopathology of low platelet count in thrombocytopenia remains unclear. Sialylation on platelet membrane glycoprotein and follicular helper T cells (TFHs) are thought to be the novel platelet clearance pathways. The aim of this study was to clarify the roles of platelet desialylation and circulating TFHs in patients with immune thrombocytopenia (ITP) and non-ITP thrombocytopenia. We enrolled 190 patients with ITP and 94 patients with non-ITP related thrombocytopenia including case of aplastic anemia (AA) and myelodysplastic syndromes (MDS). One hundred and ten healthy volunteers were included as controls. We found significantly increased desialylated platelets in patients with ITP or thrombocytopenia in the context of AA and MDS. Platelet desialylation was negatively correlated with platelet count. Meanwhile, the circulating TFH levels in patients with thrombocytopenia were significantly higher than those of normal controls, and were positively correlated with desialylated platelet levels. Moreover, TFHs-related chemokine CXCL13 and apoptotic platelet levels were abnormally high in ITP patients. The upregulation of pro-apoptotic proteins and the activation of the MAPK/mTOR pathway were observed in the same cohort. These findings suggested that platelet desialylation and circulating TFHs may become the potential biomarkers for evaluating the disease process associated with thrombocytopenia in patients with ITP and non-ITP.

Genomic heterogeneity contributed to different prognosis between adult and pediatric acute lymphoblastic.

The prognosis of acute lymphoblastic leukemia (ALL) in adults is inferior to that in children. Hence, ALL remains challenging to cure in the adult population. Aberrant genetic alterations have been observed in ALL, although the patterns of differential gene alterations in adult and pediatric ALL have not been comprehensively determined on a genome-wide scale. We investigated the biologic differences in genomic profiles between adults (n = 64) and children (n = 54) with ALL and relationship between genomic heterogeneity and prognosis. The 2 populations showed similar common mutation types but an increased prevalence of genetic alterations in adult ALL. The median numbers of gene mutations were 17 (range: 1-53) and 4.5 (range: 1-19) per sample in adult and pediatric ALL, respectively (p < 0.001). An increased number of gene mutations and age were significantly correlated (R2  = 0.5853, p < 0.001). We identified 122 and 53 driver genes in adult and pediatric ALL samples, respectively. IKZF1, IDH1, and TTN mutations were significantly enriched in adult patients with ALL. KRAS, ARID1A, and CREBBP mutations were significantly enriched in pediatric patients with ALL (p < 0.05). The incidence of relapse was 40.0% and 9.6% in adult and pediatric patients with ALL, respectively (p = 0.003). The overall survival and relapse-free survival of adult patients with ALL were poorer than those of pediatric patients with ALL (p = 0.002 and p < 0.001, respectively). This genomic landscape enhances the understanding of the biologic differences in ALL between the 2 populations and provides insight for developing therapeutic approaches.

Initial experience from the transgastric endoscopic peritoneoscopy and biopsy: a stepwise approach from the laboratory to clinical application.

BACKGROUND AND AIM: Natural-orifice translumenal endoscopic surgery (NOTES) is a newly minimally invasive technique that gives access to the abdominal cavity via transgastric, transcolonic, transvaginal or transvesical routes. The aim of the present study was to evaluate the safety and feasibility of transgastric endoscopic peritoneoscopy and biopsy from laboratory to clinical application. METHODS: With the animals under general anesthesia, a sterile esophageal overtube was placed and a gastric antibiotic lavage was performed. Subsequently, a needle-knife and through-the-scope dilating balloon were used to make an anterior gastric wall incision through which a therapeutic gastroscope was advanced into the peritoneal cavity. After 2 weeks, another transgastric endoscopic exploration was performed in a different location of the stomach. The peritoneal cavity was examined before the gastric incision was closed. After 4 weeks of observation, necropsy was performed. In the clinical application, after gastric lavage, the first step was the creation of the gastrotomy under general anesthesia, sometime under direct vision of the laparoscopic scope. Then the endoscope can be maneuvered in the peritoneal cavity. And peritoneoscopy and biopsy were performed. Biopsies can be obtained from any suspicious areas using punch biopsy forceps. The gastrotomy was then closed with clips. The gastroscopy was examined after one week. RESULTS: Twenty-eight transgastric endoscopic peritoneoscopies and biopsies in pigs and a total of five transgastric human endoscopic peritoneoscopies and biopsies have been performed. All procedures were completed satisfactorily in the pig model and all patients. There were no intraoperative or postoperative complications. CONCLUSIONS: The advantages of peritoneoscopy and biopsy appeared to be enhanced by this approach. Patients had minor postoperative pain and minimal scarring. It is safe and feasible for us to use transgastric endoscopic peritoneoscopy and biopsy in humans.

Cyclosporine A-related neurotoxicity after haploidentical hematopoietic stem cell transplantation in children with hematopathy.

BACKGROUND: To evaluate cyclosporine A (CSA)-related neurotoxicity after haploidentical hematopoietic stem cell transplantation (HID-HSCT) in children with hematopathy. METHODS: This retrospective case series study included children with hematopathy who underwent HID-HSCT at Fujian Medical University Union Hospital between February 2013 and January 2017. RESULTS: Fifty-one children (39 males) were included in the study with a median age of 8 (range, 1.1-18) years. Seven patients (13.7%) developed CSA-related neurotoxicity after a median 38 (range, - 3 to 161) days from HID-HSCT. Hypertension (5/7, 71%) was the most common prodrome. Brain magnetic resonance imaging showed posterior reversible encephalopathy syndrome in six patients and atypical abnormalities in one patient. One patient died from grade IV graft-versus-host disease (GvHD) on day + 160, and six patients were alive at the last follow-up. Four patients (71.4%) achieved complete remission, while two patients developed secondary epilepsy and exhibited persistent MRI and electroencephalogram abnormalities at the 5-year follow-up. Hypertension after CSA was more common in patients with CSA-related neurotoxicity than in those without (71% vs. 11%, P = 0.002). Five-year overall survival did not differ significantly between patients with CSA-related neurotoxicity (85.7 ± 13.2%) and those without (65.8 ± 7.2%). CONCLUSIONS: The incidence of CSA-related neurotoxicity in children with hematopathy undergoing HID-HSCT is relatively high.

High EVI1 Expression Predicts Adverse Outcomes in Children With De Novo Acute Myeloid Leukemia.

BACKGROUND: A high ecotropic viral integration site 1 (EVI1) expression (EVI1 high) is an independent prognostic factor in adult acute myeloid leukemia (AML). However, little is known of the prognostic value of EVI1 high in pediatric AML. This study aimed to examine the biological and prognostic significance of EVI1 high in uniformly treated pediatric patients with AML from a large cohort of seven centers in China. METHODS: A diagnostic assay was developed to determine the relative EVI1 expression using a single real-time quantitative polymerase chain reaction in 421 newly diagnosed pediatric AML patients younger than 14 years from seven centers in southern China. All patients were treated with a uniform protocol, but only 383 patients were evaluated for their treatment response. The survival data were included in the subsequent analysis (n = 35 for EVI1 high, n = 348 for EVI1 low). RESULTS: EVI1 high was found in 9.0% of all 421 pediatric patients with de novo AML. EVI1 high was predominantly found in acute megakaryoblastic leukemia (FAB M7), MLL rearrangements, and unfavorable cytogenetic aberrance, whereas it was mutually exclusive with t (8; 21), inv (16)/t (16; 16), CEBPA, NPM1, or C-KIT mutations. In the univariate Cox regression analysis, EVI1 high had a significantly adverse 5-year event-free survival (EFS) and overall survival (OS) [hazard ratio (HR) = 1.821 and 2.401, p = 0.036 and 0.005, respectively]. In the multivariate Cox regression analysis, EVI1 high was an independent prognostic factor for the OS (HR = 2.447, p = 0.015) but not EFS (HR = 1.556, p = 0.174). Furthermore, EVI1 high was an independent adverse predictor of the OS and EFS of patients with MLL rearrangements (univariate analysis: HR = 9.921 and 7.253, both p < 0.001; multivariate analysis: HR = 7.186 and 7.315, p = 0.005 and 0.001, respectively). Hematopoietic stem cell transplantation (HSCT) in first complete remission (CR1) provided EVI1 high patients with a tendential survival benefit when compared with chemotherapy as a consolidation (5-year EFS: 68.4% vs. 50.8%, p = 0.26; 5-year OS: 65.9% vs. 54.8%, p = 0.45). CONCLUSION: It could be concluded that EVI1 high can be detected in approximately 10% of pediatric AML cases. It is predominantly present in unfavorable cytogenetic subtypes and predicts adverse outcomes. Whether pediatric patients with EVI1 high AML can benefit from HSCT in CR1 needs to be researched further.

[Clinical Features and Prognosis of Acute Lymphoblastic Leukemia Children with P2RY8-CRLF2 Gene Rearrangement].

OBJECTIVE: To investigate the clinical features and prognostic factors of acute lymphoblastic leukemia (ALL) children with P2RY8-CRLF2 gene rearrangement. METHODS: A total of 108 children with B-cell ALL (B-ALL) were diagnosed and systematically treated according to Chinese Children's Leukemia Group (CCLG) -ALL 2008 in our hospital from January 2016 to December 2016. The 108 patients were divided into two groups according to the result of mutiplex polymerase chain reaction: group with P2RY8-CRLF2 gene rearrangement and group without P2RY8-CRLF2 gene rearrangement. The ALL children with P2RY8-CRLF2 gene rearrangement were all treated by CCLG-ALL 2008 high-risk group (HR) regimens, and the ALL children in group without P2RY8-CRLF2 gene rearrangement received different intensity chemotherapy according to clinical risk classification. RESULTS: Five (4 male and 1 female) out of 108 patients with B-ALL had P2RY8-CRLF2 gene rearrangement. In the 5 B-ALL patients with P2RY8-CRLF2 gene rearrangement, the median age of the was 4 (2-6) years old and the median WBC count was 26.2 (2.46-525.1)×109/L. These patients presented different immunophenotype, including 3 cases of common B-ALL and 2 cases of pre B-ALL. Four patients carried a normal karyotype and 1 patient carried 46, XY, der (20) [22]/46, XY[2]. For the children with P2RY8-CRLF2 gene rearrangement, 1 patient (20%) could not achieve complete remission (CR), and minimal residual disease (MRD) of 2 patients (40%) was higher than 1% on day 33 of induction chemotherapy; while in group without P2RY8-CRLF2 gene rearrangement, all the patient achieved CR, and MRD in 6 patients (5.8%) was higher than 1% on day 33 of induction chemotherapy. The 3 year event-free survival (EFS) of ALL children in group with P2RY8-CRLF2 gene rearrangement was significantly lower than that in group without P2RY8-CRLF2 gene rearrangement (60.0%±21.9% vs 85.9%±3.9%) (P<0.05). CONCLUSION: The early treatment response and prognosis of ALL children with P2RY8-CRLF2 gene rearrangement are worse, and more effective protocol is needed for this subtype patients.