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The evidence for the safety and efficacy of adding rituximab to intensive chemotherapy in pediatric patients with aggressive mature B cell non-Hodgkin lymphoma/leukemia (B-NHL/B-AL) is not yet robust. In this prospective multi-institutional trial, 419 evaluable patients ≤ 16 years of age with newly diagnosed B-NHL/B-AL were enrolled. Patients were stratified into 4 risk groups according to stage, resection status, and serum lactate dehydrogenase. Patients in group R1 received 3 therapy courses in the treatment order A-B-A. Patients in group R2 received 5 courses A-B-A-B-A. Patients in group R3 received 6 courses A-BB-AA-BB-AA-BB. For patients in group R4, rituximab was added to the chemotherapy backbone for patients in R3 (A-RBB-RAA-RBB-RAA-BB). At a median follow-up of 54 months, the 4-year event-free survival (EFS) for the entire group was 88.3 ± 1.6% (76.0 ± 4.3% in the historical study). The EFS rates according to the intention-to-treat principle were 100%, 98.6 ± 1.2%, 94.2 ± 1.8%, and 73.5 ± 3.7% for patients in treatment groups R1, R2, R3, and R4, respectively (P 0.001). There were 9 (2.1%) toxic deaths due to infection during treatment. Regarding the toxicities of rituximab, grade 3/4 thrombocytopenia, mucositis, and infection occurred in 44.0%, 33.3%, and 64.0% after courses R-BB and grade 3/4 neutropenia, thrombocytopenia, and infection occurred in 96.3%, 77.8%, and 54.1% after courses RAA. The addition of rituximab to intensive chemotherapy is feasible even in a developing country. EFS was significantly improved when compared with the historical data. clinicals.gov identifier: NCT02405676.

Symmetric peripheral gangrene is a rare but devastating complication, scarcely reported after brain surgery. We present a case of symmetric peripheral gangrene shortly after brain surgery of intracranial hematoma removal and aneurysm clipping.

OBJECTIVE: To study the association between S100A8 expression and prognosis in children with acute lymphoblastic leukemia (ALL). METHODS: The clinical data of 377 children with ALL who were treated with the CCLG-2008-ALL regimen were retrospectively reviewed. ELISA and PCR were used to measure serum protein levels and mRNA expression of S100A8. The Kaplan-Meier method was used for survival analysis and a Cox regression analysis was also performed. RESULTS: The children were followed up for 56 months, and the overall survival rate of the 377 children was 89.1%. The prednisone good response group had significantly lower S100A8 protein and mRNA levels than the prednisone poor response group (P < 0.01). In the children with standard or median risk, both S100A8 protein and mRNA levels were associated with event-free survival rate (P < 0.05). There were significant differences in S100A8 protein and mRNA levels between the children with different risk stratifications (P < 0.01). The children who experienced events had significantly higher S100A8 protein and mRNA levels than those who did not (P < 0.01). The Kaplan-Meier survival analysis and the Cox regression model suggested that S100A8 overexpression was an independent risk factor for the prognosis of children with ALL. CONCLUSIONS: High S100A8 expression may be associated with the poor prognosis of children with ALL and is promising as a new marker for individualized precise treatment of children with ALL.

An 8-year-old girl who had experienced intermittent cough and fever over a 3 year period, was admitted after experiencing a recurrence for one month. One year ago the patient experienced a recurrent oral mucosal ulcer. Physical examination showed vitiligo in the skin of the upper right back. Routine blood tests and immune function tests performed in other hospitals had shown normal results. Multiple lung CT scans showed pulmonary infection. The patient had recurrent fever and cough and persistent presence of some lesions after anti-infective therapy. The antitubercular therapy was ineffective. Routine blood tests after admission showed agranulocytosis. Gene detection was performed and she was diagnosed with dyskeratosis congenita caused by homozygous mutation in RTEL1. Patients with dyskeratosis congenita with RTEL1 gene mutation tend to develop pulmonary complications. Since RTEL1 gene sequence is highly variable with many mutation sites and patterns and can be inherited via autosomal dominant or recessive inheritance, this disease often has various clinical manifestations, which may lead to missed diagnosis or misdiagnosis. For children with unexplained recurrent pulmonary infection, examinations of the oral cavity, skin, and nails and toes should be taken and routine blood tests should be performed to exclude dyskeratosis congenita. There are no specific therapies for dyskeratosis congenita at present, and when bone marrow failure and pulmonary failure occur, hematopoietic stem cell transplantation and lung transplantation are the only therapies. Androgen and its derivatives are effective in some patients. Drugs targeting the telomere may be promising for patients with dyskeratosis congenita.

A 7-year-old girl was admitted to Xiangya Hospital due to systemic lymphadenectasis for 2 months and skin ecchymosis for 3 days. Nine months ago, the girl experienced painless nodules in the left lower extremity with no apparent causes. Three months later, dermatorrhagia and ecchymosis occurred in many regions such as the periocular areas, conjunctiva, oral mucosa, perineal area, and groin, with a "raccoon sign" in both eyes; superficial lymphadenectasis and hepatosplenomegaly were also observed in many regions. The pathological sections for the skin nodules showed malignant tumors in lymphohematopoietic cells, and in combination with clinical manifestations, immunohistochemistry, and positive results for CD4, CD56, and CD123 by bone marrow flow cytometry, the girl was diagnosed with blastic plasmacytoid dendritic cell neoplasm. Then high-risk ALL regimen was applied as the chemotherapy for this girl. At present, the girl has been followed up for 3 months; ecchymosis has disappeared, and the enlarged lymph nodes have shrunk. No abnormal cells have been found in bone marrow morphological examination, and bone marrow flow cytometry has shown that primitive precursor cells account for 1.5% and express CD33, CD34, CD123, and CD117.

Acute lymphoblastic leukemia (ALL) is the most commonly diagnosed malignancy in children. It is a heterogeneous disease, and is determined by multiple gene alterations and chromosomal rearrangements. To improve current understanding of the underlying molecular mechanisms of ALL, the present study profiled genome‑wide digital gene expression (DGE) in a population of children with ALL in China. Using second‑generation sequencing technology, the profiling revealed that 2,825 genes were upregulated and 1,952 were downregulated in the ALL group. Based on the DGE profiling data, the present study further investigated seven genes (WT1, RPS26, MSX1, CD70, HOXC4, HOXA5 and HOXC6) using reverse transcription‑quantitative polymerase chain reaction analysis. Gene Ontology analysis suggested that the differentially expressed genes were predominantly involved in immune cell differentiation, metabolic processes and programmed cell death. The results of the present study provided novel insights into the gene expression patterns in children with ALL.

To investigate the mechanism of decreasing the K562/ADM cells chemosensitivity by up-regulating expression of PTEN gene.K562/ADM cells were transient transfected with pGFP-PTEN or vector. The level of PTEN in K562/ADM cells was assayed by Western blot and RT-PCR. Cell viability on K562/ADM was determined by MTT assay. Cell apoptosis by flow cytometry. Activity of caspase-3 by Caspase Colorimetric Assay Kit. The proteins expression of LC3-I/II, Beclin1, p-Akt, p-p70S6K by Western blot. The autophagic vacuoles by MDC stain and Electron microscopy.(1) The mRNA and protein levels of PTEN in K562/ADM cells transfected with pGFP-PTEN were significantly increased compared with the control (untreated and transfected with empty vector). (2) Enhanced expression of PTEN by gene transfection resulted in a reversal of resistance to ADM. Compared with empty vector group, cell viability decreased from (94.07 ± 2.6)% to (53.83 ± 4.2)%, the cell apoptotic rate increased from (11.89 ± 1.7)% to (43.69 ± 2.3)%, meanwhile, pretreated with caspase-3 inhibitor (Z-DEVE-FMK) didn't completely inhibit the cytotoxicity of ADM to K562/ADM cells. (3) After treated with ADM for 12 and 24 h, the activities of caspase-3 in PTEN-transfected K562/ADM cells increased compared with those in pGFP-transfected K562/ADM cells \[(2.27 ± 0.13) vs (1.19 ± 0.14)\] at 12h, \[(3.15 ± 0.08) vs (1.48 ± 0.05)\] at 24 h (P0.05). (4) The protein levels of LC3-II and Beclin1 in K562/ADM cells transfected with pGFP-PTEN were increased by 83% and 18% respectively, and the protein levels of p-Akt and p-p70S6K were declined by 96% and 87% respectively, compared with those in K562/ADM cells transfected with pGFP plasmid. (5) The upregulation of PTEN in K562/ADM cells improved the number of autophagic vacuoles compared with the empty vector group.The upregulation of PTEN expression increases the chemosensitivity of K562/ADM to ADM, which may related with the inhibition of PI3K/AKT/mTOR pathway induced by PTEN gene transfection.

HMGB1 is associated with human cancers and is an activator of autophagy which mediates chemotherapy resistance. We here show that the mRNA levels of HMGB1 are high in leukemia cells and it is involved in the progression of childhood chronic myeloid leukemia (CML). HMGB1 decreases the sensitivity of human myeloid leukemia cells K562 to anti-cancer drug induced death through up-regulating the autophagy pathway, which is confirmed by the observation with an increase in fusion of autophagosomes and autophagolysosomes. When overexpressing HMGB1, both mRNA levels of Beclin-1, VSP34 and UVRAG which are key genes involved in mammalian autophagy and protein levels of p-Bcl-2 and LC3-II are increased. Luciferase assays document that over-expression of HMGB1 increases the transcriptional activity of JNK and ERK, which may be silenced by siRNA. The results suggest that HMGB1 regulates JNK and ERK required for autophagy, which provides a potential drug target for therapeutic interventions in childhood CML.

For children with acute myeloblastic leukemia (AML), multidrug resistance (MDR) reduces treatment effectiveness, and often leads to poor patient survival. While a number of factors have been described that affect MDR, the mechanisms underlying this effect remain unclear. In this study, the role of WAVE1 in MDR was investigated. Among 62 children with AML, high levels of WAVE1 were associated with poor patient outcomes. Proteomic techniques were used to identify novel WAVE1-interacting proteins from leukemia cells, one of which was the cytoskeleton regulator Ezrin. In leukemia cells, WAVE1 co-localized with both Ezrin and P-glycoprotein (P-gp), a critical regulator of the MDR phenotype. Overexpression of WAVE1 in K562 leukemia cells up-regulated P-gp and Ezrin, and reduced K562 cells' sensitivity to the chemotherapy drug adriamycin. The opposite effect was seen when WAVE1 expression was reduced via RNA interference. Critically, overexpression of WAVE1 in the absence of Ezrin did not affect P-gp levels or MDR. These data suggest that WAVE1 affects P-gp and MDR of leukemia cells through Ezrin.