Venous thromboembolism in children with acute lymphoblastic leukemia in China: a report from the Chinese Children's Cancer Group-ALL-2015 / 医学前沿

Venous thromboembolism (VTE) is a complication in children with acute lymphoblastic leukemia (ALL). The Chinese Children's Cancer Group-ALL-2015 protocol was carried out in China, and epidemiology, clinical characteristics, and risk factors associated with VTE were analyzed. We collected data on VTE in a multi-institutional clinical study of 7640 patients with ALL diagnosed in 20 hospitals from January 2015 to December 2019. First, VTE occurred in 159 (2.08%) patients, including 90 (56.6%) during induction therapy and 108 (67.92%) in the upper extremities. T-ALL had a 1.74-fold increased risk of VTE (95% CI 1.08-2.8, P = 0.022). Septicemia, as an adverse event of ALL treatment, can significantly promote the occurrence of VTE (P < 0.001). Catheter-related thrombosis (CRT) accounted for 75.47% (n = 120); and, symptomatic VTE, 58.49% (n = 93), which was more common in patients aged 12-18 years (P = 0.023), non-CRT patients (P < 0.001), or patients with cerebral thrombosis (P < 0.001). Of the patients with VTE treated with anticoagulation therapy (n = 147), 4.08% (n = 6) had bleeding. The VTE recurrence rate was 5.03% (n = 8). Patients with VTE treated by non-ultrasound-guided venous cannulation (P = 0.02), with residual thrombus (P = 0.006), or with short anticoagulation period (P = 0.026) had high recurrence rates. Thus, preventing repeated venous puncture and appropriately prolonged anticoagulation time can reduce the risk of VTE recurrence.

Blood lead level of outpatient children in Anqing from 2015 to 2018 / 中国学校卫生

Objective@#To analyze blood lead levels of children aged 0-14 in Anqing City during 2015 to 2018, to provide basic data for child poisoning prevention and control.@*Methods@#Using questionnaire surveys, physical examination, and laboratory tests to assess blood lead, age, height, weight, personal habits, environmental factors and other relevant information, to analyze associated factors of elevated blood lead levels.@*Results@#From 2015 to 2018, among the 4 406, 4 177, 3 833 and 3 381 children aged 0-14 in the pediatric outpatient, 662, 326, 225, and 56 cases were found with elevated blood lead levels (EBLLs), with the detection rate of 15.02%, 7.80%, 5.87%, and 1.66%, respectively. Detection rate in boys (16.54%, 7.31%, 6.18% and 1.88%) was similar with that of girls (16.04%, 8.51%, 5.42% and 1.33%) ( χ 2= 2.47 , 2.00, 0.99,1.53, P >0.05). Children in any age groups of 0-14 years might have EBLLs, highest in 14-year-old group in the year of 2015 and 2017. Personal behaviors associated with EBLLs included less meat and dairy products consumption, high frequent exposure to soil dust. In contrast, children who wash their hands before meals and wash toys ≥1 time/week were less likely to suffer from EBLLs ( χ 2=13.58，8.91，7.63，9.22， P <0.05). Environmental factors associated with EBLLs included were less than 50 m between the main road with residency, family members smoke, and parents engaged in construction, welding, automobile maintenance and other industries are more likely to have EBLLs, and the difference is statistically significant ( χ 2=4.92，10.63，22.95， P <0.05).@*Conclusion@#The detection rate of EBLLs in Anqing City from 2015 to 2018 depressed by year. Washing hands before meals and cleaning toys frequently could reduce the risk of EBLLs.

Multicenter clinical trial of acute lymphoblastic leukemia in elder children and adolescents / 中华血液学杂志

Objective@#To analyze the clinical characteristics and long-term outcomes with multicenter study for acute lymphoblastic leukemia (ALL) in children over 10 years old and adolescents.@*Method@#Newly diagnosed ALL patients aged from 10 to 18 years old in three hospitals were included in the study from May 1st 2005 to April 30th 2015. They were received ALL-2005/2009 protocol following up to December 31st 2016. The clinical characteristics, outcomes and the prognostic analysis were evaluated between the two protocols.@*Results@#Totally, 237 patients were involved in the study, 76 cases for ALL-2005 and 161 cases for ALL-2009 protocol. Complete remission (CR) after induction therapy was 94.5%. 64 (28.6%) patients relapsed with a median time of 14.5 months and 70 (29.5%) patients passed away during the following time. In long-term follow-up, the 5-year event-free survival (EFS) and 5-year overall survival (OS) of ALL patients were (63.1±3.3)% and (68.4±3.2)%. The 7-year EFS and OS were (61.0±3.5)% and (67.6±3.3)%.The 5-year EFS of intermediate risk group in ALL-2005 and ALL-2009 protocol were (73.6±6.1)% and (71.7±4.3)% with no difference (χ2=0.064, P=0.801). The 5-year EFS of high risk group in two protocols were (27.6±9.6)% and (33.9±9.3)%, showing no significant difference (χ2=0.296, P=0.586). Five years relapsed rate of two protocols were (33.8±5.7)% and (32.6±4.1)% with no difference (χ2=0.055, P=0.815). The mortalities were 36.8% and 29.8% separately (χ2=2.869, P=0.090). Univariate analysis indicated that age, male, risk, BCR/ABL translocation/t(9;22) and resistant to induction were risk prognostic factors in long-term survival (χ2=4.764, 4.796, 46.410, 9.560, 25.450; P=0.029, 0.029, <0.001, 0.049, <0.001). Cox multivariate analysis showed male, risk and resistant to induction were independent risk prognostic factors (RR=1.790, 2.727, 2.719; P=0.021, 0.000, 0.012).@*Conclusion@#Protocol ALL-2009 enhanced the chemotherapy intensity in intermediate risk group with no benefit of survival. BCR-ABL fusion or t(9;22) translocation was still the risk factor of prognosis. TKI inhibitor used in these patients could improve survival. EFS rate was increased a little and death rate was decreased in ALL-2009 protocol with no significant lower relapsed rate comparing with ALL-2005 protocol.

Long-term results of multicenter study based on childhood acute lymphoblastic leukemia 2005 protocol / 中华儿科杂志

Objective@#To evaluate the long-term efficacy and prognostic factors of childhood acute lymphoblastic leukemia (ALL) enrolled in Shanghai Children's Medical Center-Acute Lymphoblastic Leukemia-2005(SCMC-ALL-2005) multicenter study.@*Methods@#Between May 2005 and December 2014, 1 497 newly diagnosed ALL patients were enrolled and treated in 5 hospitals of SCMC-ALL-2005 study group, using risk-stratified SCMC-ALL-2005 protocol. Risk group classification and treatment intensity were based on clinical features, genetic abnormalities, early response to treatment and levels of minimal residual disease (MRD). Kaplan-Meier method was used to generate overall survival (OS) and event-free survival(EFS) curves. Cox proportional hazards models were used for multivariate analyses.@*Results@#The patients were followed up to December 31, 2016, the median follow-up time was 69 months (24-141 months). The 5-year and 10-year OS rates were (80.0±1.0)% and (76.0±2.0)%. The 5-year and 10-year EFS rates were (69.0±1.0)% and (66.0±2.0)%. The 5-year and 10-year relapse rates were (23.0±1.0)% and (25.0±2.0)%. The 5-year OS and EFS for low risk (LR), intermediate risk (IR) and high risk (HR) were (91.1±1.4)% and (83.3±1.8)%, (79.2±1.5)% and (68.9±1.7)%, (52.9±4.4)% and (30.0±3.8)%, respectively. MRD negative status (<0.01%) on day 55 was seen in 792 patients (82.8%) and positive MRD on day 55 was associated with poor prognosis (OR=1.9, 95%CI: 1.3-2.7, P=0.001). Twenty-four HR patients received allogeneic hematopoietic stem cell transplantation and 17(70.8%) of them were alive and in remission. A total of 164 severe adverse events occurred, 46 of them died, treatment-related mortality was 3.1%.@*Conclusions@#In this large sample research, the overall outcome for multi-center SCMC-ALL-2005 study was favorable. This helps to promote the standardized treatment of childhood ALL to the whole country. MRD results on day 55 of induction therapy have important prognostic and therapeutic implications.

Progress of diagnosis and management of non-severe aplastic anemia in children / 中华实用儿科临床杂志

Acquired aplastic anemia (AA) is a rare heterogeneous disease characterized by pancytopenia and hypoplastic bone marrow.The differential diagnosis should always take in account inherited forms of AA,like Fanconi anemia(FA),dyskeratosis-congenita(DC),and Shwachman-Diamond syndrome (SDS).Patient with transfusion-dependent non-severe aplastic anemia(NSAA),with severe AA (SAA) and very severe AA(VSAA),if an human leukocyte antigen (HLA) matched family donor(MFD) is found,then hematopoietic stem cell transplantation (HSCT) using bone marrow (BM) stem cells is the treatment of choice.If a MFD is not available,the immunosuppressive therapy (IST) with the combination of antithymocyte globulin (ATG) plus cyclosporin (CsA) still represents the first line choice.For transfusion-independent NSAA patients,most hematologists suggests no intervention,however,some studies indicate the patients with transfusion-independent NSAA may benefit from IST,and the rate of progression to SAA and transfusion-dependent NSAA is lower than other observation groups.So a multicenter randomized clinical trial is needed.

Diagnosis and treatment of iron deficiency anemia in children / 国际儿科学杂志

Iron deficiency could cause hemoglobin synthesis decrease,and then lead to iron deficiency a-nemia(IDA).The present study has found that incorrect feeding,gastrointestinal disease and deficiency of trace elements are high risks of IDA.Whether febrile seizure is associated with IDA is still controversial.Recent re-search has discovered that infant iron deficiency can lead to poor cognitive inhibitory control,while delayed cord clamping and other measures can effectively prevent IDA in children.Discontinuous complement iron agent can also achieve good effect on treatment.

Role of Th17/Treg imbalance in the immune pathogenesis and treatment of children with aplastic anemia / 中华儿科杂志

<p><b>OBJECTIVE</b>To study the role of Th17/Treg imbalance in the immune pathogenesis and therapeutic significance in childhood aplastic anemia (AA).</p><p><b>METHOD</b>We analyzed data from 43 children (male: female = 14: 29) with AA, all the cases were at the age of 2 to 14 years at diagnosis, and were hospitalized at our department of pediatrics between January 2012 and October 2013 in the Second Hospital of Anhui Medical University. All these patients were divided into 2 groups, severe AA (SAA) group (n = 25, male: female = 8: 17, 2-14 years old) and non-severe AA (NSAA) group (n = 18, male: female = 6: 12, 2-14 years old), depending on the severity at first diagnosis. As to the treatment, we analyzed data at 3 phases of treatment, diagnosis (n = 43, male: female = 14: 29, 2-14 years old), transfusion-indenpendence (n = 8, male: female = 5: 3, 2-11 years old), complete response (n = 6, male: female = 3: 3, 2-11 years old); at the same time, AA children who did not respond to the treatments were considered as failed treatment control (transfusion-indenpendence with failed treatment group, n = 5, male: female = 1: 4, 3-8 years old; complete response failed treatment group, n = 4, male: female = 2: 2, 4-11 years old). The ratio of Treg and Th17 cells in CD4(+) T cells were tested by flow cytometry. The levels of IL-6 and IL-17 in plasma were determined by ELISA. During the same period, 25 age-matched healthy children (male: female = 12: 13, 3-14 years old) were recruited as normal control, 9 cases (male: female = 5: 3, 2-11 years old) of AA children induced by chemotherapy as diagnosis control group. Differences in variables were analyzed using ANOVA and t-tests or the Kruskal-Wallis and Mann-Whitney U-tests, as appropriate. Correlation analysis was evaluated by the Spearman rank correlation test.</p><p><b>RESULT</b>(1) The ratio of Th17 cells in newly diagnosed AA patients were higher than that of normal group or diagnosis control group [1.63% (1.27%, 2.48%) vs. 0.4% (0.35%, 0.51%) or 0.50% (0.45%, 0.75%), both P < 0.01] while the ratio of Treg cells was lower [4.24% (3.10%, 5.29%) vs. 7.03% (6.56%, 7.48%) or 7.50% (6.60%, 8.30%), both P < 0.01] and the proportion of Th17/Treg were significantly higher [0.53(0.34, 0.69) vs. 0.06 (0.05, 0.07) or 0.09 (0.08,0.11), both P < 0.01]. (2) The levels of IL-6 and IL-17 in newly diagnosed AA patients were higher than in normal group [ (223 ± 92) vs. (116 ± 18) ng/L, (26.2 ± 12.0) ng/L vs. (10.6 ± 2.1) ng/L, P both < 0.01]. There was a positive correlation between Th17 cells and some Th17 cells related cytokines such as IL-17 and IL-6 (r = 0.62, 0.64, P both < 0.01). (3) The ratio of Th17, Th17/Treg, and the levels of IL-6 and IL-17 in children with SAA were also higher than in normal group [1.80% (1.25%, 2.61%) vs. 0.40% (0.35%, 0.51%), 0.57% (5.10%,0.82%) vs. 0.06% (0.05%, 0.07%), (225 ± 108) vs. (116 ± 18) ng/L, (25.9 ± 12.6) vs. (10.6 ± 2.1)ng/L, all P < 0.01]. NSAA also higher than normal group. The ratio of Treg in children with SAA and NSAA was less than that in normal group (P all < 0.01). However, the ratio of Th17, Treg, Th17/Treg, and the levels of IL-6 and IL-17 had no significant difference between SAA and NSAA (all P > 0.05). (4) In different stages of treatment, such as diagnosis, transfusion-indenpendence, complete response, there were significant differences in the ratio of Th17 and Th17/Treg (both P < 0.05) but not in Treg (P > 0.05).</p><p><b>CONCLUSION</b>The imbalance of Th17/Treg cells and abnormally increased cytokines related to Th17 cells exist in peripheral blood of AA children, but did not significantly affect the severity of AA in preliminary diagnosis. After treatment with immunosuppression, AA was gradually relieved as the imbalance of Th17/Treg was corrected.</p>

Outcome of childhood B-cell acute lymphoblastic leukemia treated with SCMC-ALL-2005 protocol / 临床儿科杂志

Objective To analyze the outcome of childhood B-cell acute lymphoblastic leukemia treated (ALL) with SCMC-ALL-2005 protocol. Methods Newly diagnosed B-cell ALL from May 1, 2005 to April 30, 2009 in ifve hospitals were treated and followed up according to SCMC-ALL-2005 protocol. Results A total of 601 cases with newly diagnosed B-cell ALL were enrolled. Among them, 539 cases (89.68%) were followed up until September 30, 2011. In 601 patients, there were 284 low-risk cases (LR group), 231 moderate-risk cases (MR group) and 86 high-risk cases (HR group) which were treated with SCMC-ALL-2005 protocol. The total complete remission rate during the period of induction was 98.84%and 7 cases did not achieve complete remission. The median time of the ifrst event occurring was 35 months (2.94 years). Among 539 cases completing follow-up, 403 cases (74.77%) completed treatment including 223 cases (86.43%) in LR group, 150 cases (73.17%) in MR group and 30 cases (39.47%) in HR group. The rate of cases completing treatment was signiifcantly different among three groups (P=0.001). The completion rate was highest in LR group and lowest in HR group. The 3-year overall survival (OS) rate was (83.3±1.8)%, and the 3-year EFS (event-free survival) rate was (79.2±1.9)%using a Kaplan-Meier method. The 5-year OS rate was (79.5±3.3)%, and the 5-year EFS rate was (70.9±3.7)%. There were signiifcant differences in 3-year EFS rate and 5-year EFS rate among three groups (P<0.05). Conclusions Childhood B-ALL treated with SCMC-ALL-2005 protocol achieved a better therapeutic effect and prognosis. The multi-center collaborative research is useful for the standard treatment of ALL.

Clinical significance of CD4+CDHi25 regulatory T cells in childhood acute leukemia / 白血病·淋巴瘤

Objective To evaluate the proportion and clinical significance of CD4+CD25+ regulatory T cells in childhood acute lymphocyte leukemia(AEL)during different therapeutic stages.Methods 55 peripheral blood samples from 40 children patients with ALL were detected by muhiparameter flow cytometry with fluoresce-hbeled monoclonal antibody.Results Treg cells phenotypically express not only CD62L but also FoxP3 protein.In patients with ALL standard-risk the proportion of CD4+CD25Hi was(1.04±0.33)% in the first course of induction treatment, (1.60±0.44)% in maintenance treatment groups, and(1.29±0.30)% in complete remission groups respectively,while in patients with ALL the intermediate and high risk during maintenance therapy was(2.24±0.75)%.Conclusion Compared with healthy children,the proportion of Treg ceHs in ALL is significantly higher,and may be related to the effect of chemical treatment and severity of ALL.The elevated proportion of Treg may contribute to disease relapse.

Treatment of two case childhood acute lymphoblastic leukemia by HLA-mismatched unrelated umbilical cord blood transplantation / 中华血液学杂志

<p><b>OBJECTIVE</b>To explore the hematopoietic and immunologic reconstitution and transplantation-related complications of HLA one locus mismatched unrelated umbilical cord blood transplantation for the treatment of hematological malignancies.</p><p><b>METHODS</b>Two children with acute lymphoblastic leukemia received HLA-mismatched unrelated umbilical cord blood transplantation. The conditioning regimens were BU-CTX (case 1) and BU-CTX plus BCNU (case 2). GVHD prophylaxis regimen consisted of cyclosporine (CsA) and mycophenolate mofetil (MMF). The patients received 14.6 x 10(7) nucleated cells/kg with 7.24 x 10(5) CD(34)(+) cells/kg and 16.24 x 10(7) nucleated cells/kg with 21.11 x 10(5) CD(34)(+) cells/kg, respectively.</p><p><b>RESULTS</b>The two recipients, ANC > 0.5 x 10(9)/L occurred at day 27 and day 17, BPC > 50 x 10(9)/L at day 53 and day 46, the peripheral blood counts normalization at day 60 and day 52, the immune function normalization at day 134 and day 122 and the DNA fingerprinting showing engraftment at day 19 and day 17, respectively. The donor-recipient pair of case 1 was male to female, and the chromosome karyotype of recipients bone marrow and peripheral blood cells showed 100%, 46, XY cells at day 49. Grade II acute graft versus host disease (aGVHD) occurred at day 26 (case 1) and day 21 (case 2). The two recipients have survived for 353 days and 256 days.</p><p><b>CONCLUSION</b>The hematopoietic and immunologic reconstitution in umbilical cord blood transplantation were earlier and more durable. The transplantation-related complications were less and aGVHD were milder.</p>

A high performance capillary electrophoresis method for determination of methotrexate in serum / 中华检验医学杂志

Objective To establish a rapid assay for the determination of methotrexate (MTX) in serum.Method The assay was based on the ultraviolet absorbance of methotrexate at 306 nm. The separation of the drug was done by high performance capillary electrophoresis (HPCE). The bare fused-silica capillary was 60 cm in total length, 50.5 cm in efficient length and 75?m in diameter. The voltage of 25 kV was applied. The running buffer was 75 mmol/L phosphate, pH7.4. The performance of methodology was evaluated.Result The complete separation of MTX was achieved within 10 min. The linearity of the assay was from 1.1 ?mol/L to 1100.0 ?mol/L. The minimal detection limit was 0.55 ?mol/L.The recovery of MTX was from 88.2% to 98.2%. Within-run precision was 4.2% and between-run precision was ~5.4%. Conclusion The result indicated that the method was an effective method for clinical and scientific research with advantages of rapidity, simplicity and accuracy.