Clinical effect of the SCMC APL-2010 regimen in treatment of acute promyelocytic leukemia in children: an analysis of 44 cases / 中国当代儿科杂志

OBJECTIVE@#To study the clinical effect of the SCMC APL-2010 regimen in the treatment of acute promyelocytic leukemia (APL) in children.@*METHODS@#A retrospective analysis was performed for the clinical data of 44 children with APL who received treatment with the SCMC APL-2010 regimen between April 2010 and July 2016. The Kaplan-Meier survival analysis was used to evaluate event-free survival (EFS) rate and overall survival (OS) rate.@*RESULTS@#Of the 44 children with APL, 42 (95%) achieved a complete remission (CR) after one course of treatment and 1 achieved CR after two courses of treatment, with an overall CR rate of 98%. The 9-year EFS and OS rates were 96%±3% and 97.7%±2.2% respectively. As for adverse events, 41 (93%) had infection, 29 (66%) had granulocyte reduction, 12 (27%, 1 died) had differentiation syndrome, 16 (36%) had liver dysfunction, 12 (27%) had adverse gastrointestinal reactions, and 7 (16%) had QT prolongation, 1 (2%) had orchitis, and no secondary neoplasm was observed.@*CONCLUSIONS@#Children with APL receiving the SCMC APL-2010 regimen have a good prognosis and can achieve a long-term survival, while treatment-related infection is commonly seen.

Research advances in pharmacogenomics of mercaptopurine / 中国当代儿科杂志

Mercaptopurine is a common chemotherapeutic drug and immunosuppressive agent and plays an important role in the treatment of acute lymphoblastic leukemia and inflammatory bowel disease. It may cause severe adverse effects such as myelosuppression, which may result in the interruption of treatment or complications including infection or even threaten patients' lives. However, the adverse effects of mercaptopurine show significant racial and individual differences, which reveal the important role of genetic diversity. Recent research advances in pharmacogenomics have gradually revealed the genetic nature of such differences. This article reviews the recent research advances in the pharmacogenomics and individualized application of mercaptopurine.

Outcomes of 104 children with B-cell non-Hodgkin lymphoma / 中华血液学杂志

<p><b>OBJECTIVE</b>To analyze outcomes and prognostic factors of children with B-cell non-Hodgkin lymphoma (B-NHL).</p><p><b>METHODS</b>One hundred and four newly diagnosed B-NHL children were enrolled in protocol of B-NHL 2001. The statistics were performed by SPSS 13.0.</p><p><b>RESULTS</b>Of 104 children (79 males, the median age of 7.1 years), 60, 32 and 4 patients were diagnosed with Burkitt lymphoma, diffuse large B-cell lymphoma and unclassifiable B-cell lymphoma, respectively. Four patients were in stage Ⅰ, 27 stage Ⅱ, 55 stage Ⅲ and 18 stage Ⅳ; 1, 26 and 77 patients were allocated into R1, R2 and R3 risk groups, respectively. Three patients never got complete remission (CR), 9 patients relapsed after CR with the duration of relapse from 1 to 7 months after chemotherapy. The estimated 5-year EFS of 104 patients was (86.7 ± 3.5)%. Univariable analyses identified that risk factors for recurrence were of higher staging, elevated LDH, serum ferritin and poor early response. Age, sex, pathologic diagnosis, original tumor, bone or marrow involvement, C-MYC and risk group were not found to be associated with the risk of failure to treatment. Multivariable COX regression models confirmed serum ferritin as a significant independent prognostic marker.</p><p><b>CONCLUSION</b>B-NHL 2001 protocol was reasonable for B-NHL children. Higher staging, elevated LDH, serum ferritin and poor early response increased risk for recurrence.</p>

Long-term follow-up of childhood low-risk ALL patients treated with SCMC-ALL-2005 protocol / 中华血液学杂志

<p><b>OBJECTIVE</b>To evaluate the long-term efficacy of SCMC-ALL-2005 protocol in treatment of low-risk childhood acute lymphoblastic leukemia (ALL).</p><p><b>METHODS</b>From May 1, 2005 to April 30, 2009, 387 patients enrolled into SCMC-ALL-2005 protocol. Based on the characteristics of cell morphology, immunology, cytogenetics and molecular biology and treatment response, 158 patients were fit into the low-risk treatment group. All the cases were registered in pediatric oncology network database (POND). The clinical characteristics and outcome were analyzed.</p><p><b>RESULTS</b>Until December 31, 2012, the 5-year event free survival (EFS) and overall survival (OS) is (77.76±3.37)% and (89.55±2.83)%, respectively. Median follow-up time is 5.33 y (3.75-7.70 y). Five patients (3.16%) died of complication, all of them were severe infections. Twenty-seven patients (17.09%) relapsed, including 13 bone marrow relapse (8.23%), 5 testis relapse (5.32% of boys, 2 of unilateral and 3 bilateral), 6 central nerve system relapse (CNS, 3.80%), 1 relapse in both bone marrow and CNS, 1 relapse in both bone marrow and testis, and 1 right ovary and fallopian tube relapse. Relapse is related to positive minimal residual disease. Two cases (1.27%) occurred second tumors, 4 patients (2.53%) gave up treatment in complete remission without special reasons.</p><p><b>CONCLUSION</b>The EFS and life quality of SCMC-ALL-2005 protocol in the treatment of childhood low-risk ALL is satisfactory. The treatment-related mortality rate is lower, and the long-term EFS is higher than that of XH-99 protocol.</p>

Correlation between blood T-cell receptor rearrangement excision circles levels and severe infection in children with acute lymphoblastic leukemia / 中国当代儿科杂志

<p><b>OBJECTIVE</b>This study quantitatively examined signal joint T-cell receptor rearrangement excision circles (sjTRECs) levels in peripheral blood of children with acute lymphoblastic leukemia (ALL) at different stages in order to evaluate the role of sjTRECs in predicting severe infection postchemotherapy.</p><p><b>METHODS</b>sjTRECs levels in peripheral blood were measured by fluorescent quantitation-polymerase chain reaction in 30 children with newly diagnosed ALL, 36 children with ALL who accepted chemotherapy but were not infected, 30 children with ALL who had severe infection after chemotherapy, and 50 normal children.</p><p><b>RESULTS</b>Blood sjTRECs levels in the normal group (394 ± 270 copies/103 MNC) were significantly higher than those in the other three groups (P<0.05). Blood sjTRECs levels in the chemotherapy group without infection (96 ± 78 copies/103 MNC) were significantly lower than those in the newly diagnosed ALL group (210 ± 219 copies/103 MNC) (P<0.05). The chemotherapy group with severe infection showed the lowest blood sjTRECs levels (48 ± 40 copies/103 MNC) in the four groups.</p><p><b>CONCLUSIONS</b>The measurement of blood sjTRECs levels might be helpful for predicting the occurrence of severe infection postchemotherapy in children with ALL.</p>

Relationship between asparagine synthetase expression level and cell sensitivity to L-asparaginase in human leukemic cell lines / 中国实验血液学杂志

This study was purposed to explore the relationship between asparagine synthetase (AsnS) mRNA expression level and the sensitivity of leukemic cell lines to L-asparaginase. The AsnS mRNA expression level in 8 cell lines (Jurkat, HL-60, U937, NB4, THP-1, Namalwa, Karpas299 and K562) was determined by real-time quantitative PCR (RQ-PCR) based on fluorescence dye Eva Green before and after treatment with L-Asp, and the cell proliferation rates were analyzed by CCK-8 assay. The results showed that there was a significant disparity of AsnS expression level in 8 cell lines, and there were significant increases of AsnS expression level in cells co-cultured with L-Asp (p < 0.05). Of all these eight cell lines, cells sensitive to L-asparaginase had lower AsnS expression level and cells resistant to L-asparaginase had higher AsnS expression. U937 which was the most sensitive to L-asparaginase had the lowest AsnS expression level, while K562 was natural resistant to L-asparaginase and possessed of the highest AsnS level. It is concluded that the AsnS plays a critical role in regulating cellular biological behavior after depletion of asparagine, the AsnS mRNA expression level in cells reflects the sensitivity of cells to L-Asp. The results may imply the possibility for the use of L-asparaginase in leukemia with lower AsnS expression level.

Causes of deaths of children with malignant tumors during hospitalization in a single center / 中华儿科杂志

<p><b>OBJECTIVE</b>To investigate the main causes of deaths and the influencing factors in children with malignant tumors in the hospital, explore the possible way to improve the treatment.</p><p><b>METHODS</b>Clinical data of 84 patients with malignant tumors who died during hospitalization in the Department of Hematology/Oncology from June 1999 to December 2008 were collected and retrospectively analyzed. Major causes of deaths and their influencing factors were analyzed.</p><p><b>RESULTS</b>(1) Treatment related complications which occurred in 73 cases (86.9%) were the leading cause of death, including infection-related death which was the most common cause of 51 cases (60.7%), hemorrhage-related death occurred in up to 28 cases (33.3%), and acute tumor lysis syndrome (ATLS) related death occurred in 2 cases (2.4%), graft versus host disease (GVHD) related death after allogeneic hematopoietic stem cell transplantation occurred in 4 cases (4.8%). Moreover, primary diseases related death occurred in 30 cases (35.7%). (2) In this group, there were no significant differences in treatment phases when the death occurred among patients with leukemia (56 cases), lymphoma (9 cases) and other non-hematopoietic and lymphoid tissue tumors (7 cases, chi(2) = 4.784, P = 0.310). (3) The infection related death increased significantly when WBC count was lower than 1.0 x 10(9)/L, which is totally different from those whose WBC was higher than or equal to 1.0 x 10(9)/L (chi(2) = 25.486, P < 0.001). (4) Twenty-six cases were detected to be infected with definite pathogens; different pathogens were identified 36 times in the 26 patients. Gram-negative bacteria (15/36, 41.7%) were the most common pathogens, followed by fungal organisms (14/36, 38.9%) and gram-positive bacteria (7/36, 19.4%).</p><p><b>CONCLUSION</b>More attention should be paid to the prevention and treatment of cancer therapy related complications in children with malignant tumors. Infection was the leading cause of death, gram-negative bacteria and fungi were predominating pathogens. Application of effective antibiotics and combined antifungal drugs timely, especially in the remission induction or first chemotherapy period as well as in the period of neutropenia, may reduce mortality of children with malignant tumors significantly.</p>

Clinical report on protocol HL-98 for childhood Hodgkin's Lymphoma / 中华血液学杂志

<p><b>OBJECTIVE</b>To improve the long-term prognosis of childhood Hodgkin's lymphoma (HL) by standard treatment protocol HL-98.</p><p><b>METHODS</b>Patients were divided into low (R(1)), middle (R(2)) and high-risk (R(3)) groups based on staging, tumor size and with or without B symptoms. Patients of R(1), R(2) and R(3) groups were given 4, 6, and 9 courses of chemotherapy, respectively. Low dose radiotherapy to involved area was given to patients with residual disease at the end of chemotherapy. All patients diagnosed between 1998 and Dec. 2008 were enrolled. The software of SPSS 11.0 was used and the event free survival (EFS) was generated by Kaplan-Meier.</p><p><b>RESULTS</b>There was a total of 26 patients with male 20 and female 6. The average age was 97 (30 to 179) months and median age 94.5 months. Three patients were in stage I, 4 in stage II, 9 in stage III and 10 in stage IV. Of 26 patients, 24 were found with neck tumor, 12 with mediastinum tumor, 11 with spleen infiltration and 5 with B symptom. Four patients were allocated into R(1) group, 12 R(2) group and 10 R(3) group. Eight of 26 with residual disease received radiotherapy, 7 received 20-26 Gy and 1 received 36 Gy. To Jun 2009, 21 (80.76%) of them kept in complete remission (CR) at 10 to 120 months follow-up (average 36 months, and median 31 months). Five cases relapsed (1 of stage III and 4 of stage IV) within 5 to 12 months. Three out of 4 in stage IV with B symptom relapsed. The estimated 5-year overall survival (OS) was 85.9% and EFS was 73.7%.</p><p><b>CONCLUSION</b>The estimated 5-year EFS indicated that protocol HL-98 is reasonable good. Patients of stage I and II can obtain a good prognosis without radiotherapy.</p>

Study on NPM1 gene mutations in childhood acute myeloid leukemia / 中华血液学杂志

<p><b>OBJECTIVE</b>To examine the incidence and clinical significance of NPM1 mutations in childhood acute myeloid leukemia (AML) patients.</p><p><b>METHODS</b>NPM1 mutations of 70 newly diagnosed childhood AML were detected by high resolution melting (HRM) analysis on the LightCycler 480. The incidence and clinical significance were analyzed.</p><p><b>RESULTS</b>NPM1 mutations were identified in 32 (45.7%) of the 70 AML children. There was no significant difference in clinical characteristics between patients with or without NPM1 mutation, but patients with NPM1 mutation had a higher platelet count (P = 0.013). There was also no significant difference in NPM1 mutation between normal and abnormal karyotype groups. In AML-ETO or PML-RARα positive groups, the incidence of NPM1 mutations was significant lower (P = 0.048). There was no significant difference in response rates after induction therapy (P = 0.217), but the complete remission (CR) rate was higher in the NPM1-mutated group (81.3%). There was a trend toward higher event-free survival (EFS) and overall survival (OS) rates in the NPM1 mutated patients than that in wild NPM1 patients (EFS = 53.8% vs 41.4%, OS = 52.7% vs 39.2%), but the difference was not statistically significant (P = 0.374 and 0.380).</p><p><b>CONCLUSION</b>NPM1 mutations were relatively common in our cohort of AML patients. There was no significant difference in clinical characteristics between patients with and without NPM1 mutation. The NPM1 mutation patients group seemed to have better therapy response, but the difference was not statistically significant.</p>

Report on induction efficacy of protocol ALL-2005 and middle term follow-up of 158 cases of childhood acute lymphoblastic leukemia / 中华血液学杂志

<p><b>OBJECTIVE</b>To reduce the risk of infection during the induction therapy while to ensure remission rates, and to evaluate the protocol ALL-2005.</p><p><b>METHODS</b>The minimal residual disease (MRD) was detected by flow cytometry on day 35 and 55 of induction therapy. The efficacy of induction and the clinic grouping were evaluated by MRD level. From May 1, 2005 to April 30, 2007, 158 children with newly diagnosed ALL were enrolled in this study. According to clinic grouping criteria of ALL-2005, patients were stratified into 3 groups: low-risk( LR), intermediate-risk (MR) and high-risk (HR). The remission rates, therapy related complication during induction, and the relationship between MRD level on day 35 and 55 of induction and prognosis were analyzed. The endpoints are disease-free survival (DFS), relapse and death of any cause. Patients lost to follow-up were censored at the time of their withdrawal.</p><p><b>RESULTS</b>Of the 158 patients, 59 were LR, 93 MR and 6 HR. The CR rate on day 35 was 98.1%. There were detectable MRD in 139 (88.0%) patients. In 94 patients (68.6%) MRDs were < or = 0.01% on day 35 being 73.1% (49/67) for LR and 63.4% (45/71) for MR (P = 0.219). During induction therapy, 43 patients (27.2%) developed infection and among them 1.3% (2/158) suffered serious infection and 0.6% (1/158) died of complication. Four patients (2.5%) in CR were lost follow-up, 17 patients (10.8%) relapsed, including 4 patients (4.3%) with MRD < or = 0.01% and 10 (23.3%) >0.01% on day 35 (P = 0.003). One died of severe malnutrition and infection in CR. With a median follow-up of 20 (12-35) months, the estimated 30 month DFS for whole group was (81.6 +/- 4.5)% including (94.1 +/- 3.3)% for LR, (82.8 +/- 4.4)% for MR, and (91.0 +/- 5.4)% for MRD < or = 0.01%, (67.1 +/- 9.5)% for MRD >0.01% on day 35 and (89.1 +/- 5.3)% for MRD < or = 0.01% and (46.9 +/- 15.6)% for MRD >0.01% on day 55.</p><p><b>CONCLUSION</b>The risk of infection and therapy related death during induction with protocol ALL-2005 are lower, while the remission rate and quality of the induction are better. Longer follow-up is needed to estimate the long-term result.</p>

Clinical characteristics and treatment outcome of 36 cases with non-Hodgkin's lymphoma arising from mediastinum in children / 中华儿科杂志

<p><b>OBJECTIVE</b>Non-Hodgkin's lymphoma (NHL) presenting as mediastinal mass is usually progressive and may cause severe respiratory distress and death. This study aimed to summarize the clinical features and prognosis of NHL arising from mediastinum.</p><p><b>METHODS</b>Totally 36 patients with NHL arising from mediastinum reported herein were diagnosed between 1999 and 2007. Their clinical characteristics, pathologic classification, diagnosis, outcome of different treatment protocol were retrospectively analyzed. Of these 36 patients, 25 were male, 11 were female (2.2:1). The mean age was 7.9 (range 1 - 12) years. Diagnosis was established on pathology that was achieved by mediastinal mass or peripheral lymph nodes biopsy, while some were diagnosed based on bone marrow or pleural effusion cytology study and immunophenotyping. For staging, the St. Jude system was applied. Patients received T-NHL-CCCG97, T-NHL-2002 or B-NHL-2001 protocol according to morphology and immunophenotyping. Patients who experienced superior vena cava syndrome (SVCS) and/or superior mediastinum syndrome (SMS) received induction chemotherapy with cyclophosphamide (C), vincristine (O) and prednisone (P) for one week.</p><p><b>RESULTS</b>Twenty-seven cases experienced mediastinal mass or peripheral lympho nodes biopsy and were diagnosed by histopathology and immunohistochemistry. Of them, 24 were lymphoblastic lymphoma and 3 were anaplastic large cell lymphoma. Nine patients were diagnosed by cytological study of bone marrow aspiration or pleural fluid. All the 36 cases were T-cell type. Twenty-four cases were in stage III, 12 in stage IV. Twenty-four patients had urgent situation of SVCS and airway obstruction, 22 patients reached good response after emergency management including COP induction chemotherapy and pleural effusion suction. Twenty-nine cases achieved complete remission (CR) while in 6 patients the disease relapsed. Thirteen patients died from disease progression, relapse or severe infection during chemotherapy. The Kaplan-Meier estimate of 5-year progression-free survival (PFS) was 61% +/- 8% (median follow up 35 months) for these 36 patients.</p><p><b>CONCLUSION</b>Establishment of a diagnosis as soon as possible was important to reduce the mortality and improve long term survival of patients. Induction chemotherapy for emergency situation was efficacious. The regimen of T-NHL-CCCG97, T-NHL-2002, and B-NHL-2001 for NHL arising from mediastinum based on pathological classification is feasible.</p>

A novel mutation in the BMPR2 gene in familial pulmonary arterial hypertension / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Familial pulmonary arterial hypertension (FPAH) is an autosomal dominant disorder characterized by plexiform lesions of endothelial cells in pulmonary arterioles which leads to elevated pulmonary arterial pressure, right-sided heart failure and death. Heterozygous mutations in the bone morphogenetic protein type II receptor gene (BMPR2) have been found to underlie a majority of FPAH cases. More than 140 distinct mutations have been identified in FPAH cases and in idiopathic pulmonary arterial hypertension (IPAH) cases, but only one mutation has been reported in Chinese patients.</p><p><b>METHODS</b>A three-generation pedigree of FPAH and another 10 patients with IPAH were collected. In the family, two of the 9 surviving and one deceased family member were diagnosed as FPAH. The entire protein-coding region and intron/exon boundaries of the BMPR2 gene were amplified by PCR using DNA samples from affected individuals. Direct sequencing of PCR products was performed on both the sense and antisense strands. To confirm the segregation of the mutation within the family and exclude the presence of the mutation in normal subjects, the relevant exon was amplified by PCR, followed by mutation-specific RPLP analysis.</p><p><b>RESULTS</b>In the Chinese pedigree with FPAH an A-to-T transition at position 1157 in exon 9 of the BMPR2 gene was identified which resulted in a Glu386Val mutation. We confirmed the segregation of the mutation within the family and excluded the presence of the mutation in a panel of 200 chromosomes from normal subjects. No mutation was detected in BMPR2 in the other 10 patients with IPAH.</p><p><b>CONCLUSIONS</b>This amino acid substitution occurs at a glutamic acid that is highly conserved in all type II TGF-beta receptors. The nearly invariant Glu forms an ion pair with an invariant Arg at position 491 thereby helping to stabilize the large lobe. Substitution of Arg at position 491 is the most frequently observed missense mutation in FPAH, but until now no mutations at position 386 have been found in FPAH. The predicted functional impact of the Glu386Val mutation and its absence in healthy controls support the mutation as the cause of FPAH.</p>

Influence of different conditions on two-dimensional gel electrophoresis of proteins from human acute promyelocytic leukemia cell line NB4 / 中国实验血液学杂志

The aim of this study was to explore the effect of different conditions on two-dimensional gel electrophoresis of proteins from human acute promyelocytic leukemia cell line NB4. The 24 cm pH 3-10 linear immobilized pH gradient (IPG) strips were chosen, the isoelectric focusing was carried out by using IPGphor. Then, the second-dimensional SDS-PAGE was performed. After silver staining, the gel was analyzed by ImageMaster 2D Elite. The results showed that low ion intensity sample washing buffer improved the performance of isoelectric focusing. The lysis buffer containing 7 mol/L urea and 40 mmol/L DTT could solubilize the most proteins from NB4 cell line. The rehydration solution containing thiourea and urea increased the low molecular weight protein points to be resolved in the area of basic end. The reasonable sample load and Volt/hour of NB4 were about 100 micro g and 63 200 V/h for the 24 cm pH 3-10 IPG strips. It is concluded that the proteins from NB4 and similar cell line are complicated and affected by many factors, so that, it is very important to select the right methods for sample preparation and the conditions of two-dimensional gel electrophoresis.