Yonggong Yang

Autologous hematopoietic stem cell transplantation for acute myeloid leukemia in first complete remission: a meta-analysis of randomized trials.

Background: For those patients who are not candidates for allogeneic stem cell transplantation (SCT) or who do not have an HLA-matched donor, it is unclear whether consolidation therapy with autologous SCT results in a survival benefit compared with further intensive post-remission non-myeloablative chemotherapy or no further therapy. Methods: A meta-analysis evaluating autologous SCT versus further chemotherapy or no treatment for acute myeloid leukemia (AML) in first complete remission (CR1) was completed. The search used the following combined search terms in Medline, Embase, the Cochrane Controlled Trials Register, the Cochrane Library, the Web of Science and the China National Knowledge Infrastructure. Results: Overall, 13 studies of 12 randomized controlled trials were identified. Four studies were in pediatric patients and 9 were in adults. For adults, AML in CR1 compared with non-SCT, lower relapse and higher transplantation-related mortality were associated with autologous SCT, a significant disease-free survival benefit of autologous SCT was documented, and there was no difference in overall survival when studies were pooled. For pediatric AML in CR1, there were no differences in relapse, transplantation-related mortality, disease-free survival and overall survival. Significantly less survival from relapse impairment was found for autologous SCT. Conclusion: Our results support the conclusion that autologous SCT should not be considered as the first-line post-remission therapy for AML patients in CR1.

Unrelated donor umbilical cord blood transplantation versus unrelated donor bone marrow transplantation in adult and pediatric patients: A meta-analysis

The effect of unrelated donor bone marrow transplantation (UBMT) and unrelated donor cord blood transplantation (UCBT) on the outcome of patients with hematological diseases remains controversial. We conducted a meta-analysis using data from controlled clinical trials comparing UCBT to UBMT in patients undergoing hematopoietic stem cell transplantation. Pooled comparisons of studies of UCBT and UBMT in children found that the incidence of chronic graft-versus-host disease (GVHD) was lower with UCBT (relative risk [RR]=0.41; 95% confidence interval [CI] (0.25, 0.68)), and the incidence of grades II-IV aGVHD was also significantly different (RR=0.69; 95% CI (0.55, 0.86)). The incidence of relapse was also lower with UCBT (RR=0.72; 95% CI (0.59, 0.87)). There was no difference in OS in children when studies were pooled (Hazard ratio [HR]=1.25; 95% CI (0.87, 1.78)). For adults, OS (HR=1.26; 95% CI (1.13, 1.40)) was statistically different. Thus, UCBT led to inferior outcomes than UBMT in adults.

MTHFR C677T polymorphisms and childhood acute lymphoblastic leukemia: A meta-analysis

To date, case-control studies on the association between methylenetetrahydrofolate reductase (MTHFR) C677T and childhood acute lymphoblastic leukemia have provided either controversial or inconclusive results. To clarify the effect of MTHFR C677T on the risk of childhood acute lymphoblastic leukemia, a meta-analysis of all case-control observational studies was performed. Heterogeneity (I(2)=65%, P<0.0001) for C677T among the studies was extreme. The random effects (RE) model showed that the 677T allele was not associated with a decreased susceptibility risk of childhood acute lymphoblastic leukemia compared with the C allele [OR=0.96, 95% confidence interval (CI) (0.88-1.04), P=0.34]. The contrast of homozygotes, recessive model and dominant model produced the same pattern of results as the allele contrast. Although MTHFR C677T was associated with increased risks of colorectal cancer, leukemia, and gastric cancer, our pooled data suggest no evidence for a major role of MTHFR C677T in the carcinogenesis of childhood acute lymphoblastic leukemia.

Meta-analysis of randomised clinical trials comparing idarubicin + cytarabine with daunorubicin + cytarabine as the induction chemotherapy in patients with newly diagnosed acute myeloid leukaemia.

Background To determine whether the use of idarubicin+cytarabine (IA) is more effective than the use of daunorubicin+cytarabine (DA) as induction chemotherapy for patients with newly diagnosed acute myeloid leukaemia. Methods A computer-based search was performed. Randomised trials comparing IA with DA as induction therapy for newly diagnosed AML were included in this meta-analysis. The primary outcome of interest for our analysis was survival (disease-free survival, event-free survival and overall survival); the secondary endpoint was complete remission. Results Ten trials with 4,060 patients were eligible for this meta-analysis. Our pooled results suggest that IA is associated with a significant advantage in CR (RR = 1·23; 95% CI = 1·07–1·41, p = 0.004), EFS (HR = 0·64; 95% CI = 0·45–0·91, p = 0.013), and OS (HR = 0·88; 95% CI = 0·81–0·95, p = 0.02) but not in DFS (HR = 0·90; 95% CI = 0·80–1·00, p = 0.06). In the subgroup analysis, age had a significant interaction with OS and CR benefits. Conclusion Our analysis indicated that IA could improve the duration of overall survival compared to DA as induction therapy for young patients with newly diagnosed AML. Further study is needed to determine whether IA can produce clinical benefits in selected genetic or molecular subgroups of young AML patients.

Prophylactic use of granulocyte colony-stimulating factor after chemotherapy does not affect survival rate in acute myeloid leukemia: a meta-analysis

increased rates of complete remission. In our previous study, we found that prophylactic use of G-CSF after induction chemotherapy had the potential to increase the complete remission rate [2] . In this study, we evaluated the impact that prophylactic use of G-CSF after chemotherapy had on the survival rate of AML patients. The objective of this meta-analysis was to determine the prophylactic effect of G-CSF on improving overall survival in AML patients, compared with placebo or no therapy. We identified the randomized control trails (RCTs) by searching the following electronic databases: Medline, Embase, the Cochrane controlled trials register, the Cochrane Library and the Science Citation Index. Additional relevant trials were hand-searched according to the reference lists from the trials identified in the electronic databases (all the data retrieved were updated to December 2008). The following criteria were used for the selection of each study in the meta-analysis: (1) study design: RCTs, with or without blinding; (2) study population: AML patients; (3) intervention: G-CSF; (4) controls: placebo or no treatment; (5) time of the intervention: after chemotherapy, and (6) outcome measure: overall survival (OS). Survival outcome data were synthesized using a time-toevent hazard ratio (HR) as the metric to assess the extent Acute myeloid leukemia (AML) is a heterogeneous group of diseases characterized by the unlimited clonal proliferation of transformed hematopoietic precursor cells, as well as impaired normal hematopoiesis. Despite the significant progress that has been made in the understanding of AML biology and the application of novel strategies to treat AML, the results from current therapeutic studies remain unsatisfactory. Granulocyte colony-stimulating factor (G-CSF) stimulates both the proliferation and differentiation of neutrophil precursors; however, the therapeutic effect of G-CSF treatment on AML remains uncertain. Priming with G-CSF has been investigated as a strategy to increase the sensitivity of leukemia cells to chemotherapy by promoting the entry of leukemic blast cells into the chemotherapy-sensitive phase of the cell cycle. However, such an effect of G-CSF on AML has not been consistent with a recent meta-analysis [1] . G-CSF is used to facilitate more dose-intense treatments and to decrease treatment-related complications. Chemotherapy-induced neutropenia is a major dose-limiting side-effect of AML chemotherapy and is associated with substantial morbidity, mortality and cost. If growth factors could be used to decrease the incidence of bacterial and fungal infections, then treatment outcomes may improve, thus leading to decreased mortality rates and Received: March 23, 2009 Accepted after revision: April 15, 2009 Published online: June 19, 2009

Low-temperature glycol methacrylate resin embedding method: A protocol suitable for bone marrow immunohistochemistry, PCR, and fish analysis

Molecular analyses such as fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) are demanded to improve diagnostic accuracy in addition to immunohistopathology of bone marrow (BM) trephine specimens. Conventional BM embedding method needs decalcification, and its procedure may impair tissue morphology and DNA quality. Here, we report an undecalcified method by which glycol methacrylate resin is polymerized at low temperature (4°C). Using this method, BM enzyme activity and antigenic determinants are well preserved, and moreover, DNA extracted from plastic embedding sections is suitable for PCR amplification and sequencing, FISH analysis can be well done because of the DNA integrity of BM sections. If working with BM trephine specimen, our protocol offers the possibility to combine superior morphology with modern molecular analysis. Microsc. Res. Tech. 73:1067–1071, 2010.

Prognostic relevance of protein expression, clinical factors, and MYD88 mutation in primary bone lymphoma

Primary bone lymphomas (PBLs) are composed of malignant lymphoid cells presenting in osseous sites, without supra-regional lymph node or extranodal involvement. We systematically characterized the immunophenotype and the myeloid differentiation factor 88 (MYD88)-L265P gene mutation status in PBL. Clinical data from 19 patients with PBL treated at Nanjing Drum Tower Hospital between 2009 and 2015 were analyzed retrospectively. Protein expression patterns were identified immunohistochemically, and MYD88 mutation was assessed using polymerase chain reaction and direct DNA sequencing. Fifteen patients presented with diffuse large B-cell lymphoma. Clinical factors favoring a good prognosis were an age < 60 years and rituximab treatment. B-cell lymphoma 2 expression was detected in 5/15 diffuse large B-cell lymphoma patients, and was associated with a poor prognosis in a univariate model. Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling factors were upregulated in PBLs. All eighteen evaluable PBL samples harbored wild-type MYD88. These data thus suggest that age and rituximab treatment are independent prognostic factors determining overall survival, and that activation of JAK/STAT3 signaling may promote the pathogenesis of PBL. Moreover, the absence of MYD88-L265P mutation in PBL indicate there are distinct pathogenetic backgrounds among extranodal lymphomas.

Prognostic value of expression of nuclear factor kappa-B/p65 in non-GCB DLBCL patients

PURPOSE We estimated the expression of nuclear factor kappa B/p65 in non-germinal center B-cell-like subtype diffuse large B-cell lymphoma, to investigate its relationship to clinicopathological features, and to further evaluate its prognostic value and clarify its impact on survival. RESULTS Among the 49 patients enrolled in this study, 14 (28.6%) had positive p65 expression. The negative p65 group had significantly better survival compared to the positive p65 group in terms of both the 3-year estimated OS (91.2% vs. 39.3%, p = 0.003) and PFS (75.6% vs. 26.5%, p = 0.002). In patients with 4 or more risk factors, p65 was an independent prognostic factor of OS (HR 5.99, 95%CI=1.39-25.75, p=0.016) and PFS (HR 4.01, 95%CI=1.15-14.00, p=0.029). MATERIALS AND METHODS The expression of the NF-κB/p65 protein was deteremined by immunohistochemistry in 49 non-GCB DLBCL. Survival was assessed by the Kaplan-Meier method and Cox multivariate analysis. The median patient follow-up period was 24 months. CONCLUSIONS The expression of NF-κB/p65 has prognostic value in high risk non-GCB DLBCL, and it is a suitable target for the development of new therapies.

JAK2, MPL, and CALR mutations in Chinese Han patients with essential thrombocythemia

ABSTRACT Background: Mutations in Janus kinase 2 (JAK2), myeloproliferative leukemia (MPL), and CALR are highly relevant to Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms. Methods: Assessing the prevalence of molecular mutations in Chinese Han patients with essential thrombocythemia (ET), and correlating their mutational profile with disease characteristics/phenotype. Results: Of the 110 subjects studied, 62 carried the JAK2 V617F mutation, 21 had CALR mutations, one carried an MPL (W515) mutation, and 28 had non-mutated JAK2, CALR, and MPL (so-called triple-negative ET). Mutations in JAK2 exon 12 were not detected in any patient. Two ET patients had both CALR and JAK2 V617F mutations. Comparing the hematological parameters of the patients with JAK2 mutations with those of the patients with CALR mutations showed that the ET patients with CALR mutations were younger (p = 0.045) and had higher platelet counts (p = 0.043). Conclusion: Genotyping for CALR could be a useful diagnostic tool for JAK2/MPL-negative ET, since the data suggest that CALR is much more prevalent than MPL, therefore testing for CALR should be considered in patients who are JAK2 negative as its frequency is almost 20 times that of MPL mutation.