Rong-Fu Zhou

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 induction chemotherapy in patients with newly diagnosed acute myeloid leukemia may increase the complete remission rate: a meta-analysis of five randomised controlled trials

Acute myeloid leukemia (AML) is a malignant disease resulting from acquired genetic mutations that block the differentiation of primitive hematopoietic cells and thereby cause immature myeloid precursors to accumulate. Adults undergoing AML induction chemotherapy have a much greater incidence of contracting infections that require hospitalisation as well as deadly infections than adults with solid tumors. Granulocyte colony-stimulating factor (G-CSF) was purified and its gene was cloned in 1984. G-CSF shortens the duration of chemotherapy-induced neutropenia and reduces complications due to infections typically associated with cytotoxic chemotherapy [1,2]. Thus, the British Society of Hematology (BSH) produced guidelines that recommend G-CSF therapy after induction, when appropriate, to reduce the hospital stay or antibiotic usage [3]. Randomised controlled trials (RCTs) using GCSF have been published over the past few decades, with conflicting results. Most of these studies demonstrated that the complete remission (CR) rate, disease-free survival (DFS), event-free survival and overall survival (OS) were not affected by G-CSF; however, some studies demonstrated a high CR rate and DFS when using G-CSF [4,5]. Hematological remission and long-term hematological control of acute myeloblastic leukemia are induced and maintained by G-CSF therapy [6]. Our primary objective was to determine whether prophylaxis with G-CSF in patients with AML produced a higher CR rate after the induction chemotherapy. Trials were identified by searching electronic databases, including MEDLINE, EMBASE, the Cochrane controlled trials register, the Cochrane Library and the Science Citation Index, updated to December 2007, and reference lists from the trials selected by electronic searching were handsearched to identify further relevant trials. The major conference abstracts were hand-searched to identify other potentially relevant studies for inclusion in this meta-analysis. The following quality criteria were used to select each study: (a) study design: RCTs, with or without blinding; (b) study population: newly diagnosed AML patients; (c) intervention: G-CSF; (d) controls: placebo or no treatment; (e) time of the intervention: after the first induction chemotherapy and (f) outcome measures: the CR rate after the first induction chemotherapy. According to the selection criteria, a total of eight studies were retrieved [4,7– 13]. Among these studies, three were excluded because of no information on the CR rate after the first induction course [11–13] (we have tried to contact the corresponding investigators of the studies excluded, but with no reply). Finally, a meta-analysis of pooled data from Dombret et al. [5], Heil et al. [7], Bradstock et al. [8], Goldstone et al. [9] and Usuki et al. [10], which were all published as full articles, was performed to assess the correlation between

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.

Doxorubicin-loaded platelets conjugated with anti-CD22 mAbs: a novel targeted delivery system for lymphoma treatment with cardiopulmonary avoidance

B-cell lymphoma accounts for approximately 85% of all adult non-Hodgkins lymphoma cases. Doxorubicin (DOX) is an indispensable drug for the treatment of non-Hodgkins lymphoma. However, DOX causes severe cardiotoxicity, which limits its use in conventional treatment strategies. In this study, we developed a novel drug delivery system for lymphoma treatment: DOX-loaded platelets that were conjugated with anti-CD22 monoclonal antibodies (mAbs) (DOX–platelet–CD22). Platelets are bio- and immune-compatible drug carriers that can prolong the circulation time of drugs. Anti-CD22 mAb-labeled platelets can precisely deliver DOX to tumor cells. Our in vitro and in vivo experiments showed the enhanced antitumor activity and attenuated cardiotoxicity of DOX when delivered as DOX–platelet–CD22. Compared with other delivery systems, the uptake of DOX–platelet–CD22 by macrophage-like cells decreased. Moreover, DOX–platelet–CD22 showed platelet properties, such as tumor cell-induced platelet aggregation. Therefore, targeted chemotherapy that is mediated by DOX–platelet–CD22 is a promising option for lymphoma treatment.B-cell lymphoma accounts for approximately 85% of all adult non-Hodgkins lymphoma cases. Doxorubicin (DOX) is an indispensable drug for the treatment of non-Hodgkins lymphoma. However, DOX causes severe cardiotoxicity, which limits its use in conventional treatment strategies. In this study, we developed a novel drug delivery system for lymphoma treatment: DOX-loaded platelets that were conjugated with anti-CD22 monoclonal antibodies (mAbs) (DOX-platelet-CD22). Platelets are bio- and immune-compatible drug carriers that can prolong the circulation time of drugs. Anti-CD22 mAb-labeled platelets can precisely deliver DOX to tumor cells. Our in vitro and in vivo experiments showed the enhanced antitumor activity and attenuated cardiotoxicity of DOX when delivered as DOX-platelet-CD22. Compared with other delivery systems, the uptake of DOX-platelet-CD22 by macrophage-like cells decreased. Moreover, DOX-platelet-CD22 showed platelet properties, such as tumor cell-induced platelet aggregation. Therefore, targeted chemotherapy that is mediated by DOX-platelet-CD22 is a promising option for lymphoma treatment.

High-dose chemotherapy followed by autologous stem cell transplantation as a first-line therapy for high-risk primary breast cancer: a meta-analysis.

Background and Objectives Several trials have generated conflicting results about the results of high-dose chemotherapy followed by autologous stem cell transplantation (HDCT) for primary breast cancer. This meta-analysis summarizes the available evidence from all suitable studies. Design and Methods Prospective, randomized trials with HDCT as a first-line therapy for primary breast cancer were included in this meta-analysis. The primary outcome of interest for our analysis was survival (disease-free survival and overall survival); secondary endpoints included treatment-related mortality (TRM) and second (non-breast) cancers. We used a median age of 47, a PR positive rate of 50% and a premenopausal rate of 70% as cutoff values to complete the subgroup analyses, which were pre-planned according to the prepared protocol. Results Fourteen trials with 5747 patients were eligible for the meta-analysis. Compared with non-HDCT, non-significant second (non-breast) cancers (RR = 1.28; 95% CI = 0.82–1.98) and higher TRM (RR = 3.42; 95% CI = 1.32–8.86) were associated with HDCT for primary breast cancer. A significant DFS benefit of HDCT was documented (HR = 0.89; 95% CI = 0.79–0.99). No difference in OS (overall survival) was found when the studies were pooled (HR = 0.91; 95% CI = 0.82–1.00, p = 0.062). In subgroup analysis, age and hormone receptor status had a significant interaction with prolonged DFS and OS. Conclusions HDCT has a benefit on DFS and OS compared to SDC in some special patients with high-risk primary breast cancer.

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.