| PART I Association of SNPs in microRNA-related genes with TCL survivalSection I DICER rs3742330 is associated with TCL survivalBackground and Objective:DICER, an endonuclease in RNase III family, is essential for the RNA interference pathway. Aberrant expression of DICER has been shown in various cancers including certain subtypes of T cell lymphoma (TCL), which is associated with patient prognosis. A single-nucleotide polymorphism (SNP) rs3742330A>G has been identified in the DICER gene. This SNP is located in the 3'untranslated region that is important for DICER mRNA transcript stability. We investigated whether rs3742330 is associated with TCL survival.Materials and Methods:We genotyped DICER rs3742330 with the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method in a cohort of 163 TCL patients and explored the association of the SNP with overall survival (OS).Results:Significant association between DICER rs3742330 and TCL survival was found. Patients carrying the GG genotype (N= 12) had a significantly increased OS compared with those carrying the GA and AA genotypes (N= 70 and N= 81, respectively; log rank test P= 0.024). The significant association was remained in patients with mature T type (log rank test P= 0.026). In multivariate Cox-regression analysis, rs3742330 proved to be an independent predictor for OS, with hazard ratios (HRs) for patient death rate of 9.09 (95% onfidence interval (CI) 1.23-67.27, P= 0.031) for the GA genotype and 9.871 (95% CI 1.34-72.79, P= 0.025) for the AA genotype.Conclusions:DICER rs3742330 is associated with TCL survival.Section ? SNPs in microRNA-related genes are associated with TCL survivalBackground and Objective:Elaborate evaluation of prognosis of TCL is vital for current therapy and future stratified and individualized therapy. MicroRNAs (miRNAs) and their related genes play important roles in cancer development and progression. Results of section ? have showed that DICER rs3742330 is associated with TCL survival. In order to further study the association between SNPs in miRNA-related genes and TCL survival, we assessed the effect of more SNPs in miRNA-related genes on TCL survival in a larger cohort of patients.Materials and Methods:We genotyped 13 selected SNPs located in 12 miRNA-related genes with the PCR-RFLP method in 220 TCL patients and explored the association of these SNPs with OS.Results:Among the 13 SNPs, four (DROSHA rs6877842, DICER rs3742330, mir149 rs2292832, and mir499 rs3746444) were significantly associated with TCL OS after adjusting for subtype and International Prognostic Index (IPI) score. The significant association was remained in patients with mature T type or in patients with an IPI score of 0-1. Furthermore, a dose-dependent cumulative effect of the four SNPs on TCL survival was observed. Comparing with patients with zero, one or two unfavorable genotypes, those with three unfavorable genotypes was at a 2.53-fold (95% CI 1.06-6.00, P= 0.036) increased risk of death, and the risk further increased to 5.31-fold (95% CI 2.24-12.57, P= 0.00015) for those with all four unfavorable genotypes (Ptrend= 0.00004). Survival tree analysis showed higher order interactions between these SNPs.Conclusions:The results suggested that miRNA-related SNPs are associated with TCL survival and they may be used individually and jointly to predict TCL survival.PART II Effect of different intervention factors on AML survival: Cochrane systematic reviewsSection I Effect of induction therapy with idarubicin on the survival of newly diagnosed AML:a Cochrane systematic reviewBackground and Objective:Anthracycline combined with cytarabine has been the standard for induction therapy of newly diagnosed acute myeloid leukaemia (AML) for several decades. Theoretically, idarubicin (IDA) might be the most effective and tolerable anthracycline. However, different clinical trials have given out different results. Therefore, a Cochrane systematic review was conducted to assess the efficacy and safety of IDA versus other anthracyclines in induction therapy of newly diagnosed AML.Methods:We identified relevant randomized controlled trials (RCTs) by searching the Cochrane Library, MEDLINE, EMBASE, Chinese BioMedical Literature Database (CBM), relevant conference proceedings and database of ongoing trials. RCTs that compared IDA with other anthracyclines in induction therapy of newly diagnosed AML were meta-analyzed. HRs were used as effect measures for OS and relapse-free survival (RFS), and risk ratios (RRs) as effect measures for complete remission (CR) rate, incidences of death during induction therapy, relapse and adverse events (AEs).Results:A total of 27 RCTs involving 9540 newly diagnosed AML patients were eligible for this systematic review and included in four separate meta-analyses in which IDA compared with different anthracyclines.Eighteen RCTs (N=6746) assessed IDA versus daunorubicin (DNR). The main meta-analyses showed that IDA compared with DNR statistically significantly prolonged OS (HR= 0.89,95% CI 0.81-0.97, P= 0.01) and RFS (HR= 0.89,95% CI 0.82-0.97, P= 0.009), and increased CR rate (RR= 1.05,95% CI 1.01-1.10, P= 0.02), although may increase the incidence of death during induction therapy (RR= 1.19,95% CI 1.02-1.38, P= 0.03). There were no statistically significant differences between arms in the incidences of relapse (RR= 0.85,95% CI 0.71-1.01, P= 0.06) and various grades 3/4 AEs.Eight RCTs (N= 2419) evaluated IDA versus mitoxantrone (MIT). The main meta-analyses found no statistically significant difference between arms in OS (HR= 0.98, 95% CI 0.89-1.08, P= 0.69), RFS (HR= 0.88,95% CI 0.70-1.10, P= 0.26), CR rate ((RR = 0.97,95% CI 0.92-1.03, P= 0.32), the incidences of death during induction therapy (RR = 1.10,95% CI 0.88-1.38, P= 0.39) and relapse (RR= 0.99,95% CI 0.80-1.22, P= 0.89). The incidences of various grades 3/4 AES were all similar between arms.Two RCTs (N= 211) compared IDA with doxorubicin (DOX). One trial showed no statistically significant difference in RFS between arms (HR= 0.62,95% CI 0.34-1.14, P= 0.12). The main meta-analysis for CR rate showed a statistically significantly improved CR rate with IDA compared with DOX (RR-1.28,95% CI 1.03-1.59, P= 0.02). One trial showed no statistically significant difference in the incidence of grades 3/4 cardiac toxicity between arms.Two RCTs (N= 1037) evaluated IDA versus zorubicin (ZRB). One trial showed no statistically significant difference in RFS between arms (HR= 1.25,95% CI 0.83-1.88, P= 0.29). The main meta-analyses for CR rate and incidence of death during induction therapy both showed no statistically significant difference between arms (CR rate:RR= 1.04,95% CI 0.96-1.13, P= 0.31; incidence of death during induction therapy:RR= 0.75,95% CI 0.50-1.13, P= 0.17). One trial showed that IDA statistically significantly reduced the incidence of grades 3/4 mucositis.Conclusions:IDA compared with DNR in induction therapy of newly diagnosed AML prolonged OS and RFS, increased CR rate, although may increase the incidence of death during induction therapy. The currently available evidence did not show any difference between IDA and MIT used in induction therapy of newly diagnosed AML. There is insufficient evidence regarding IDA versus DOX and IDA versus ZRB to deduct final conclusions.Section II Effect of adding gemtuzumab ozogamicin to induction therapy on the survival of newly diagnosed AML:a Cochrane systematic reviewBackground and Objective:Gemtuzumab ozogamicin (GO) is a targeted antineoplastic agent comprised of a recombinant anti-CD33 humanized antibody linked to calicheamicin. Previous trials have showed conflicting results concerning the effect of adding GO to induction therapy on the survival of adult newly diagnosed AML. A Cochrane systematic review was conducted to resolve this controversial issue.Methods:Relevant RCTs were identified by searching the Cochrane Library, MEDLINE, EMBASE and CBM. RCTs that compared adding GO to induction therapy with induction therapy alone for adult newly diagnosed AML were meta-analyzed. HRs were used as effect measures for OS and RFS, and odds ratios (ORs) as effect measures for CR rate, incidences of resistance disease, relapse and AEs.Results:Data of 3596 patients (1798 GO and 1798 controls) from five RCTs were analyzed. Compared with induction therapy alone, adding GO significantly prolonged OS (HR= 0.93,95% CI 0.86-1.00, P= 0.05) and RFS (HR= 0.87,95% CI 0.79-0.95, P= 0.003), decreased the incidences of resistant disease (OR= 0.71,95% CI 0.55-0.93, P= 0.01) and relapse (OR= 0.75,95% CI 0.63-0.90, P= 0.002), but had no effect on CR rate (OR= 1.15,95% CI 0.91-1.46, P= 0.24). Sensitivity analysis yielded similar results. Subgroup analysis identified that cytogenetics might be an influencing factor for the effect of adding GO. In addition, the risks of grade 3-4 nausea/vomiting, diarrhea and liver aspartate transaminase (AST) elevation were increased in GO arm.Conclusions:Adding GO to induction therapy for adult newly diagnosed AML can significantly prolong OS and RFS, decrease incidences of resistant disease and relapse, but may increase risks of grade 3-4 nausea/vomiting, diarrhea and liver AST elevation.Section ? Effect of consolidation therapy with high-dose cytarabine on the survival of AML in first complete remission:a Cochrane systematic reviewBackground and Objective:Early studies established high-dose cytarabine (HDAC) as first-line therapy for AML patients in first complete remission (CR1) without donor for allogeneic hematopoietic stem cell transplantation (HSCT). However, new evidence has challenged this notion. A Cochrane systematic review was conducted to clarify the role of HDAC in treatment of these patients.Methods:Relevant RCTs were identified by searching the Cochrane Library, MEDLINE, EMBASE, reference lists of included studies and relevant reviews. RCTs that compared HDAC with other therapies for AML in CR1 without donor were meta-analyzed. HRs were used as effect measures for OS and RFS, and RR as effect measure for treatment related mortality (TRM).Results:Twelve RCTs including 3927 patients were identified. HDAC resulted into a significantly improved OS (HR= 0.90,95% CI 0.81-0.99, P= 0.03) and RFS (HR= 0.91, 95% CI 0.83-0.98, P= 0.02), but a similar TRM (RR= 0.87,95% CI 0.63-1.21, P= 0.40). Sensitivity analyses showed consistent trend with the main analysis of all these endpoints. There were no differences in effect on OS, RFS and TRM between subgroups defined by study region, sponsorship, median time of follow-up, HDAC cycles, and comparator.Conclusion:Compared with other therapy options for AML patients in CR1 without donor for allogeneic HSCT, HDAC can significantly prolong OS and RFS, also doesn't increase TRM. |
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