Arsenic trioxide replacing or reducing chemotherapy in consolidation therapy for acute promyelocytic leukemia (APL2012 trial)

As all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are widely accepted in treating acute promyelocytic leukemia (APL), deescalating toxicity becomes a research hotspot. Here, we evaluated whether chemotherapy could be replaced or reduced by ATO in APL patients at different risks. After achieving complete remission with ATRA-ATO–based induction therapy, patients were randomized (1:1) into ATO and non-ATO groups for consolidation: ATRA-ATO versus ATRA–anthracycline for low-/intermediate-risk patients, or ATRA-ATO–anthracycline versus ATRA–anthracycline–cytarabine for high-risk patients. The primary end point was to assess disease-free survival (DFS) at 3 y by a noninferiority margin of –5%; 855 patients were enrolled with a median follow-up of 54.9 mo, and 658 of 755 patients could be evaluated at 3 y. In the ATO group, 96.1% (319/332) achieved 3-y DFS, compared to 92.6% (302/326) in the non-ATO group. The difference was 3.45% (95% CI –0.07 to 6.97), confirming noninferiority (P < 0.001). Using the Kaplan–Meier method, the estimated 7-y DFS was 95.7% (95% CI 93.6 to 97.9) in ATO and 92.6% (95% CI 89.8 to 95.4) in non-ATO groups (P = 0.066). Concerning secondary end points, the 7-y cumulative incidence of relapse (CIR) was significantly lower in ATO (2.2% [95% CI 1.1 to 4.2]) than in non-ATO group (6.1% [95% CI 3.9 to 9.5], P = 0.011). In addition, grade 3 to 4 hematological toxicities were significantly reduced in the ATO group during consolidation. Hence, ATRA-ATO in both chemotherapy-replacing and -reducing settings in consolidation is not inferior to ATRA–chemotherapy (https://www.clinicaltrials.gov/, {"type":"clinical-trial","attrs":{"text":"NCT01987297","term_id":"NCT01987297"}}NCT01987297).

The treatment of all-trans retinoic acid (ATRA) combined with anthracycline-based chemotherapy has remarkably improved the prognosis of patients with acute promyelocytic leukemia (APL), achieving over 90% complete remission (CR) and 60 to 80% long-term survival (1–6). For patients relapsed from ATRA-chemotherapy, arsenic trioxide (ATO) was initially used as salvage therapy and showed a satisfactory outcome (7–9). Then, the treatment of newly diagnosed APL with an ATRA-ATO combination therapy was reported in 2004, which demonstrated curative effects in 90% of patients (10–13). The advantage of ATO as the front-line treatment of APL has been further validated by a number of international working groups (14–18). Meanwhile, an exploratory study on ATRA-ATO with or without gemtuzumab ozogamicin (GO, the cytotoxic agent calicheamicin linked an anti-CD33 monoclonal antibody) by the MD Anderson Cancer Center suggested that a deescalating cytotoxic regimen might be feasible for APL patients (14, 19).A large body of evidence has been obtained to show that both ATRA and ATO target the APL-specific PML-RARA oncoprotein and the two agents may exert a synergistic effect in achieving a curative clinical effect in most APL (2, 9). However, in our previous studies, though ATRA-ATO were used as main therapeutic agents for induction, the consolidation was based on chemotherapy rather than ATO, which could cause life-threatening myelosuppression and cardiotoxicity (10, 11). Besides, risk-stratified treatment had not been introduced, leading to probable overtreatment for low- risk (a white blood cell [WBC] count ≤ 10 × 10⁹/L and a platelet count > 40 × 10⁹/L) to intermediate-risk (a WBC count ≤ 10 × 10⁹/L and a platelet count ≤ 40 × 10⁹/L) patients (20). These issues warranted further clinical investigations to address the role of ATRA-ATO in consolidation and to adapt the treatment protocols to distinct clinical risks. In order to optimize the treatment protocols by reducing their relevant toxicities and costs, as well as further improving therapeutic efficacy and tolerance, we proposed a multicenter randomized trial, APL2012, deriving from our previous ATRA-ATO–based therapy taking into consideration of Sanz risk stratification (20). The objective of this study was to examine whether chemotherapy could be replaced or reduced in consolidation therapy by ATO in patients with APL at different risks.     

Arsenic exposure and tobacco consumption: Biomarkers and risk assessment

Arsenic is measurable in tobacco and cigarette mainstream smoke (MSS). Whether arsenic has an independent role in diseases associated with tobacco consumption is not known. Epidemiology and biomonitoring data and probabilistic risk assessment (PRA) methods were used to investigate this potential association. Analysis of data from the National Health and Nutrition Examination Survey (NHANES) showed that urine arsenic concentrations in tobacco consumers were not different or were lower than levels in non-consumers of tobacco. Additionally, urine arsenic levels from NHANES tobacco consumers were five-times or more lower than levels reported in epidemiology studies to be associated with adverse health effects. Results of PRA indicated that mean non-cancer hazard estimates and mean incremental lifetime cancer risk estimates were within accepted ranges. Taken together, these results suggest that arsenic may not be independently associated with tobacco consumption or diseases related to tobacco consumption.     

云南昭通燃煤中砷的释放规律及其环境效应研究

目的探讨燃煤型氟中毒病区燃煤中砷的实际燃烧释放规律及其环境效应。方法于2005—2010年,在云南昭通系统采集了24户农户的煤、拌煤粘土、煤泥、煤渣以及新鲜玉米和烘烤玉米样品进行砷含量的检测,并计算煤泥中砷元素的燃烧释放量及释放率,分析了煤泥中砷释放量与烘烤玉米中砷增加量的关系。结果煤中砷含量为0.72~14.35 mg/kg,中位数为3.92 mg/kg;拌煤粘土中砷含量为1.66~66.59 mg/kg,中位数为17.22 mg/kg;煤泥中砷含量为1.81~29.52 mg/kg,中位数为7.79 mg/kg;煤泥中砷的释放量为0.09~22.47 mg/kg,中位数为2.00 mg/kg;煤泥中砷的释放率为0.92%~76.10%,中位数为31.76%;新鲜玉米中的砷含量为未检出~0.03 mg/kg,中位数为0.02 mg/kg,远低于GB 2762—2005《食品中污染物限量》中砷限量(0.2 mg/kg);烘烤玉米中的砷含量为未检出~0.34 mg/kg,中位数为0.09 mg/kg,与新鲜玉米相比有了大幅增加,超标率仅为23.8%。粘土与煤泥中砷释放量呈正相关(P=0.001),而砷释放量与烘烤玉米砷增加量间无统计学相关性(P=0.604)。结论拌煤粘土是燃煤中砷污染物释放的重要来源。烘烤玉米中砷污染程度不仅与煤泥中砷释放量有关,而且受到烤房条件、敞炉结构、烘烤时间等多种因素的影响。     

2011—2013年广西农田土壤砷调查

目的了解广西农田土壤砷的污染状况。方法于2011—2013年对广西29个县(区)共580个村农田土壤中的砷含量进行检测和评价。结果共采集农田土壤样品1 740件,62.07%的土壤砷含量低于自然背景值;土壤坤含量范围为0.54~1 212 mg/kg,平均值为19.67 mg/kg,中位数为11.7 mg/kg,众数为10.6 mg/kg,砷的点位超标率为18.62%,最高超标39.4倍。土壤砷重度污染占0.63%,中度污染占1.90%,轻度污染占4.08%,轻微污染占12.01%。结论广西农田土壤砷含量的超标应引起关注。     

基质金属蛋白抑制因子-1 mRNA在饮水砷暴露肝损伤小鼠肝组织中的表达

目的 探讨基质金属蛋白酶抑制因子-1(TIMP-1)mRNA在饮水砷暴露肝损伤小鼠肝组织中的表达及意义.方法 50只雄性小鼠被随机分成对照组、亚砷酸钠组(iAs3+组,300 mg/L)、砷酸钠组(iAs5+组,300 mg/L).10个月后处死小鼠,肝功能检查血清丙氨酸转氨酶(ALT)、天门冬氨酸氨基转移酶(AST)、球蛋白(GLB);部分肝组织进行HE染色;Trizol-酚-氯仿一步法提取小鼠肝组织总RNA,紫外分光光度法测定总RNA及纯度,实时荧光定量PCR法测定肝组织中TIMP-1 mRNA的表达,以18S基因作为质控.结果 ALT在对照组(36.67±3.51)、iAs3+组(61.46±13.85)和iAs5+组(43.31±4.21)组间比较差异有统计学意义(F=6.559,P＜0.05);iAs3+组与对照组比较差异有统计学意义(P＜0.05),iAs5+组与对照组、iAs3+组比较差异无统计学意义(P＞0.05);AST在对照组(135.00±20.42)、iAs3+组(510.86±59.01)和iAs5+组(258.93±22.40)组间比较差异有统计学意义(F=83.327,P＜0.05);GLB在对照组(20.86±0.61)、iAs3+组(26.94±3.73)和iAs5+组(24.59±5.27)组间比较差异无统计学意义(F=2.800,P＞0.05).肝组织病理检查显示,肝组织中有明显的肝细胞坏死和再生,TIMP-1 mRNA表达组间比较差异有统计学意义(F=17.337,P＜0.05).结论 TIMP-1基因在水砷暴露肝损伤小鼠肝组织损伤、肝纤维化形成过程中可能起重要作用.     

维甲酸、三氧化二砷诱导NB4细胞TRAIL基因表达的研究

目的：研究全反式维甲酸(ATRA)或三氧化二砷(As2O3)诱导急性早幼粒细胞白血病(APL)NB4细胞肿瘤坏死因子相关的凋亡诱导配体(TRAIL)基因的表达及其治疗APL的机制。方法：采用RT—PCR检测TRAIL基因表达的变化。结果：10^-6mol／L的ATRA作用6h或10^-6mol／L的As2O3作用12h，即可诱导TRAIL基因表达。结论：ATRA或As2O3能诱导NB4细胞TRAIL基因表达，TRAIL基因可能以类似“旁分泌”的作用方式杀伤NB4细胞。诱导TRAIL基因介导的细胞凋亡可能是ATRA或As2O3治疗APL的机制之一。     

砷氟中毒地区儿童智力水平及生长发育调查与评价

目的探讨砷、氟暴露对儿童智力和生长发育的影响。方法在砷、氟中毒地区,按照所选取病区的不同类别分为4组,即高砷高氟组、高氟组、高砷组、对照组,分析比较各组间儿童智力和生长发育水平的差异。结果高砷高氟组、高氟组儿童平均智商低于对照组(q=3.05、q=4.31,P<0.05、P<0.01)。高砷组儿童智商处于最低水平,与对照组(q=8.59,P<0.01)、高氟组(q=4.88,P<0.01)、高砷高氟组(q=3.89,P<0.05)比较,差异均具有统计学意义。儿童智商与其尿砷(t=2.81,P<0.01)和尿氟(t=2.05,P<0.05)组间比较,分别呈负相关。高氟组儿童身高低于对照组(t=2.40,P<0.05)、高砷组儿童体质量低于对照组(t=3.37,P<0.05)、高砷高氟组儿童肺活量低于对照组(t=2.73,P<0.05)。结论高砷、高氟的摄入均可影响儿童智力和生长发育,其中以高砷对儿童智力的影响更为明显,提示长期砷、氟暴露对儿童的智力和生长发育将产生不良的影响。     

The role of mitochondrial targeting in arsenic trioxide-induced apoptosis in myeloid cell lines

Data regarding the role of mitochondria in arsenic trioxide (As2O3)-induced apoptosis are controversial. We investigated the contribution of caspases and mitochondrial depolarization to As2O3-induced apoptosis in the myeloid cell lines NB-4, HL-60 and U-937. Caspase inhibition reduced the amount of cells with As2O3 (20 micromol/l)-induced mitochondrial depolarization by about 50% in all cell lines. As2O3 also induced dose-dependent phosphatidylserine exposure in cells without depolarized mitochondria. We conclude that caspase activation is of similar importance in As2O3-induced apoptosis in myeloid cell lines as direct mitochondrial targeting and mitochondria are not necessary for caspase activation downstream of mitochondria.     

Fumaric acids as a novel antagonist of TLR-4 pathway mitigates arsenic-exposed inflammation in human monocyte-derived dendritic cells

Abstract

Exposure to environmentally relevant doses of arsenic has several harmful effects on the human immune system. In traditional Eastern medicines, nettle has been used as an anti-inflammatory agent to treat rheumatism and osteoarthritis. Fumaric acid (FA) as a major effective compound in nettle was chosen based on very accurate virtual screening to find antagonist for TLR4/MD structure. In this study, the in vitro therapeutic effects of FA on arsenic-exposed monocytes-derived dendritic cells (MDDCs) were evaluated. All the canonical functions of dendritic cells in bridging innate and adaptive immune system including phagocytosis and antigen-presenting capacity, and also cytokines secretion, were evaluated after exposure to arsenic/FA. FA profoundly over-expressed antigen-presenting capacity of MDDCs after exposure to arsenic through the upregulation of MHCιι. However, phagocytosis capacity of arsenic-exposed MDDCs is not compensated for, by treatment with FA. Arsenic up-regulates pro-inflammatory cytokines independents of TLR4 pathway. FA surprisingly mitigates the up-regulation of IL-1β and TNF-α but not TLR4 and NF-kB. Moreover, FA increases the viability of MDDCs even at a high dose of arsenic. Totally, FA reduced inflammatory factors induced by arsenic. This finding confirmed that nettle and other medicinal plants containing similar structures with FA could be further analyzed as valuable candidates for the reduction of drastic effects of arsenic in human immune systems.