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Folic acid supplementation enhances arsenic methylation: results from a folic acid and creatine supplementation randomized controlled trial in Bangladesh.
Bozack, AK, Hall, MN, Liu, X, Ilievski, V, Lomax-Luu, AM, Parvez, F, Siddique, AB, Shahriar, H, Uddin, MN, Islam, T, et al
The American journal of clinical nutrition. 2019;(2):380-391
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Abstract
BACKGROUND Arsenic exposure through drinking water persists in many regions. Inorganic As (InAs) is methylated to monomethyl-arsenical species (MMAs) and dimethyl-arsenical species (DMAs), facilitating urinary excretion. Arsenic methylation is dependent on one-carbon metabolism, which is influenced by nutritional factors such as folate and creatine. OBJECTIVE This study investigated the effects of folic acid (FA) and/or creatine supplementation on the proportion of As metabolites in urine. DESIGN In a 24-wk randomized, double-blinded, placebo-controlled trial, 622 participants were assigned to receive FA (400 or 800 μg per day), 3 g creatine per day, 400 μg FA + 3 g creatine per day, or placebo. The majority of participants were folate sufficient; all received As-removal water filters. From wk 12-24, half of the participants receiving FA received placebo. RESULTS Among groups receiving FA, the mean decrease in ln(%InAs) and %MMAs and increase in %DMAs exceeded those of the placebo group at wk 6 and 12 (P < 0.05). In the creatine group, the mean decrease in %MMAs exceeded that of the placebo group at wk 6 and 12 (P < 0.05); creatine supplementation did not affect change in %InAs or %DMAs. The decrease in %MMAs at wk 6 and 12 was larger in the 800 µg FA than in the 400 µg FA group (P = 0.034). There were no differences in treatment effects between the 400 µg FA and creatine + FA groups. Data suggest a rebound in As metabolite proportions after FA cessation; at wk 24, log(%InAs) and %DMAs were not significantly different than baseline levels among participants who discontinued FA supplementation. CONCLUSIONS The results of this study confirm that FA supplementation rapidly and significantly increases methylation of InAs to DMAs. Further research is needed to understand the strong cross-sectional associations between urinary creatinine and As methylation in previous studies. This trial was registered at https://clinicaltrials.gov as NCT01050556.
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Arsenic trioxide intravenous infusion combined with transcatheter arterial chemoembolization for the treatment of hepatocellular carcinoma with pulmonary metastasis: Long-term outcome analysis.
Hu, HT, Yao, QJ, Meng, YL, Li, HL, Zhang, H, Luo, JP, Guo, CY, Geng, X
Journal of gastroenterology and hepatology. 2017;(2):295-300
Abstract
OBJECTIVE To evaluate the safety, clinical efficacy, and long-term outcome of arsenic trioxide (As2 O3 ) intravenous infusion for pulmonary metastases in patients with HCC. MATERIALS AND METHODS Sixty consecutive patients who were diagnosed with advanced hepatocellular carcinoma (HCC) with pulmonary metastasis were randomized 1:1 into the treatment and control groups. Treatment group underwent transcatheter arterial chemoembolization (TACE) for the primary liver tumor and then underwent As2 O3 treatment, whereas control group underwent TACE alone. The treatment group underwent a continuous 5-h intravenous infusion of 10 mg/day As2 O3 . The course of As2 O3 treatment was initiated 3-5 days after TACE (to allow liver and gastrointestinal function to recover) and continued for 14 consecutive days. All patients in the treatment group underwent at least four treatment courses. Response to treatment was evaluated after four treatment courses. RESULT In treatment group, two patients had a complete response (CR), six had a partial response (PR), 10 had stable disease (SD), and 12 had progressive disease. A clinically effective rate (CR + PR) was achieved in 26.7%, and the clinical benefit rate (CR + PR + SD) was 60%. In the control group, no patients had a CR or PR, five had SD, and 25 had progressive disease. The clinically effective rate was 0%, and the clinical benefit rate was 16.7%. The overall 1-year survival was 56.7% in treatment group and 36.7% in control group. The overall 2-year survival was 16.7% in treatment group and 3.3% in control group. CONCLUSION Transcatheter arterial chemoembolization plus an intravenous infusion of As2 O3 effectively controlled pulmonary metastasis and prolonged overall survival in patients with HCC compared with TACE alone.
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Randomized clinical control study of locoregional therapy combined with arsenic trioxide for the treatment of hepatocellular carcinoma.
Wang, H, Liu, Y, Wang, X, Liu, D, Sun, Z, Wang, C, Jin, G, Zhang, B, Yu, S
Cancer. 2015;(17):2917-25
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Abstract
BACKGROUND The objective of this study was to determine the efficacy and safety of locoregional therapy (LRT) combined with arsenic trioxide (As2 O3 ) treatment in primary hepatocellular carcinoma (HCC) patients. METHODS One hundred twenty-five primary HCC patients were recruited for a randomized controlled study. Patients were randomly divided into group A (n = 61) and group B (n = 64). All patients received transarterial chemoembolization. Group A patients were given As2 O3 at 10 mg/d for 4 courses (21 days per course) with a 2-week interval between courses. Survival times, therapeutic responses, extrahepatic metastases, and adverse events were recorded. RESULTS A better therapeutic response was found in group A patients, as shown by higher objective response rate (ORR) and clinical benefit rate (CBR) values in group A versus group B (ORR, 81.96% [95% confidence interval (CI), 72.32%-91.62%] vs 59.37% [95% CI, 47.34%-71.41%], χ(2) = 7.650, P < .05; CBR, 95.08% [95% CI, 89.66%-100.00%] vs 81.25% [95% CI, 71.69%-90.81%], χ(2) = 5.659, P < .05). There were fewer patients with extrahepatic metastases in group A versus group B (group A, 6 cases or 9.84% [95% CI, 2.36%-17.31%]; group B, 12 cases or 18.75% [95% CI, 9.19%-28.31%]). The survival rate for group A patients was significantly higher than that for group B patients (P < .05). No significant differences were found between the 2 groups in terms of hematology or digestive system, liver, or kidney dysfunction except for facial and limb edema. CONCLUSIONS LRT combined with As2 O3 treatment prevents extrahepatic metastasis and prolongs the survival time for primary HCC patients.
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Randomized phase III trial of retinoic acid and arsenic trioxide versus retinoic acid and chemotherapy in patients with acute promyelocytic leukemia: health-related quality-of-life outcomes.
Efficace, F, Mandelli, F, Avvisati, G, Cottone, F, Ferrara, F, Di Bona, E, Specchia, G, Breccia, M, Levis, A, Sica, S, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014;(30):3406-12
Abstract
PURPOSE A randomized clinical trial compared efficacy and toxicity of standard all-trans-retinoic acid (ATRA) plus chemotherapy versus ATRA plus arsenic trioxide in patients with newly diagnosed, low- or intermediate-risk acute promyelocytic leukemia (APL). Here, we report health-related quality-of-life (HRQOL) results. PATIENTS AND METHODS HRQOL was a secondary end point of this trial. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 was used to assess HRQOL at end of induction and after consolidation therapy. All analyses were based on 156 patients who received at least one dose of treatment, with groups defined according to randomly assigned treatment. Primary analysis was performed, estimating mean HRQOL score over time and differences between treatment arms using a linear mixed model. RESULTS Overall, 162 patients age 18 to 70 years were enrolled. Of these, 150 and 142 patients were evaluable for HRQOL after induction therapy and third consolidation course, respectively. Overall compliance with HRQOL forms was 80.1%. The largest difference, favoring patients treated with ATRA plus arsenic trioxide, was found for fatigue severity (mean score difference, -9.3; 95% CI, -17.8 to -0.7; P = .034) at end of induction therapy. This difference was also clinically relevant. HRQOL differences between treatment arms at end of consolidation showed that for several scales, differences between treatment arms were marginal. CONCLUSION Overall, current HRQOL findings further support the use of ATRA plus arsenic trioxide as preferred first-line treatment in patients with low- or intermediate-risk APL.
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Arsenic trioxide in front-line therapy of acute promyelocytic leukemia (C9710): prognostic significance of FLT3 mutations and complex karyotype.
Poiré, X, Moser, BK, Gallagher, RE, Laumann, K, Bloomfield, CD, Powell, BL, Koval, G, Gulati, K, Holowka, N, Larson, RA, et al
Leukemia & lymphoma. 2014;(7):1523-32
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Abstract
The addition of arsenic trioxide (ATO) to frontline therapy of acute promyelocytic leukemia (APL) has been shown to result in significant improvements in disease-free survival (DFS). FLT3 mutations are frequently observed in APL, but its prognostic significance remains unclear. We analyzed 245 newly diagnosed adult patients with APL treated on intergroup trial C9710 and evaluated previously defined biological and prognostic factors and their relationship to FLT3 mutations and to additional karyotypic abnormalities. FLT3 mutations were found in 48% of patients, including 31% with an internal tandem duplication (FLT3-ITD), 14% with a point mutation (FLT3-D835) and 2% with both mutations. The FLT3-ITD mutant level was uniformly low, < 0.5. Neither FLT3 mutation had an impact on remission rate, induction death rate, DFS or overall survival (OS). The addition of ATO consolidation improved outcomes regardless of FLT3 mutation type or level, initial white blood cell count, PML-RARA isoform type or transcript level. The presence of a complex karyotype was strongly associated with an inferior OS independently of post-remission treatment. In conclusion, the addition of ATO to frontline therapy overcomes the impact of previously described adverse prognostic factors including FLT3 mutations. However, complex karyotype is strongly associated with an inferior OS despite ATO therapy.
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Clinical, pathological and immunohistochemical effects of arsenical-ferruginous spa waters on mild-to-moderate psoriatic lesions: a randomized placebo-controlled study.
Borroni, G, Brazzelli, V, Fornara, L, Rosso, R, Paulli, M, Tinelli, C, Ciocca, O
International journal of immunopathology and pharmacology. 2013;(2):495-501
Abstract
Thermalism and spa treatments are traditionally considered effective in a number of dermatologic inflammatory conditions, yet there is scarce evidence about spring water effectiveness on psoriasis in a daily setting. We enrolled 34 patients with mild-to-moderate psoriasis in a double-blind, randomized, placebo-contralaterally-controlled trial, to evaluate Levico and Vetriolo arsenical-ferruginous water effectiveness on psoriatic lesions by daily 20-minute wet packing for 12 consecutive days. Clinical, histopathologic and immunohistochemical parameters were considered. A statistically significant difference between spa water-treated lesions and placebo-treated lesions in the same patients was demonstrated for histopathologic and immunohistochemical parameters. Since iron ions have an antiproliferative effect on epithelia, and magnesium ions have an anti-inflammatory effect, Levico and Vetriolo water effectiveness on psoriasis could be addressed to their content of these ions.
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[The clinical therapeutic effects of arsenic trioxide combined with transcatheter arterial chemoembolization in treating primary liver cancer with pulmonary metastases].
Meng, YL, Hu, HT, Li, HL, Guo, CY, Luo, JP, Yao, QJ, Cheng, HT, Xiao, JC
Zhonghua nei ke za zhi. 2012;(12):971-4
Abstract
OBJECTIVE To observe the therapeutic effects of arsenic trioxide combined with transcatheter arterial chemoembolization on treatment of primary liver cancer with pulmonary metastases. METHODS Sixty patients were randomly divided into two groups: group A (treatment group, n = 30) and group B (control group, n = 30). Group A was received periodic transcatheter arterial chemoembolization (TACE) and 10 mg arsenic trioxide by intravenous infusion for 5 hours per day, 3 days after TACE. Each cycle consisted of 14 days' administration, and repeated after 2 weeks. Each patient was received 3-4 successive cycles. Group B was received periodic TACE alone. OBJECTIVE efficiency, benefit rate, quality of life and the correlates with metastatic tumor size and number in the both groups were recorded. RESULTS The objective efficiency was 26.7% (8/30), and the benefit rate was 60.0% (18/30) in group A, while they were 0 and 16.7% (5/30) in group B with significant statistics differences (χ(2) = 7.067, P = 0.008; χ(2) = 11.915, P = 0.001). The quality of life was improved in 4 patients and stable in 18 of group A, while no patient was improved and 13 were stable in group B (χ(2) = 9.669, P = 0.008). There was a significantly positive correlation between the tumor burden and therapeutic effect (Kendall r = -0.765, P < 0.001; Spearman r = -0.821, P < 0.001). CONCLUSION Arsenic trioxide combined TACE is an effective treatment method in treating primary liver cancer with pulmonary metastases.
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Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710.
Powell, BL, Moser, B, Stock, W, Gallagher, RE, Willman, CL, Stone, RM, Rowe, JM, Coutre, S, Feusner, JH, Gregory, J, et al
Blood. 2010;(19):3751-7
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Abstract
Arsenic trioxide (As(2)O(3)) is a highly effective treatment for patients with relapsed acute promyelocytic leukemia (APL); its role as consolidation treatment for patients in first remission has not been defined. We randomized 481 patients (age ≥ 15 years) with untreated APL to either a standard induction regimen of tretinoin, cytarabine, and daunorubicin, followed by 2 courses of consolidation therapy with tretinoin plus daunorubicin, or to the same induction and consolidation regimen plus two 25-day courses of As(2)O(3) consolidation immediately after induction. After consolidation, patients were randomly assigned to one year of maintenance therapy with either tretinoin alone or in combination with methotrexate and mercaptopurine. Ninety percent of patients on each arm achieved remission and were eligible to receive their assigned consolidation therapy. Event-free survival, the primary end point, was significantly better for patients assigned to receive As(2)O(3) consolidation, 80% compared with 63% at 3 years (stratified log-rank test, P < .0001). Survival, a secondary end point, was better in the As(2)O(3) arm, 86% compared with 81% at 3 years (P = .059). Disease-free survival, a secondary end point, was significantly better in the As(2)O(3) arm, 90% compared with 70% at 3 years (P < .0001). The addition of As(2)O(3) consolidation to standard induction and consolidation therapy significantly improves event-free and disease-free survival in adults with newly diagnosed APL. This trial was registered at clinicaltrials.gov (NCT00003934).
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[Relationship between radiotherapy enhancing effect of arsenic trioxide and the proliferation and apoptosis of related protein in nasopharyngeal carcinoma patients].
Lin, YC, Li, DR, Lin, W
Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine. 2007;(8):704-7
Abstract
OBJECTIVE To explore the mechanism of arsenic trioxide (ATO) in enhancing radiotherapy in nasopharyngeal carcinoma (NPC) patients. METHODS Seventy-four patients with NPC of T(1-4) N(0-1)M0 were randomized into two groups: 35 patients in Group A were treated with conventional radiotherapy alone, and the 39 in Group B received radiotherapy and additional administering of ATO. The regressions of nasopharyngeal lesions and cervical lymph nodes were compared between the two groups at 40 Gy of radiation was given. And biopsy of the tissue from NPC was taken before treatment and 24 h after radiation of 20 Gy to determine the-expressions of proliferating cell nuclear antigen (PCNA), Bcl-2, Bax and p53 protein by immunohistochemistry. RESULTS When irradiation for 40 Gy, the completely regression rates of nasopharyngeal lesion were 20.0% (7/35) in Group A and 43.6% (17/39) in Group B, showing significant difference between them (chi2 = 4.684, P = 0.003), but no significant difference was shown between the two groups in regression rate of cervical lymph node. Expression of PCNA, Bax, Bcl-2 and p53 protein was reduced in both groups, but significant difference only showed between pre- and post-treatment in PCNA (Z = -2.449, P = 0.014) and Bax protein (Z = -3.031, P = 0.002) in Group B. Significantly reduction of PCNA (Z = -2.656, P = 0.008), Bax (Z = -2.359, P = 0.018) and p53 protein (Z = -1.999, P = 0.046) in patients with complete tumor regression at radiation for 20 Gy, while in those with no complete tumor regression only PCNA showed significant reduction (Z = -32.815, P = 0.015). CONCLUSION ATO shows effect in enhancing radiotherapy on NPC patients, its mechanism might be associated with the down-regulation of PCNA and apoptosis related protein and the inhibition on tumor proliferation and apoptosis inducing.
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Effects of arsenic trioxide administration styles on leukocytosis.
Zhou, J, Meng, R, Sui, XH, Meng, L, Yang, BF
Chinese medical sciences journal = Chung-kuo i hsueh k'o hsueh tsa chih. 2006;(2):111-4
Abstract
OBJECTIVE To study the effects of constantly slow intravenous arsenic trioxide (As2O3) infusion regimen on decreasing leukocytosis in vivo and in vitro. METHODS Three kinds of leukemia cells, NB4, K562, and acute promyelocytic leukemia (APL) cells, were cultured in the media with constant concentration and varying concentrations of As2O3 respectively for 24 hours. Seventy-five patients were enrolled in two groups randomly. In trial group, 37 patients received continuously slow intravenous As2O3 infusion regimen for 24 hours with an infusion rate of 8 drips per minute and total infusion duration of about 18-21 hours daily. In control group, 38 patients received routine regimen with an infusion rate of 45-55 drips per minute and total infusion duration of about 2-3 hours daily for 24 hours. The daily As2O3 dosage was 0. 16 mg/kg. The intracellular arsenic concentration was measured by atomic fluorescence assay. The apoptosis rate of cells, CD33- CD11b+ cells, and CD33+ CD11b- cells were monitored by flow cytometry. RESULTS The apoptosis rates of NB4, K562, and APL leukemia cells in the media with constant As2O3 concentration were 56.6% +/- 2.4%, 27.6% +/- 3.1%, and 52.2% +/- 2.8%, respectively, which were significantly higher than those with changing As2O3 concentration (23.2% +/- 2.1%, 11.0% +/- 2.5%, and 21.0% +/- 2.5%, respectively, P < 0.01). The apoptosis rates of APL, M2 type acute myeloid leukemia (AML-M2), and chronic myeloid leukemia (CML) patients in the trial group (28.5% +/- 1.9%, 9.5% +/- 0.6%, and 12.5% +/- 1.8%) were also significantly higher than those in control group (8.5% +/- 2.2%, 2. 9% +/- 0.8%, and 4.5% +/- 1.2%; P < 0.05). The ratios of CD33 CD11b- and CD33- CD11b+ cells in control group were significantly higher than those in trial group. CONCLUSION The continuously slow intravenous As2O3 infusion regimen can obtain high efficiency of apoptosis and low differentiation proportion, relieve leukocytosis, and gain maximal therapeutic benefit.