Superiority of anthracycline-free treatment in standard-risk acute promyelocytic leukemia: A systematic review and comparative epidemiological analysis.

BACKGROUND: Recent advances in the treatment of acute promyelocytic leukemia (APML) have seen unprecedented improvements in patient outcomes. However, such rapid growth in understanding often leads to uncertainty regarding superiority among candidate treatment regimens, especially when further scrutinized from an epidemiological perspective. AIMS: The aim of this systematic review with epidemiological analysis was to identify and compare commonly utilized protocols for standard-risk APML with a particular focus on complete remission (CR), overall/disease-free survival (DFS), and reported adverse events. METHODS AND RESULTS: Medline, Scopus, and CINAHL were interrogated to identify studies utilizing all-trans retinoic acid (ATRA) in addition to arsenic trioxide (ATO) and/or anthracyclines such as idarubicin (IDA) in the treatment of de-novo APML. After collation of studies, an epidemiological analysis was subsequently performed to compare protocols with regards to outcomes of interest using number needed to benefit (NNB) and number needed to harm (NNH) measures. Seventeen articles, describing 12 distinct trials, were included in the analysis. These trials made use of three unique protocols; CR rates were 94%-100% for ATO/ATRA regimens, 95%-96% for ATO/ATRA/anthracycline regimens, and 89%-94% for ATRA/anthracycline regimens. Epidemiological analysis demonstrated NNB for CR was 9.09 (ATO/ATRA vs. ATRA/IDA) and 20.00 (ATO/ATRA vs. ATO/ATRA/IDA), NNH for neutropenia was -3.45 (ATO/ATRA vs. ATRA/IDA), and NNH for infection was -3.13 (ATO/ATRA vs. ATRA/IDA) and -1.89 (ATO/ATRA vs. ATO/ATRA/IDA). CONCLUSION: The ATO/ATRA regimen is superior to chemotherapy-containing protocols at inducing remission and promoting survival in patients with APML. The regimen is better tolerated than the proposed alternatives with fewer adverse events. Future research opportunities include quantifying APML epidemiology and pursuing oral arsenic as an option for simplification of therapeutic protocols.

Clinical Indicators of Hepatotoxicity in Newly Diagnosed Acute Promyelocytic Leukemia Patients Undergoing Arsenic Trioxide Treatment.

Arsenic trioxide (ATO)-induced hepatotoxicity is often observed in acute promyelocytic leukemia (APL) patients and decreases therapeutic effect of ATO. Thus, concerns over hepatotoxicity have been raised. The aim of this study was to explore some noninvasive clinical indicators that can be used to guide the individualized application of ATO in the future. APL patients treated with ATO were identified retrospectively via electronic health records at our hospital from August 2014 through August 2019. APL patients without hepatotoxicity were selected as controls. The association between putative risk factors and ATO-induced hepatotoxicity was estimated with ORs and 95% CIs, which were calculated using the chi-square test. The subsequent multivariate analysis was performed using logistic regression analysis. In total, 58.04% of patients experienced ATO-induced hepatotoxicity during the first week. Elevated hemoglobin (OR 8.653, 95% CI, 1.339-55.921), administration of nonprophylactic hepatoprotective agents (OR 36.455, 95% CI, 7.409-179.364), non-single-agent ATO to combat leukocytosis (OR 20.108, 95% CI, 1.357-297.893) and decreased fibrinogen (OR 3.496, 95% CI, 1.127-10.846) were found to be statistically significant risk factors for ATO-induced hepatotoxicity. The area under the ROC curve values were 0.846 for "overall ATO-induced hepatotoxicity" and 0.819 for "early ATO-induced hepatotoxicity." The results revealed that hemoglobin ≥ 80 g/L, nonprophylactic hepatoprotective agents, and non-single-agent ATO and fibrinogen < 1 g/L are risk factors for ATO-induced hepatotoxicity in newly diagnosed APL patients. These findings can enhance the clinical diagnosis of hepatotoxicity. Prospective studies should be performed in the future to validate these findings.

Acute kidney injury in acute promyelocytic leukemia: a possible adverse effect of high dose arsenic trioxide in obese patients.

Arsenic trioxide (ATO)-based regimens are standard in acute promyelocytic leukemia (APL). ATO-related nephrotoxicity has not been reported. We reviewed APL patients treated with ATO to identify cases of acute kidney injury (AKI). Clinically significant cases were characterized. Multivariate analysis was performed to identify predictors of idiopathic, clinically significant AKI. One hundred and eight patients were included. ATO dose was 0.15 mg/kg/day using actual body weight with no dose cap. Thirty-one (28.7%) AKI cases were identified, 10 (32.3%) clinically significant. Six were idiopathic; five required dialysis. The proportion with significant, idiopathic AKI was 15.8% in patients receiving >15mg ATO versus 0% in those receiving ≤15mg (p = 0.001). On multivariate analysis, only ATO dose was a significant predictor of clinically significant AKI (odds ratio of 1.91, 95%CI, 1.19-3.07, p = 0.007). High-dose ATO may be associated with significant nephrotoxicity. We recommend that ATO dose be capped at 15 mg to minimize toxicity for this curable disease.

Arsenic trioxide: applications, mechanisms of action, toxicity and rescue strategies to date.

Arsenical medicine has obtained its status in traditional Chinese medicine for more than 2,000 years. In the 1970s, arsenic trioxide was identified to have high efficacy and potency for the treatment of acute promyelocytic leukemia, which promoted many studies on the therapeutic effects of arsenic trioxide. Currently, arsenic trioxide is widely used to treat acute promyelocytic leukemia and various solid tumors through various mechanisms of action in clinical practice; however, it is accompanied by a series of adverse reactions, especially cardiac toxicity. This review presents a comprehensive overview of arsenic trioxide from preclinical and clinical efficacy, potential mechanisms of action, toxicities, and rescue strategies for toxicities to provide guidance or assistance for the clinical application of arsenic trioxide.

The efficacy and adverse events of arsenic trioxide for the patients with myelodysplastic syndrome: a systematic review and component network meta-analysis.

BACKGROUND: Arsenic trioxide (ATO) might be effective for myelodysplastic syndrome (MDS) by apoptosis induction and demethylation. But ATO has not been widely recommended for small sample and conflicting conclusion of existing trials. This review aimed to systematically evaluate the efficacy of regimens containing ATO for the MDS and explore optimal combination. METHOD: Randomized clinical trials (RCTs) about ATO regimens were retrieved from China National Knowledge Infrastructure, Embase and PubMed. With odds ratio (OR) as the effect size, network meta-analysis (NMA) and component network meta-analysis (CNMA) were conducted by R and 'netmeta' package, after study selection, quality assessment and data extraction. RESULT: Thirty-night RCTs were included with a total of 2125 patients, including 1235 treated by ATO containing regimen. With support therapy alone as reference, no inconsistency and heterogeneity were observed. Although NMA did not demonstrate better efficacy of ATO alone, the result of CNMA indicated that ATO was effective in the improvement of overall remission (ORR) [OR = 2.09(1.61, 2.71)] and complete remission (CR) [OR = 1.66(1.25, 2.21)]. Five ATO-containing regimens reported could effectively improve ORR, some of them benefit in CR or hematological improvement (HI) as well. ATO + Traditional Chinese Medicine (TCM), ATO + Thalidomide (T)+TCM, ATO + Chemotherapy (Chem)+T + TCM were regarded as the optimal combination, which improved both ORR, CR and HI in theory. ATO did not increase the risk of common adverse events compared to supportive therapy [(OR = 0.90(0.67, 1.21)]. CONCLUSION: ATO may be an effective and well-tolerant option for patients with myelodysplastic syndrome.

Sulfhydryl compound levels are associated with ATO-induced side effects in acute promyelocytic leukemia patients.

OBJECTIVE: The remarkable effect of arsenic trioxide (ATO) was verified, but side effects are generally observed in acute promyelocytic leukemia (APL) patients, especially leukocytosis and hepatotoxicity. Our aims are to study predictors and reduce ATO-induced side effects without inhibiting efficacy. METHODS: Sulfhydryl in ATO-treated APL patients was detected by the Spectra Max M5 microplate reader. And patients were divided into high and low sulfhydryl groups according to median sulfhydryl concentration. The onset time of leukocytosis and the peak value of WBC were compared . Correlations between hepatotoxicity indicators and sulfhydryl concentrations were analysed. RESULTS: The concentration of sulfhydryl before treatment was significantly higher in the high sulfhydryl group. Leukocytosis ((7.0 ± 5.5) vs. (14.6 ± 8.5) day) and the peak value of WBC occurred earlier in the low sulfhydryl group ((10.8 ± 5.9) vs. (19.3 ± 5.5) day) than in the high group, and the peak value was significantly lower in the low sulfhydryl group ((24.04 ± 15.05) × 109/L) than in the high group ((42.95 ± 25.57) × 109/L). The elevated liver enzymes were smaller in the higher sulfhydryl group between time points before treatment and the treatment one week later (ΔALT 66.57 vs. 9.85 U/L, ΔAST 59.52 vs. 17.76 U/L), as between time points before treatment and peak value. There was a negative correlation between sulfhydryl and elevated liver enzymes. CONCLUSIONS: Higher sulfhydryl compounds contribute to ameliorating ATO-induced leukocytosis and hepatotoxicity in APL patients. The low sulfhydryl before treatment can advance the onset of leukocytosis. For patients with higher sulfhydryl in the early stage, close monitoring of liver enzymes is warranted instead of prophylactic applying any hepatoprotective intervention, to maintain ATO efficacy.

A method for scoring 4-nitroquinoline 1-oxide-induced murine esophageal squamous neoplasia.

A mouse model for esophageal squamous cell carcinoma (ESCC) is induced by oral administration of the carcinogen 4-nitroquinoline 1-oxide (4-NQO). There is not an objective method for determining histopathologic severity of disease in this model. We aim to create a clearly defined and easily applied scoring system that can quantify the severity of 4-NQO-induced murine ESCC. Fifteen wild-type C57BL/6J mice were treated with 4-NQO for 8 (n = 8) or 16 (n = 7) weeks, while the rest (n = 9) were treated with vehicle, as 8 weeks of 4-NQO typically results in dysplasia and 16 weeks in carcinoma. We identified histologic abnormalities of the esophagus in this model and developed metrics to grade severity of dysplasia, papillomas, and invasion. Scores were then calculated using quantitative digitized image analysis for measuring depth and extent of each feature within the entire sample. Each feature was also assigned a weight based on its relation to cancer severity. Histology scores were significantly different in the three groups, suggesting that this method can discriminate dysplasia from carcinoma. This model can be applied to any mouse treated with 4-NQO.

Long-term real-world outcomes of patients with acute promyelocytic leukaemia treated with arsenic trioxide and all-trans retinoic acid without chemotherapy-a retrospective, single-centre study.

Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) form the backbone of the treatment of acute promyelocytic leukaemia (APL), with the addition of chemotherapy for high-risk patients. We describe our experience of treating patients with APL of all risk classes with ATO and ATRA without chemotherapeutic agents. Patients received induction with ATO and ATRA followed by three cycles of consolidation with ATO and ATRA (each 1 month apart) after achieving morphological remission. Patients with intermediate- and high-risk disease received a further 2 years of maintenance with ATRA, 6-mercaptopurine and methotrexate. A total of 206 patients were included in the study. The majority of the patients were intermediate risk (51.9%), followed by high risk (43.2%). Differentiation syndrome was seen in 41 patients (19.9%). Overall, 25 patients (12.1%) died within 7 days of initiating therapy. Seven patients relapsed during follow-up. The mean (SD) estimated 5-year event-free survival (EFS) and overall survival (OS) in the entire cohort was 79% [5.8%] and 80% [5.8%] respectively. After excluding patients who died within 7 days of therapy initiation, the mean (SD) estimated 5-year EFS and OS was 90% [5.8%] and 93% [3.9%] respectively. Our study shows that treatment of all risk classes of APL with ATO and ATRA without chemotherapy is associated with excellent long-term outcomes in the real-world setting.

Long-term retrospective study of retinoic acid combined with arsenic and chemotherapy for acute promyelocytic leukemia.

Chemotherapy, all-trans retinoic acid (ATRA), and arsenic are effective options for acute promyelocytic leukemia (APL). We conducted a 20-year retrospective analysis of newly diagnosed (ND) APL patients treated with arsenic, ATRA and mitoxantrone. After achieving complete remission (CR), patients received 3-5 cycles of chemotherapy followed by AS4S4 maintenance for 3 years. Eighty-eight ND APL patients were treated with either oral AS4S4 (n = 42) or arsenic trioxide (ATO) (n = 46). The 8-year overall survival (OS) rate was 100% in the AS4S4 group and 90% in the ATO group. The disease-free survival (DFS) rates were 100% and 87.1% (p = 0.027), respectively. Patients in the ATO group had more side effects. A subsequent cohort of 33 ND APL patients received triple therapy with oral AS4S4, ATRA, and chemotherapy. The 13-year OS and DFS rates were 100% and 90.9%. Our long-term analyses show that APL patients with oral AS4S4 had better outcomes compared to ATO, with no need for hospitalization.

Treatment Outcomes Of Patients With Newly Diagnosed Acute Promyelocytic Leukemia; Experience From A Developing Country.

BACKGROUND: Acute promyelocytic leukaemia (APL) characterized by t (15;17) leading to formation of fusion protein PML-RARA is an acute leukaemia with highest mortality. A remarkable improvement in the outcomes has been witnessed due to evolution of highly effective targeted therapies replacing the traditional chemotherapy is most patients. However limited data is available regarding treatment outcomes of APL using various novel regimens from developing countries like Pakistan. METHODS: This was a retrospective descriptive study which included APL patients treated at AFBMTC Rawalpindi from 2005 to 2020. It included a total of 51 eligible patients with a diagnosis of de novo APL confirmed by the presence of PML-RARA transcript or presence of t (15;17) by cytogenetics or FISH analysis. The protocols used for treatment included the UKAML MRC 12, the LPA-99/LPA-2005 PETHEMA, the APML4 and non-chemotherapy based ATO-ATRA protocol. RESULTS: The study included 51 patients in which 31 (60.78%) were male and 20 (39.2%) were female. The median age at diagnosis was 30 years (range 5-70). The commonest symptom was fever seen in 43 (84.3%) patients and bruising was the commonest physical finding present in 44 (86.3%) patients. High-risk patients were 23 (46.1%), 18 (35.3%) were intermediate risk and 10 (19.6%) were low risk. The LPA99/LPA2005 was most frequently employed protocol being used in 36 (72%) patients. There were 2 deaths during induction and 44 (86.3%) achieved CR post induction. The median follow up time was 32 months (range 1 to 190 months) with an overall survival (OS) of 76.5% and a relapse free survival (RFS) of 66.7. CONCLUSIONS: Our study shows APL is a highly curable malignancy and outcomes have improved with newer non chemotherapy based therapies. It can also be concluded that outcomes of APL gradually improved over the past 2 decades due to improvement in supportive care, provision of blood products and use of newer protocols. The prognosis remains less favourable in high risk patients.

Analysis of risk factors for early death in patients with acute promyelocytic leukaemia treated with arsenic trioxide.

To date, no specific studies have evaluated early death (ED) in patients with acute promyelocytic leukaemia (APL) homogeneously treated with arsenic trioxide induction therapy and investigated according to the white blood cell (WBC) count at onset. Such patients were retrospectively analysed in this study, including 314 patients with a WBC count ≤ 10 × 109/L (standard-risk (SR) group) and 144 with a WBC count > 10 × 109/L (high-risk (HR) group). The baseline clinical characteristics and risk factors for ED were compared between the two groups. The incidence of fibrinogen < 1.0 g/L and elevated serum uric acid, aspartate aminotransferase and creatinine levels were higher in the HR group than in the SR group (P = 0.001; P < 0.001; P < 0.001; P = 0.044, respectively). The ED rate was significantly higher in the HR group than in the SR group (29.17% vs. 10.83%, P < 0.001). The main cause of ED was bleeding, followed by infection and differentiation syndrome (DS) in the HR group, while it was bleeding, followed by DS and infection in the SR group. Male sex, age > 50 years old, and fibrinogen < 1.0 g/L were independent risk factors for ED in the SR group. Increased serum creatinine levels, decreased albumin levels, and fibrinogen < 1.0 g/L were independent risk factors for ED in the HR group. Overall, the incidence of ED was higher in the HR group, and the baseline clinical characteristics, causes, times, and predictors of ED in the HR group differed from those in the SR group.

Arsenic trioxide dose capping to decrease toxicity in the treatment of acute promyelocytic leukemia.

Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) combination therapy yields high complete remission and disease-free survival rates in acute promyelocytic leukemia (APL). ATO is dosed on actual body weight and high ATO doses in overweight patients may contribute to increased toxicity. We performed a retrospective, two-center study comparing toxicities in patients who received the Lo-Coco et al ATRA/ATO regimen with capped ATO, ≤10 mg/dose, and non-capped ATO, >10 mg/dose. A total of 44 patients were included; 15 received doses ≤10 mg and 29 received >10 mg. During induction, there was no difference in the incidence of grade ≥3 hepatotoxicity, grade ≥3 QTc prolongation, neurotoxicity, and cardiac toxicity between groups. In consolidation, patients receiving >10 mg/dose experienced a greater incidence of neurotoxicity (66.7% vs 22.2%; p = 0.046). Capping doses saved $24634.37/patient and reduced waste of partially-used vials. At a median follow-up of 27 months, no disease relapses occurred in either group. This represents an opportunity to improve the safety profile of this highly effective regimen.

Induced Autophagy of Macrophages and the Regulation of Inflammatory Effects by Perovskite Nanomaterial LaNiO3.

Perovskite nanomaterials (NMs) possess excellent physicochemical properties and have promising applications in light-emitting diodes (LEDs), lasers, photodetectors, and artificial synapse electronics. Potential exposure to these NMs happens in the manufacture and application of the perovskite-based products, however, the biological safety of these NMs is still unknown. Here, we used the LaNiO3 NM (LNO), a typical kind of perovskite nanostructures to study the interaction with macrophages (J774A.1) and to explore its biological effects at the cellular level. Firstly, we characterized the properties of LNO including the size, shape, and crystal structure using Transmission electronic microscope (TEM), Dynamic lighting scattering (DLS), and X-ray diffraction (XRD). Secondly, to gain a better understanding of the biological effect, we evaluated the effect of LNO on cell viability and found that LNO induced cell autophagy at a concentration of 5 µg/ml and influenced the inflammatory response based on RT-PCR result. Finally, we demonstrated the mechanism that LNO causes cell autophagy and immune response is probably due to the metal ions released from LNO in acidic lysosomes, which triggered ROS and increased lysosomal membrane permeation. This study indicates the safety aspect of perovskite NMs and may guide the rational design of perovskite NMs with more biocompatibility during their manufacture and application.

Herpes zoster during arsenic trioxide therapy for acute promyelocytic leukemia.

Historically, arsenic exposure has been associated with herpes zoster (HZ) infection, however the risk is not well characterized in arsenic trioxide (ATO) treated patients with acute promyelocytic leukemia (APL). We aimed to characterize the risk of HZ in 112 ATO treated patients with APL with and without antiviral prophylaxis (AVP). HZ occurred in 13/112 (11.6%) within 6 months of completing ATO, including one case of HZ encephalitis. AVP reduced the incidence of HZ (17.5% vs. 4.1%, RR 0.24 [95% CI 0.05-1.0, p = .025]) with a number needed to treat of 7.7. HZ despite AVP occurred later than HZ in patients without AVP (7.8 vs. 2.3 months from starting ATO, p = .11). Older age and prior HZ increased the risk of HZ in patients not receiving AVP. Routine AVP should be considered in patients with APL receiving ATO, particularly in older patients and those with a history of HZ.

Evaluation of the efficacy and safety of arsenic trioxide dosing in obese patients with acute promyelocytic leukemia.

Arsenic trioxide (ATO) is the backbone of acute promyelocytic leukemia (APL) treatment and is dosed based on weight with no upper limit, therefore obese patients receive large doses and may be vulnerable to adverse effects and dose holdings. Twenty-seven patients receiving ATO during induction were categorized as obese (N = 16) or non-obese (N = 11) based on body mass index (BMI) ≥30 kg/m2 in this retrospective study. Doses were held or modified due to composite adverse effects in 9 (56%) obese patients and 7 (64%) non-obese patients (p = 1.00). There were higher rates of dose holdings (13% versus 0%; p = .5) and dose modifications (13% versus 0%; p = .5) due to hepatotoxicity in obese versus non-obese patients. There were no differences in efficacy parameters. These data suggest that obese patients have similar overall incidence of adverse effects to ATO as non-obese patients; any difference in risk of hepatotoxicity will require clarification in a larger study.

Severe Wernicke encephalopathy and acute pancreatitis due to all-trans-retinoic acid and arsenic trioxide during treatment of acute promyelocytic leukaemia: a case report.

A 55-year-old woman developed acute promyelocytic leukaemia during treatment with all-trans-retinoic acid and arsenic trioxide. Initially, she presented with symptoms of epigastric pain, vomiting, and nausea, and she developed acute pancreatitis. She was treated with parenteral nutritional supplementation for 20 days. However, the patient continued to develop refractory hyponatraemia, hypotension, and apathy. Finally, the patient was diagnosed with Wernicke encephalopathy (WE) using head magnetic resonance imaging. The patient underwent high-dose intravenous thiamine administration, and her symptoms were alleviated. WE is a rare adverse event during acute pancreatitis therapy. Acute pancreatitis that is caused by all-trans-retinoic acid and arsenic trioxide is a rare complication of acute promyelocytic leukaemia during chemotherapy. Further study is essential to improve our comprehension of the risk factors for complications in patients with acute promyelocytic leukaemia, considering that the associated complications were potentially caused by multiple etiological factors. A better understanding of these risk factors may help to improve the prognosis of patients with acute promyelocytic leukaemia at an early stage.

Low-Dose Radiation Exposure with 56MnO2 Powder Changes Gene Expressions in the Testes and the Prostate in Rats.

To investigate the biological effects of internal exposure of radioactive 56MnO2 powder, the major radioisotope dust in the soil after atomic bomb explosions, on male reproductive function, the gene expression of the testes and the prostate was examined. Ten-week-old male Wistar rats were exposed to three doses of radioactive 56MnO2 powder (41-100 mGy in whole body doses), stable MnO2 powder, or external 60Co γ-rays (2 Gy). Animals were necropsied on Days 3 and 61 postexposure. The mRNA expressions of testicular marker protein genes and prostatic secretory protein genes were quantified by Q-RT-PCR. On Day 3 postexposure, the testicular gene expressions of steroidogenesis-related enzymes, Cyp17a1 and Hsd3b1, decreased in 56MnO2-exposed groups. Germ cell-specific Spag4 and Zpbp mRNA levels were also reduced. On postexposure Day 61, the Cyp11a1 gene expression became significantly reduced in the testes in the group exposed to the highest dose of 56MnO2, while another steroidogenesis-related StAR gene mRNA level reduced in the 60Co γ-rays group. There were no differences in Spag4 and Zpbp mRNA levels among groups on Day 61. No histopathological changes were observed in the testes in any group following exposure. Expression in the prostatic protein genes, including CRP1, KS3, and PSP94, significantly decreased in 56MnO2-exposed groups as well as in the 60Co γ-rays group on Day 61 postexposure. These data suggest that the internal exposure to 56MnO2 powder, at doses of less than 100 mGy, affected the gene expressions in the testis and the prostate, while 2 Gy of external γ-irradiation was less effective.

Investigating the health disparities in the association between lifestyle behaviors and the risk of head and neck cancer.

Many studies have reported a positive association between lower socioeconomic status (SES) and higher head and neck cancer (HNC) risk. Fewer studies have examined the impact of SES on the association between alcohol or cigarette use and HNC risk. The current case-control study (1104 HNC cases and 1363 controls) investigated the influence of education, a SES indicator, on the association between HNC and the use of alcohol, cigarettes, or betel quids in Taiwan, a country with universal health care. Our results showed a larger increase in HNC risk associated with alcohol among those with lower educational level (odds ratio [OR] = 2.07; 95% confidence interval [CI], 1.53-2.80) than those with higher educational level (OR = 1.38; 95% CI, 1.04-1.85) (heterogeneity-P = .03). Educational level had an influence on the association between alcohol use and HNC risk among those with genetic susceptibility (ALDH2-deficient) to the carcinogenic effect of alcohol. The association between cigarette or betel quid use and HNC risk was similar between the high and low educational groups. National policies and social interventions have led to the decline in the prevalence of cigarette and betel quid users in Taiwan. In contrast, due to the lack of adequate alcohol control policies, alcohol consumption in Taiwan has continued to rise. A higher impact of alcohol on HNC risk among lower SES individuals even with universal health care could be the result of insufficient alcohol control policies in Taiwan.