Ming-Tsang Wu

Carcinogenetic impact of ADH1B and ALDH2 genes on squamous cell carcinoma risk of the esophagus with regard to the consumption of alcohol, tobacco and betel quid

The consumption of alcohol, tobacco and betel quid has been found to be an important contributor to esophageal squamous cell carcinoma (ESCC) in Taiwan. The genotoxic effect of the ADH1B and ALDH2 genes modulating an individuals alcohol‐metabolizing capacity on ESCC may be linked to drinking behavior, intake pattern and other exogenous factors. To investigate the interplay of these genetic and environmental factors in determining the risk of ESCC, a multicenter case‐control study was conducted. Here, 406 patients with pathology‐proven ESCC, as well as 656 gender, age and study hospital matched controls were recruited. Genetic polymorphisms of ADH1B and ALDH2 appeared to correlate with the abstinence of alcohol, though not with tobacco and betel quid. Within the same levels of alcohol consumption, carcinoma risks increased along with an increase in the numbers of ADH1B*1 and ALDH2*2 alleles. The inactive ALDH2*1/*2 genotype was found to multiplicatively interact with a low‐to‐moderate (0.1–30 g/day) and a heavy (>30 g/day) ethanol intake to increase the ESCC risk (the joint aOR = 14.5 and 102.6, respectively). Among low‐to‐moderate drinkers, a smoking‐dependent carcinogenetic effect for the ADH1B*1/*1 and ALDH2*1/*2+*2/*2 genotypes was recognized, with significant risks found in smokers, but not in nonsmokers. Further, a supra‐multiplicative combined risk of ESCC for alcohol and tobacco use was identified among carriers of the ADH1B*1/*1 genotype (p for interaction = 0.042). In conclusion, the interplay of the ADH1B and ALDH2 genotypes, in conjunction with a behaved drinking habit and a practiced drinking pattern, along with continued tobacco consumption, plays an important pathogenic role in modulating ESCC risk.

Validation of chromogenic in situ hybridization for detection of EGFR copy number amplification in nonsmall cell lung carcinoma

Epidermal growth factor receptor (EGFR) gene copy number correlates with response to tyrosine kinase inhibitors in patients with nonsmall cell lung carcinoma. Fluorescence in situ hybridization (FISH), a standard methodology to detect EGFR copy number abnormalities in nonsmall cell lung carcinoma, is limited by instrumentation and cost. Chromogenic in situ hybridization (CISH) is an emerging alternative detection technique using light microscopy, but its utility in assessing EGFR copy number in lung cancer is not established. To address the utility of CISH, we studied paraffin-embedded nonsmall cell lung carcinoma specimens from 77 Taiwanese nonsmoking women treated by surgery alone. We recorded the number of signals per tumor cell nucleus, correlated EGFR copy number by CISH with FISH results, and used receiver operating characteristics to identify cut-off points for the CISH results. Tumors were classified as adenocarcinoma (n=28), mixed adenocarcinoma with bronchioloalveolar features (n=25), bronchioloalveolar carcinoma (n=2), squamous cell carcinoma (n=15), and adenosquamous carcinoma (n=7). By FISH, 29% of cases had no amplification, 18% had low polysomy, 35% had high polysomy, and 12% had gene amplification. EGFR copy number detected by CISH highly correlated with FISH (Spearman r=0.81, P<0.0001). We determined the optimal EGFR CISH cut-off points that discriminate between no amplification and low polysomy (2.8 signals, P=0.09); no amplification plus low polysomy and high polysomy plus gene amplification (4.5 signals, P<0.0001); and high polysomy and gene amplification (7.1 signals, P=0.0003). CISH is an alternative assay to FISH in determining EGFR copy number status that may contribute to stratification of patients with nonsmall cell lung carcinoma for clinical trials and identify a subset of patients that should be treated with tyrosine kinase inhibitors.

Environmental exposure to cooking oil fumes and cervical intraepithelial neoplasm

The fumes from cooking oil, similar to cigarette smoke, contain numerous carcinogens such as polycyclic aromatic hydrocarbons, aromatic amines, nitro-polycyclic aromatic hydrocarbons, etc. In this study, we examined the association between exposure to cooking oil fumes and the risk of cervical intraepithelial neoplasm. The study population in this nested case-control study consisted of women above the age of 19 years living in Chia-Yi County, located in the southwestern Taiwan, who had received pap smear screening between October, 1999, and December, 2000 (n=32,466). The potential cases were women having lesions greater than cervical intraepithelium neoplasm II (> or =CIN2) reconfirmed by cervical biopsy (n=116). The potential controls (case: control=1:2) were age-matched (+/-2 years) and residence-matched women who had normal pap smears within 6 months of the cases. In total, 100 cases and 197 controls were completely interviewed by public health nurses about cooking methods, ventilation, and other potential risk factors. Women who cooked at home in a kitchen (n=269) without the presence of a fume extractor at least once a week between the ages of 20 and 40 had a 2.29 times higher risk [95% confidence interval (CI)=1.08-4.87] of developing cervical intraepithelial neoplasm than those who did not cook once a week in such a kitchen during the same age span, after adjusting for other potential confounders. This finding was further strengthened by the finding that women who did not use the fume extractors had a 2.47 times higher risk (95% CI=1.15-5.32) of developing cervical intraepithelial neoplasm than women who cooked in kitchens with fume extractors that were always switched on while cooking. We also found a joint protective effect of fume extractor use among women older than 40 years (n=202) if they used the extractors during both age spans of their lives, ages 20-40 and >40 years. Comparing our findings on women more than 40 years old who used fume extractors during both periods, we found a 2.05-fold greater risk (95% CI=0.86-4.86) for those who used exhaust fans during only one of the two age spans and a 3.46-fold greater risk in those who had not used an exhaust fan for either period (95% CI=1.08-11.10) (trend test, P=0.02). While exposure to cooking oil fumes may cause cervical intraepithelial neoplasm, women can be protected from this risk by always cooking in kitchens equipped with fume extractors and by keeping them on while cooking.

Food intake and the occurrence of squamous cell carcinoma in different sections of the esophagus in Taiwanese men.

OBJECTIVEnThe main objective of this study was to further elucidate the effect of consuming various foods on the development of squamous cell carcinoma (SCC) in three different sections of the esophagus.nnnMETHODSnA total of 343 patients with SCC of the esophagus and 755 cancer-free control subjects were recruited for this study from 1996 to 2005.nnnRESULTSnWe found that intake of vegetables, raw onions/garlic, and fruits are significantly protective against esophageal SSC risk, whereas intake of hot foods can significantly increase its risk. There was a significant inverse relation between the frequency of tea consumption and esophageal SCC risk (P for trend = 0.005), with a 0.5-fold lower risk associated with the intake of unfermented tea (green tea, oolong tea, or jasmine tea). The effects of dietary factors on esophageal SCC were similar in all subsites, with the exception of consumption of coffee. Coffee consumption was more pronounced in having a protective effect in the middle third section compared with the lower third section of the esophagus (adjusted odds ratio 0.4, 95% confidence interval 0.2-0.9), although this protective effect was marginally significant (adjusted odds ratio 0.6, 95% confidence interval 0.4-1.0) against esophageal SCC in all subsites. Our data also suggest that discomfort when eating hot foods may exert a carcinogenic effect by direct contact with the esophageal mucosa and tend to have more harmful effects in the upper than in the lower esophagus. In contrast, vegetables, fruits, and tea with components that are thought to inhibit carcinogenesis by absorbed components affected all subsites similarly.nnnCONCLUSIONnOur results add additional information that certain dietary components may affect carcinogenesis locally and systemically.

A population-based, case–control study of green tea consumption and leukemia risk in southwestern Taiwan

ObjectiveThis study investigated the association between green tea consumption and leukemia.MethodsA total of 252 cases (90.3% response) and 637 controls (53.4% response) were enrolled. Controls were matched for cases on age and gender. Information was collected on participants’ living habits, including tea consumption. Green tea was used as a standard to estimate the total amount of individual catechin consumption. We stratified individual consumption of catechins into four levels. Conditional logistic regression models were fit to subjects aged 0–15 and 16–29xa0years to evaluate separate associations between leukemia and catechin consumption.ResultsA significant inverse association between green tea consumption and leukemia risk was found in individuals aged 16–29xa0years, whereas no significant association was found in the younger age groups. For the older group with higher amounts of tea consumption (>550 units of catechins), the adjusted odds ratio (OR) compared with the group without tea consumption was 0.47 [95% confidence interval (CI)xa0=xa00.23–0.97]. After we adjusted for smoking status and medical irradiation exposure, the overall OR for all participants was 0.49 (95% CIxa0=xa00.27–0.91), indicating an inverse relation between large amounts of catechins and leukemia.ConclusionDrinking sufficient amounts of tea, especially green tea, which contains more catechins than oolong tea and black tea, may reduce the risk of leukemia.

A case-control study of parental occupation, leukemia, and brain tumors in an industrial city in Taiwan.

We conducted a case-control study in an industrial city in Taiwan to determine whether parents of newly diagnosed patients who were younger than 30 years old with leukemia or brain tumors or the patients themselves were more likely to have been employed in certain occupations or industries. Job histories were collected for parents (and for subjects if they worked) on 103 newly diagnosed cases of leukemia, 74 newly diagnosed cases of brain tumors, and 417 controls matched for age and sex. All jobs since the age of 16 that the subjects held for more than 6 months, a total of approximately 4000 jobs, were coded for occupation and industry according the standard four-digit system used in Taiwan. Matched-pair analyses were performed comparing cases and controls among all jobs held by subjects and both parents using four-digit occupation and industry codes. Separate analyses also were performed for parental jobs held during the preconception, perinatal, and postnatal periods. Odds ratios (ORs) were adjusted for subject smoking, parental smoking, and exposure to medical radiation. Certain industry and occupation four-digit codes were significantly associated with increased odds ratios of childhood tumors. Including work during any or all periods, leukemias were more common in children of fathers who had worked (1) as wood treaters (adjusted OR 16.03, 95% confidence interval CI = 1.77–145.5), and (2) as building finishers and related trades workers (adjusted OR 4.08, 95% CI = 1.12–14.8), whereas brain tumors were more common in children of mothers who had worked (1) in electronic parts and components manufacturing (adjusted OR 13.78, 95% CI = 1.47–129.0) and 2) as textile and garment workers (adjusted OR 7.25, 95% CI = 1.42–37.0), as well as in subjects who had worked with certain electronic parts and components (adjusted OR 28.67, 95% CI = 2.88–285.6). Leukemias were more common in children of fathers who had worked in the preconception period (1) as wood treaters (adjusted OR 12.17, 95% CI = 1.36–109.2), (2) as building finishers and related trades workers (adjusted OR 4.08, 95% CI = 1.12–14.8), (3) as electronic equipment assemblers (adjusted OR 4.56, 95% CI = I 1.05–19.9), and (4) as certain other assemblers (adjusted OR 10.24, 95% CI = 1.02–102.6). In addition, leukemias were more common in children of fathers who had worked in the perinatal period (1) as wood treaters (adjusted OR 13.08, 95% CI = 1.36–125.5) and (2) as building finishers and related trades workers (adjusted OR 4.51, 95% CI = 1.04–19.6). Brain tumors were more common in children of mothers who had worked in the preconception period (1) in electronic parts and components manufacturing (adjusted OR 11.81, 95% CI = 1.20–116.3), and (2) as textile and garment workers (adjusted OR 7.25, 95% CI = 1.18–31.0).

Maternal and offspring genetic variants of AKR1C3 and the risk of childhood leukemia

The aldo-keto reductase 1C3 (AKR1C3) gene located on chromosome 10p15-p14, a regulator of myeloid cell proliferation and differentiation, represents an important candidate gene for studying human carcinogenesis. In a prospectively enrolled population-based case-control study of Han Chinese conducted in Kaohsiung in southern Taiwan, a total of 114 leukemia cases and 221 controls <20 years old were recruited between November 1997 and December 2005. The present study set out to evaluate the association between childhood leukemia and both maternal and offsprings genotypes. To do so, we conducted a systematic assessment of common single-nucleotide polymorphisms (SNPs) at the 5 flanking 10 kb to 3 UTR of AKR1C3 gene. Gln5His and three tagSNPs (rs2245191, rs10508293 and rs3209896) and one multimarker (rs2245191, rs10508293 and rs3209896) were selected with average 90% coverage of untagged SNPs by using the HapMap II data set. Odds ratios and 95% confidence intervals were adjusted for age and gender. After correcting for multiple comparisons, we observed that risk of developing childhood leukemia is significantly associated with rs10508293 polymorphism on intron 4 of the AKR1C3 gene in both offspring alone and in the combined maternal and offspring genotypes (nominal P < 0.0001, permutation P < 0.005). The maternal methylenetetrahydrofolate reductase A1298C polymorphism was found to be an effect modifier of the maternal intron 4 polymorphism of the AKR1C3 gene (rs10508293) and the childhood leukemia risk. In conclusion, this study suggests that AKR1C3 polymorphisms may be important predictive markers for childhood leukemia susceptibility.

Exposure to Environmental Tobacco Smoke and Urinary 1-Hydroxypyrene Levels in Preschool Children

Environmental tobacco smoke (ETS) contains relatively high concentrations of polycyclic aromatic hydrocarbons (PAHs). Urinary 1‐hydroxypyrene (1‐OHP), a metabolite of pyrene, is a good indicator of PAH exposure in occupational studies. In this study, we investigated the relationship between urinary 1‐OHP concentration and ETS exposure in preschool children. Forty preschool children, aged 24‐76 months, were studied during November and December, 1999. Two spot‐urine specimens (one in the morning immediately after the subject woke up and the other at night before the subject went to bed) were collected 1 day after completion of a questionnaire, in order to determine 1‐OHP concentrations by fluorescent spectrophotometry. Overall, urinary 1‐OHP concentrations were relatively low but detectable (morning: median, 0.021 μg/g creatinine; range, 0.002‐1.019 μg/g creatinine; night: median, 0.015 μg/g creatinine; range, 0.002‐1.328 μg/g creatinine). Multiple linear regression analyses revealed that the total number of cigarettes smoked by the childrens fathers during the 3 days prior to collection of the urine specimens was significantly associated with their urinary 1‐OHP concentrations, after adjusting for other confounders. Each cigarette smoked by a childs father resulted in an average 9.6% increase in 1‐OHP concentration in the morning urine specimen (95% confidence interval = 1.8‐18.1%; p = 0.02). We did not find a significant increase in the 1‐OHP concentration in night urine specimens (p = 0.19). Although the sample size was small, these findings indicate that urinary 1‐OHP may be a suitable biomarker of ETS carcinogen exposure in children.

Plasma interleukin-1β, -6, -8 and tumor necrosis factor-α as highly informative markers of pelvic inflammatory disease

Abstract Background: The role of proinflammatory cytokines in pelvic inflammatory disease (PID) is unclear. We therefore determined whether plasma proinflammatory cytokines, interleukin-1β (IL-1β), IL-6, IL-8 and tumor necrosis factor-α (TNF-α) were useful plasma markers in PID patients. Methods: Multiplex bead array analysis was used to measure the plasma levels of proinflammatory cytokines in 50 healthy controls as well as in 41 PID patients before and after routine protocol treatments. Results: IL-1β, IL-6, IL-8 and TNF-α were significantly elevated in PID patients before antibiotic treatment than after treatment. However, IL-8 was not significantly different between healthy controls and PID patients. The relative increase in ratio of IL-6 was significantly correlated with white blood cell count (r=0.448, p=0.003), neutrophil count (r=0.472, p=0.002) and C-reactive protein level (r=0.412, p=0.008). Conclusions: IL-1β, IL-6, IL-8 and TNF-α may play an important role in the pathogenesis of PID. These biomarkers, particularly IL-6, could be useful adjuncts for the clinical diagnosis of PID. Clin Chem Lab Med 2008;46:997–1003.

Cured meat, vegetables, and bean-curd foods in relation to childhood acute leukemia risk: A population based case-control study

BackgroundConsumption of cured/smoked meat and fish leads to the formation of carcinogenic N-nitroso compounds in the acidic stomach. This study investigated whether consumed cured/smoked meat and fish, the major dietary resource for exposure to nitrites and nitrosamines, is associated with childhood acute leukemia.MethodsA population-based case-control study of Han Chinese between 2 and 20 years old was conducted in southern Taiwan. 145 acute leukemia cases and 370 age- and sex-matched controls were recruited between 1997 and 2005. Dietary data were obtained from a questionnaire. Multiple logistic regression models were used in data analyses.ResultsConsumption of cured/smoked meat and fish more than once a week was associated with an increased risk of acute leukemia (OR = 1.74; 95% CI: 1.15–2.64). Conversely, higher intake of vegetables (OR = 0.55; 95% CI: 0.37–0.83) and bean-curd (OR = 0.55; 95% CI: 0.34–0.89) was associated with a reduced risk. No statistically significant association was observed between leukemia risk and the consumption of pickled vegetables, fruits, and tea.ConclusionDietary exposure to cured/smoked meat and fish may be associated with leukemia risk through their contents of nitrites and nitrosamines among children and adolescents, and intake of vegetables and soy-bean curd may be protective.