Smoking Dose Research Articles

Abstract IA47: Resolving the complex problem of tobacco-caused lung cancer disparities in the U.S

Abstract Existing data show that lung cancer disparities are not explained by cigarette smoking dose and duration alone. Data from the Multiethnic Cohort Study show that Native Hawaiians and African Americans who smoked 10 cigarettes per day have an elevated risk of lung cancer compared to Japanese American, White, and Latino smokers. Prior studies also suggest that African Americans have slower nicotine metabolism compared to Whites. It remains unclear why we consistently observe slower rates of nicotine metabolism among African Americans, but higher rates of lung cancer since studies suggest that smokers with low levels of CPY2A6 activity may be less efficient in bioactivating tobacco smoke pre-carcinogens to carcinogens. Little is known about nicotine metabolism among Native Hawaiians and Filipinos who have disproportionate and unexplained lung cancer rates like African Americans. This study compares biomarkers of tobacco smoke exposure in Native Hawaiian, Filipino, and White young adult daily smokers. We hypothesized that Native Hawaiians and Filipinos, like African Americans, would have slower nicotine metabolism compared to Whites. We collected data on sociodemographics, smoking history, and psychosocial risk factors among young adult daily smokers aged 18-35. We measured height, weight, and carbon monoxide levels among all smokers. A saliva sample was collected from each smoker using standard passive drool procedures. The geometric means were calculated for nicotine, cotinine, trans 3' hydroxycotinine, the nicotine metabolite ratio, and expired carbon monoxide and the data were compared among racial/ethnic groups. Two analysis of covariance models tested biomarker differences among racial/ethnic groups. Model 1, the unadjusted model, contained no covariates. Model 2 included gender, body mass index (BMI), menthol smoking status, Hispanic ethnicity, and the number of cigarettes smoked per day as covariates. The sample included 44% Native Hawaiians, 16% Filipinos, and 40% Whites (n=186). Twenty-four percent of young adults were of Hispanic origin, 48% were females, and smokers had a mean BMI of 28. Forty-one percent of Filipino smokers reported Hispanic ethnicity compared to 27% of Native Hawaiian and 15% of White smokers (p< 0.02). Native Hawaiians had a higher BMI than Filipinos and Whites (31.9, 24.5, 24.8, p<0.001). Eighty-seven percent of Native Hawaiians, 72% of Filipinos, and 48% of White young adults reported menthol cigarette use. There were no differences in smoking duration or smoking consumption among racial/ethnic groups. Smokers had smoked daily for 1.5 years and smoked a mean of 14.4 cigarettes per day. In the unadjusted and adjusted models, cotinine levels were higher among Native Hawaiians compared to Whites, but these differences were not significant among racial/ethnic groups. In the unadjusted model, the nicotine metabolic ratio was significantly lower in Native Hawaiian and Filipino smokers compared to White smokers (NMR: 0.17, 0.15, 0.27, p<0.001). In the adjusted model, the nicotine metabolite ratio remained significantly lower in Native Hawaiian and Filipino smokers compared to White smokers (NMR: 0.20, 0.19, 0.33, p<0.001). In summary, our data show that Native Hawaiian and Filipino daily smokers have slower nicotine metabolism than White daily smokers as indicated by the nicotine metabolite ratio. Studies show that the nicotine metabolite ratio is a reliable phenotypic marker for CYP2A6 activity. However, is it not clear whether the algorithm suggesting that slow nicotine metabolizers have reduced lung cancer risk applies to all racial/ethnic groups. Resolving the complex problem of lung cancer disparities requires further investigation of multiple biological pathways to determine which lung cancer risk algorithms apply to specific racial/ethnic groups. Such investigations will allow to us to improve community, clinical, and policy-based interventions to reduce disparities. Citation Format: Pebbles Fagan, Eric T. Moolchan, Pallav Pokhrel, Thaddeus Herzog, Kevin Cassel, Ian Pagano, Adrian Franke, Joseph Keawe'aimoku Kaholokula, Angela Sy, Linda A. Alexander, Dennis R. Trinidad, Kari-Lyn Sakuma, Carl Anderson Johnson, Alyssa M. Antonio, Dorothy Jorgensen, Tania Lynch, Crissy Kawamoto, Mark S. Clanton. Resolving the complex problem of tobacco-caused lung cancer disparities in the U.S. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr IA47.

Aspirin, Calcitriol, and Calcium Do Not Prevent Adenoma Recurrence in a Randomized Controlled Trial

Chemopreventive strategies might be used to reduce the recurrence of colorectal adenomas and the incidence of colorectal cancer. We performed a randomized, double-blind, placebo-controlled trial to determine whether a combination of acetylsalicylic acid (aspirin), calcitriol, and calcium carbonate could prevent colorectal adenoma recurrence. We included 1107 patients with 1 or more sporadic adenoma(s) removed from the colon or rectum at centers in Europe, Russia, or the United States, from 2004 through 2010. Inclusion criteria were 1 adenoma greater than 1 cm in diameter, more than 1 adenoma of any size, or an adenoma of any size and first-degree relatives with colorectal cancer. Subjects were assigned randomly to groups given 0.5 μg calcitriol, 75 mg acetylsalicylic acid, and 1250 mg calcium carbonate (n= 209), or placebo (n= 218), each day for 3 years. The primary outcome was adenoma recurrence assessed by colonoscopy after 3 years. Secondary outcomes were the proportion of patients with advanced adenomas, the total number of colorectal adenomas, and adenoma size and features. The trial was stopped in October 2010 because of futility. In this analysis, we found no differences between groups in the rate of recurrence (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.61-1.48), adverse effects, or secondary outcomes. Subgroup analyses indicated that the treatment effects may be influenced by smoking status (nonsmokers OR, 0.65; 95% CI, 0.26-1.22 vs current smokers OR, 1.70; 95% CI, 0.70-4.09; P value interaction < .05). However, the overall interaction was not significant. In a prospective study, the combination of calcitriol, aspirin, and calcium carbonate did not prevent recurrence of colorectal adenomas over a 3-year period. The negative results might be owing to the effects of smoking or low doses of the tested agents. Clinicaltrials.gov number: NCT00486512.

Tobacco and end stage renal disease: a multicenter, cross-sectional study in Argentinian Northern Patagonia.

BackgroundSmoking and chronic kidney disease are major public health problems with common features -high prevalence and mortality, high cardiovascular risk, gender differences and high prevalence in low income people-, but the link between them is poorly recognized. Our objectives were to investigate the exposure of dialysis patients to tobacco and to know their smoking behavior.MethodsWe performed a multicenter, cross-sectional study in nine dialysis units in the Argentinian Northern Patagonia. We investigated smoker status, lifetime tobacco consumption, current tobacco use, breath carbon monoxide and % carboxyhaemoglobin. Fagerström and Richmond tests were performed for active smokers. Statistical analysis: one way ANOVA and Tukey’s test for post hoc test. For exploratory analysis, frequency tables through chi-square distribution and single correspondence analysis were performed.ResultsSix hundred thirty six patients (60.9 % males, 39.1 % females) were interviewed. Almost 70 % of them had had tobacco exposure. Excluding light smokers, the lifetime consumption was significantly different (p = 0.0052) between sexes (33.1 ± 2.4 pack/years in males and 18.2 ± 2.1 pack/years in females) The distribution of etiologies changed significantly (χ2p < 0.0001) with smoker status and the dose of tobacco smoking, with an increase in the diagnosis of nephrosclerosis in patients with high and very high lifetime consumption (from 16.1 % in non-smokers to 28.2 and 27 % respectively), and in passive smokers (from 16.1 to 27.3 %). The male preponderance of end-stage renal disease disappeared when only non-smokers were considered and grew with the increase in the lifetime consumption. Active smokers have small consumption, both low CO level and % COHb, low dependence and a good motivation to quit, but a high lifetime consumption.ConclusionsExposure of dialysis patients to tobacco is high and could be related to the progression to the final stage of the renal disease. It seems that tobacco renal damage is mostly hidden in the diagnosis of nephrosclerosis. The gender difference observed in these patients could also have a nexus with the men’s higher tobacco exposure. Active smokers have a low current consumption but a high lifetime tobacco dose.

Association between cigarette smoking and Parkinson’s disease: A meta-analysis

ObjectiveTo evaluate the association of Parkinson’s disease (PD) with smoking, and determine whether gender, source of controls, dose of smoking, and year of studies modify the observed effects of smoking on PD. MethodsAvailable publications between 1959 and 2014 from PubMed, ScienceDirect, Springer Link and Web of Science databases were searched and carefully selected. Relative risks RR of specific study were weighted to obtain a pooled RR estimate and its 95% confidence interval CI. Results61 case-control and 8 cohort studies were included. The pooled RR of PD was 0.59 (95% CI, 0.56–0.62) for ever smokers compared with never smokers. The stratified analyses indicated a somewhat greater impact of smoking on PD risk in cohort studies than in case-control studies, the protective effect was relatively significant in men more than in women and the inverse effect was slightly greater in hospital-based studies than in population-based studies. Furthermore, a significant inverse dose–response relationship was observed for the number of pack-years smoked. The summary RR for those smoking more than 30 pack-years was 0.66 (95% CI, 0.49–0.88), and 0.39 (95% CI, 0.29–0.53) for those smoking less than 30 pack-years. ConclusionThe results demonstrated the inverse association between cigarette smoking and the risk of PD. We suggest that effective drugs for PD might be developed using chemical substances derived from tobacco or tobacco smoke.

Effects of smoking severity and moderate and severe periodontitis on serum C-reactive protein levels: an age- and gender-matched retrospective cohort study

Background and purpose: C-reactive protein (CRP) which might affect cardiovascular events can be affected by chronic diseases and smoking. Since the effects of smoking dosage as well as the mutual effect of smoking and periodontitis on CRP levels have not been evaluated, we aimed to assess these.Materials and methods: This retrospective age- and gender-matched study was performed on 120 dental patients. Clinical attachment loss, pocket probing depth (PPD), bleeding on probing (BoP), O’Leary plaque index and serum CRP were recorded. Patients were divided into one control and five cohort groups (n = 20 each) according to smoking severity [pack years (PY) below or above 30] and periodontal condition (healthy periodontium and moderate/severe periodontitis). The effects of clinical measurements, age, gender, smoking and periodontitis on CRP were assessed using one- and two-way analyses of variance, Tukey and Bonferroni post hoc tests, and multiple linear regression (α = 0.05).Results: CRP concentrations were 0.07255 ± 0.009539, 0.09645 ± 0.010625, 0.122235 ± 0.018442, 0.3758 ± 0.187369, 0.81595 ± 0.0410299 and 1.8717 ± 0.652728 mg/l, respectively, in the control (PY ≤ 30 with healthy periodontium), cohort 1 (PY > 30 with healthy periodontium), cohort 2 (PY ≤ 30 with moderate periodontitis), cohort 3 (PY > 30 with moderate periodontitis), cohort 4 (PY ≤ 30 with severe periodontitis) and cohort 5 (PY > 30 with severe periodontitis). The positive effects of age, smoking severity, periodontitis and PPD, on CRP increase were significant (Regression p < 0.02). BoP had a negative effect (p = 0.015).Conclusions: Clinicians should warn the patients, especially the older ones, about the effects of their gingival health and smoking on their cardiovascular condition.

Fingerprint of Lung Fluid Ultrafine Particles, a Novel Marker of Acute Lung Inflammation

Background: Acute lung inflammation can be monitored by various biochemical readouts of bronchoalveolar lavage fluid (BALF). Objective: To analyze the BALF content of ultrafine particles (UFP; <100 nm) as an inflammatory biomarker in early diagnosis of acute and chronic lung diseases. Methods: Mice were exposed to different stress conditions and inflammatory insults (acute lipopolysaccharide inhalation, tobacco smoke and lethal dose of total body irradiation, i.e. 950 rad). After centrifugation, the cellular pellet was assessed while cytokines and ultrafine particles were measured in the soluble fraction of the BALF. Results: A characteristic UFP distribution with a D₅₀ (i.e. the dimension of the 50th UFP percentile) was shared by all tested mouse strains in the BALF of resting lungs. All tested inflammatory insults similarly shifted this size distribution, resulting in a unique UFP fingerprint with an averaged D₅₀ of 58.6 nm, compared with the mean UFP D₅₀ of 23.7 nm for resting BALF (p < 0.0001). This UFP profile was highly reproducible and independent of the intensity or duration of the inflammatory trigger. It returned to baseline after resolution of the inflammation. Neither total body irradiation nor induction of acute cough induced this fingerprint. Conclusions: The UFP fingerprint in the BALF of resting and inflamed lungs can serve as a binary biomarker of healthy and acutely inflamed lungs. This marker can be used as a novel readout for the onset of inflammatory lung diseases and for complete lung recovery from different insults.

Impact of Smoking and Brain Metastasis on Outcomes of Advanced EGFR Mutation Lung Adenocarcinoma Patients Treated with First Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors.

ObjectivesThis purpose of this study was to examine clinical-pathologic factors – particularly smoking and brain metastases – in EGFR mutation positive (M+) lung adenocarcinoma (ADC) to determine their impact on survival in patients treated with first line EGFR TKI.MethodsA retrospective review of EGFR mutation reflex testing experience for all ADC diagnosed at a tertiary Asian cancer centre from January 2009 to April 2013. Amongst this cohort, patients with advanced EGFR M+ ADC treated with first line EGFR TKI were identified to determine factors that influence progression free and overall survival.Results444/742 (59.8%) ADC reflex tested for EGFR mutations were EGFR M+. Amongst never-smokers (n=468), EGFR M+ were found in 74.5% of females and 76.3% of males, and amongst ever smokers (n=283), in 53.3% of females and 35.6% of males. Exon 20 mutations were found more commonly amongst heavy smokers (> 50 pack years and > 20 pack years, Pearson’s chi square p=0.044, and p=0.038 respectively). 211 patients treated with palliative first line TKI had a median PFS and OS of 9.2 and 19.6 months respectively. 26% of patients had brain metastasis at diagnosis. This was significantly detrimental to overall survival (HR 1.85, CI 1.09-3.16, p=0.024) on multivariate analysis. There was no evidence that smoking status had a significant impact on survival.ConclusionsThe high prevalence of EGFR M+ in our patient population warrants reflex testing regardless of gender and smoking status. Smoking status and dosage did not impact progression free or overall survival in patients treated with first line EGFR TKI. The presence of brain metastasis at diagnosis negatively impacts overall survival.

Abstract P1-03-01: Cardiac function in BRCA1/2 mutation carriers with a history of breast cancer (BC) treated with anthracyclines (anthra)

Abstract Introduction: Animal data suggest that cardiac-specific loss of BRCA1/2 genes leads to increased cardiac dysfunction in the setting of stressors such as ischemia or anthra chemotherapy (CT). Women with BRCA1/2 mutations who develop BC may receive anthra-based CT. It is not known whether BRCA1/2 mutation carriers treated for early stage BC with anthra-based CT are at higher risk for anthra-induced cardiac toxicity than similarly treated women with sporadic BC. This study investigates left ventricular ejection fraction (LVEF) and myocardial global longitudinal strain (GLS), a novel echocardiographic measure of cardiac contractility, in women with and without BRCA1/2 mutations who were treated with anthra-based CT. Methods: We identified 41 women with a history of BRCA1/2 mutation-associated BC and 52 women with a history of sporadic BC, all of whom received anthra-based adjuvant or neoadjuvant CT. We excluded women who received HER2 therapy or who had stage IV disease. BC CT was completed at least 6 months prior to study enrollment. All participants completed a cardiac questionnaire and underwent a comprehensive 2D and 3D echocardiographic exam with assessment of myocardial GLS using speckle-tracking software (QLAB10, Philips, Andover, MA). Abnormal LVEF was defined as less than 55% (50-54.9% borderline reduced and 40-49% mildly reduced) and abnormal GLS was defined as absolute value of less than 18.9%. Patients with history of hypertension (HTN) were excluded from this analysis to avoid confounding effects of HTN on GLS. Results: We present data on 57 normotensive participants, 34 BRCA1/2 mutation-carriers and 23 non-mutation carriers. Mean age was 49.5 +/- 8.7 years in the BRCA mutation-carrier group and 51.1 +/- 8.7 years in the non-mutation carrier group (p=0.496). Women with BRCA1/2 mutations were more likely to be Caucasian (p=0.026) and have undergone oophorectomy (p&amp;lt;0.001). The average time from anthra treatment to study enrollment was 5 +/- 4.4 years. Groups were well balanced with regards to age, diabetes, hyperlipidemia, history of coronary disease, smoking and cumulative dose of anthra. Four BRCA1/2 mutation-carriers (12%) and 4 non-mutation carriers (17%) had reduced GLS (p= 0.450). Mean LVEF was similar between the groups: LVEF was borderline reduced in one BRCA1/2 mutation-carrier (3%) and borderline or mildly reduced in 4 non-mutation carriers (18%)(p= 0.091). Conclusions: In this population, reduced LVEF and myocardial GLS were present in a small percentage of women treated with anthra-based CT for early stage BC. However, reduction in LVEF and myocardial GLS did not differ between the BRCA1/2 mutation carriers and the women with a history of sporadic BC. Larger studies are needed to definitively rule out a difference in cardiac toxicity by BRCA mutation status in BC survivors treated with anthra. This project is supported by Fisher Center for Familial Cancer Research Award at Lombardi Comprehensive Cancer Center. AB is supported by Georgetown-Howard Universities Center for Clinical &amp; Translational Science (GHUCCTS) post-doctoral KL2 Award (5KL2TR000102-04). Citation Format: Filipa Lynce, Ana Barac, Karen L Smith, Mihriye Mete, Lynette Wray, Madeline Nardacci, Pia Herbolsheimer, Raquel Nunes, Sandra M Swain, Robert Warren, Claudine Isaacs. Cardiac function in BRCA1/2 mutation carriers with a history of breast cancer (BC) treated with anthracyclines (anthra) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-03-01.

Impact of transcutaneous neuromuscular electrical stimulation on dysphagia in patients with head and neck cancer treated with definitive chemoradiation

The purpose of this study was to investigate the role of transcutaneous neuromuscular electrical stimulation (TNMES) therapy in maintaining swallowing function during chemoradiation for locally advanced head and neck cancer. We retrospectively compared 43 consecutive patients with locally advanced head and neck cancer treated with TNMES (treatment group) to 55 control patients. Validated swallowing scale scores were assigned. All patients' swallowing scores declined post-chemoradiotherapy. A difference in mean decline in scores for the control group versus the treatment group using the Functional Oral Intake Scale (FOIS) was seen, favoring TNMES intervention (23% vs 7%; p = .015). Age, race, >10 pack-years smoking, diabetes, stage, nodal disease, accelerated fractionation, weight loss, dietary modification, no TNMES, and radiotherapy dose were all significant for poorer scores on the swallowing scales. TNMES should be considered an adjunct to dysphagia reduction and possible prevention in patients with locally advanced head and neck cancer. Further studies should be conducted to define the benefit of TNMES intervention.

210Po inhalation due to smoking: a dose estimation

Smoking is the second reason for developing lung cancer. Our goal was to determine how the amount of 210Po in the tobacco is distributed among the cigarette parts and what percentage reaches the respiratory system, calculating the effective dose. 210Po from tobacco, filter and ash samples were measured from seven Romanian cigarette brands by alpha spectrometry. The obtained average results were 13.97 ± 1.75 mBq/cigarette in the tobacco; 1.61 ± 0.25 mBq/cigarette in the filter and 3.33 ± 0.29 mBq/cigarette in the ash. The dose originating from active smoking was estimated to have an average of 8.36 ± 0.91 μSv/year, while the passive smoking dose reaching the respiratory system was 5.92 ± 0.49 μSv.

Smoking and potentially preventable hospitalisation: The benefit of smoking cessation in older ages

AimsReducing preventable hospitalisation is a priority for health systems worldwide. This study sought to quantify the contribution of smoking to preventable hospitalisation in older adults and the potential benefits of smoking cessation. MethodsSelf-reported smoking data for 267,010 Australian men and women aged 45+ years linked with administrative hospital data were analysed using Cox's models to estimate the effects on risk of hospitalisation for congestive heart failure (CHF), diabetes complications, chronic obstructive pulmonary disease (COPD) and angina. The impacts of smoking and quitting smoking were also quantified using risk advancement periods (RAP). ResultsThe cohort included 7% current smokers, 36% former smokers and 57% never smokers. During an average follow-up of 2.7 years, 4% of participants had at least one hospitalisation for any of the study conditions (0.8% for CHF, 1.7% for diabetes complications, 0.8% for COPD and 1.4% for angina). Compared to never smokers, the adjusted hazard ratio for hospitalisation for any of the conditions for current smokers was 1.89 (95% CI 1.75–2.03), and the RAP was 3.8 years. There were strong dose-response relationships between smoking duration, smoking intensity and cumulative smoking dose on hospitalisation risk. The excess risk of hospitalisation and RAP for COPD was reduced within 5 years of smoking cessation across all age groups, but risk reduction for other conditions was only observed after 15 years. ConclusionSmoking is associated with increased risk of preventable hospitalisation for chronic conditions in older adults and smoking cessation, even at older ages, reduces this risk.

Risk factors for poor neonatal adaptation after exposure to antidepressants in utero.

Infants exposed to antidepressants in utero are at risk of developing poor neonatal adaptation (PNA). This study identified risk factors for PNA. In this cohort study, data on mothers and infants admitted to the maternity ward of a general hospital between 2007 and 2012 were analysed. All infants were exposed to an antidepressant during the last trimester of foetal life. The main outcome measure was PNA, defined as at least one Finnegan scores of four or more during admission. Risk factors analysed for their possible association with PNA included type of feeding, type and dosage of antidepressant, prematurity and maternal smoking, anxiety and depression. We included 247 infants in the study and 157 (64%) developed PNA. Formula feeding was associated with an increased risk of PNA compared to breastfeeding or mixed feeding (OR 3.16 95% CI 1.40-7.13 p = 0.003). Selective serotonin reuptake inhibitors (SSRIs) were associated with an increased risk of PNA compared to serotonin and noradrenaline reuptake inhibitors (OR 2.52 95% CI 1.07-5.95 p = 0.04). Dosage did not influence the risk of PNA (OR 1.50 95% CI 0.89-2.52 p = 0.13). Formula feeding and exposure to SSRIs were associated with development of PNA, but dosage was not.

Impulse control disorders and related behaviours (ICD-RBs) in Parkinson's disease patients: Assessment using "Questionnaire for impulsive-compulsive disorders in Parkinson's disease" (QUIP).

Background:There is limited data on the prevalence of impulse control disorder and related behaviors (ICD-RBs) in Indian patients with Parkinson's Disease (PD). In the context of potential genetic and environmental factors affecting the expression of ICD-RBs, studying other multiethnic populations may bring in-sights into the mechanisms of these disorders.Objectives:To ascertain point prevalence estimate of ICD-RBs in Indian PD patients, using the validated “Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease (QUIP)” and to examine their association with Dopamine replacement therapy (DRT).Materials and Methods:This was a hospital based observational cross-sectional study. After taking informed consent, patients and their informants (spouse, or primary caregiver) were made to complete the QUIP, and were instructed to answer questions based on behaviors that occurred anytime during PD that lasted at least four consecutive weeks.Results:Total of 299 patients participated in the study. At least one ICD-RB was present in 128 (42.8%), at least one Impulse control disorder (ICD) was present in 74 (24.75%) and at least one Impulse control related compulsive behaviour (ICRB) was present in 93 (31.1%) patients. Punding was the most frequent (12.4%) followed by hyper sexuality (11.04%), compulsive hobbyism (9.4%), compulsive shopping (8.4%), compulsive medication use (7.7%), compulsive eating (5.35%), walkabout (4%) and pathological gambling (3.3%). ≥ 2 ICD-RBs were observed in 15.7% of patients. After multivariate analysis, younger age of onset, being unmarried were specifically associated with presence of ICD. Longer disease duration was specifically associated with presence of ICRB. Whereas smoking and higher dopamine levodopa equivalent daily doses (DA LEDD) were associated with both presence of ICD and ICRB. Higher LD LEDD was specifically associated with presence of ICD-RB.Conclusions:Our study revealed a relatively higher frequency of ICD-RBs, probably because of the use of screening instrument and because we combined both ICDs and ICRBs. Also high proportion of DA use (81.6%) among our patients might be responsible. The role of genetic factors that might increase the risk of developing ICD-RBs in this population needs further exploration.

Dose-response relationship between cigarette smoking and female sexual dysfunction.

ObjectiveTo evaluate whether smoking is a risk factor for female sexual dysfunction (FSD) and to determine the relationship between the cumulative smoking dose and FSD in premenopausal women.MethodsThe study population consisted of sexually active premenopausal women. The frequency of FSD and female sexual function index (FSFI) total score were evaluated according to the smoking status (never/former and current smokers). Evaluation of sexual function was done using FSFI questionnaire, and women with FSFI score of ≤26.55 were considered to have FSD. In current smokers, sexual function was also evaluated according to the cumulative smoking dose and nicotine dependency.ResultsA total of 900 women were included, and the frequency of current smokers and the frequency of FSD were 62 (6.9%) and 496 (55.1%), respectively. In current smokers, the frequency of FSD was significantly higher and the median total FSFI score was significantly lower than in never/former smokers, and this difference of FSD remained significant after adjustment for confounding variables. Among current smokers, the cumulative smoking dose (pack-years) and the total FSFI score showed negative correlation, in which increased cumulative smoking dose was associated with lower total FSFI score (r=-0.278, P<0.05). In terms of nicotine dependency, the total FSFI score of moderately to heavily nicotine dependent smokers was significantly lower than that of lightly dependent smokers.ConclusionIn premenopausal women, current smoking was an independent risk factor for FSD. And cumulative smoking dose and nicotine dependency were associated with higher risk of FSD.

Olfactory dysfunction in Parkinson's disease: Positive effect of cigarette smoking.

There is compelling evidence from over 60 epidemiological studies that smoking significantly reduces the risk of Parkinson's disease (PD). In general, those who currently smoke cigarettes, as well as those with a past history of such smoking, have a reduced risk of PD compared to those who have never smoked. Recently it has been suggested that a cardinal nonmotor sensory symptom of PD, olfactory dysfunction, may be less severe in PD patients who smoke than in PD patients who do not, in contrast to the negative effect of smoking on olfaction described in the general population. We evaluated University of Pennsylvania Smell Identification Test (UPSIT) scores from 323 PD patients and 323 controls closely matched individually on age, sex, and smoking history (never, past, or current). Patients exhibited much lower UPSIT scores than did the controls (P < 0.0001). The relative decline in dysfunction of the current PD smokers was less than that of the never- and past-PD smokers (respective Ps = 0.0005 and 0.0019). Female PD patients outperformed their male counterparts by a larger margin than did the female controls (3.66 vs. 1.07 UPSIT points; respective Ps < 0.0001 and 0.06). Age-related declines in UPSIT scores were generally present (P < 0.0001). No association between the olfactory measure and smoking dose, as indexed by pack-years, was evident. PD patients who currently smoke do not exhibit the smoking-related decline in olfaction observed in non-PD control subjects who currently smoke. The physiological basis of this phenomenon is yet to be defined.

Detection of in vivo DNA damage induced by very low doses of mainstream and sidestream smoke extracts using a novel assay.

Mainstream (MS) smoke, the main smoke inhaled by active smokers, and sidestream (SS) smoke, the main component of secondhand smoke, induce a wide range of DNA lesions. Owing to technical limitations, the in vivo levels of tobacco-induced DNA damage are unknown. Recently, the authors developed a highly sensitive primer-anchored DNA damage detection assay (PADDA) to quantify endogenous and induced DNA damage. To quantify the in vivo levels of DNA damage induced by MS and SS smoke extracts in human cells using PADDA and define the strand-specific patterns of DNA damage and repair following exposure to diverse doses of MS and SS smoke. Human epithelial cells were exposed to escalating doses of hydrogen peroxide (H2O2), MS, or SS smoke. TP53 gene DNA damage was quantified using PADDA at various time points. DNA double-strand breaks were detected by immunofluorescence analysis of phosphorylated histone H2AX (γ-H2AX). Cell viability was determined by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Data were collected and analyzed by t-test in 2012-2014. A dose-dependent increase in DNA damage was detected in vivo with increasing doses of H2O2, MS, and SS smoke. Even 1 hour of exposure to very low doses of MS or SS smoke resulted in significant DNA damage (p<0.01). MS and SS smoke induced distinctive strand-specific patterns of DNA damage and DNA repair kinetics. Very low concentrations of MS and SS smoke induce significant DNA damage in human cells. Application of PADDA to population studies has major potential to establish biomarkers of susceptibility to tobacco-induced diseases.

Fibroblast growth factor receptor 1 gene amplification is associated with poor survival in patients with resected esophageal squamous cell carcinoma.

To investigate the frequency and the prognostic impact of fibroblast growth factor receptor 1 (FGFR1) gene amplification in 526 curatively resected esophageal squamous cell carcinoma (ESCC). Using fluorescent in situ hybridization, high amplification was defined by an FGFR1/centromer 8 ratio is ≥ 2.0, or average number of FGFR1 signals/tumor cell nucleus ≥ 6.0, or percentage of tumor cells containing ≥ 15 FGFR1 signals or large cluster in ≥ 10%. Low amplification was defined by ≥ 5 FGFR1 signals in ≥ 50%. FGFR2 and FGFR3 mutations were assessed by direct sequencing in 388 cases and no mutation was detected. High and low amplification were detected in 8.6% and 1.1%, respectively. High FGFR1 amplification had significantly shorter disease-free survival (34.0 vs 158.5 months P=0.019) and overall survival (52.2 vs not reached P=0.022) than low/no amplification group. After adjusting for sex, smoking, stage, histology, and adjuvant treatment, high FGFR1 amplification had a greater risk of recurrence (adjusted hazard ratio [AHR], 1.6; P=0.029) and death (AHR, 1.53; P=0.050). High amplification was significantly higher in current smokers than former and never-smokers (Ptrend<0.001) and increased proportional to smoking dosage. High FGFR1 amplification is a frequent oncogenic alteration and an independent poor prognostic factor in resected ESCC.

Abstract 4152: Differences in nicotine metabolism among five racial/ethnic groups with disparate risks for lung cancer: The multiethnic cohort study

Abstract Introduction: Globally, lung cancer is the most common cancer and the leading cause of cancer-related deaths. Smoking is a well-established risk factor for this disease; however, self-reported dose does not fully explain the differences in lung cancer risk observed across ethnic/racial populations. Compared to whites, for the same lifetime number of cigarettes smoked, African Americans (AA) and Native Hawaiians (NH) have substantially higher rates of lung cancer, whereas Japanese Americans (JA) and Latinos (LA) have lower rates of disease. These differences may be due to variations in nicotine metabolism, thereby influencing smoking behavior. Methods: Using overnight or first morning urine samples collected in the Multiethnic Cohort study (MEC), we examined nicotine metabolism among 2,300 cancer-free smokers of five racial/ethnic groups with different lung cancer risks: AA (n=356), NH (n=330), whites (n=444), LA (n=459) and JA (n=711). Total and free urinary nicotine metabolites: nicotine, cotinine, and trans-3-hydroxycotinine (3-OH) were measured by liquid chromatography tandem mass spectrometry. Smoking dose was quantified by urinary nicotine equivalents (NE)=total cotinine + total nicotine + total 3-OH. The respective glucuronidation ratio of each metabolite was calculated as the total metabolite minus the free metabolite divided by the free metabolite. CYP2A6 enzymatic activity ratio was calculated as: (total cotinine + 3-OH)/ NE. To examine the difference in metabolite levels across racial/ethnic groups, covariate-adjusted geometric means were computed for each group from linear regression models, adjusting for age at urine collection, sex, creatinine, BMI, and CYP2A6 activity ratio (for the NE and glucuronides models), cigarettes per day (CPD) (for the NE model) or NE (for the glucuronides and CYP2A6 activity models). Results: We found that NE and nicotine, cotinine and 3-OH glucuronidation and CYP2A6 activity differed by race/ethnicity (p≤0.002). For NE, AA had the highest levels, followed by whites, LA, NH and JA (geometric means=30.9, 28.5, 28.3, 27.2 and 25.7 nmol/mL, respectively). For CYP2A6 activity, the ratio was highest in AA, followed by LA, whites, NH and JA (geometric means= 0.80, 0.81, 0.77, 0.73 and 0.62, respectively). We found that for each racial/ethnic group NE was greater for smokers in the higher compared to the lower tertile of CYP2A6 activity. This trend was significant for all groups, except NH (p-trend's= 0.02 [AA], 0.30 [NH], &amp;lt;0.0001 [W, LA and JA]; p-interaction&amp;lt;0.005). Conclusion: CYP2A6 enzymatic activity affects smoking dose beyond CPD, which in part may explain the relatively lower risk of lung cancer of Japanese Americans. Further investigation of racial differences in lung cancer risk using nicotine biomarkers is warranted. Citation Format: Sung-Shim L. Park, Christian Caberto, Maarit Tiirikainen, Lynne Wilkens, Daniel Stram, Christopher A. Haiman, Stephen S. Hecht, Sharon Murphy, Loic Le Marchand. Differences in nicotine metabolism among five racial/ethnic groups with disparate risks for lung cancer: The multiethnic cohort study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4152. doi:10.1158/1538-7445.AM2014-4152

Abstract 2856: Fibroblast growth factor receptor 1 gene amplification as an independent prognostic factor for recurrence in patients with resected squamous cell esophageal cancer

Abstract Purpose To evaluate investigate the prognostic role of fibroblast growth factor receptor 1 (FGFR1) amplification in patients with surgically resected esophageal squamous cell carcinoma (ESCC). Patients and methods Gene copy number of FGFR1 was investigated in microarrayed tumors from 549 patients with ESCC who underwent curative esophagectomy. Gene copy number was evaluated by fluorescent in situ hybridization, and an FGFR1 amplified tumor (FGFR1 amp+) was prespecified if one of the following criteria is fulfilled: (I) FGFR1/centromer 8 (CEN8) ration is ≥ 2.0, (II) average gene copy nucleus is ≥ 6.0, and (III) percentage of tumor cells containing ≥ 15 gene copies or large cluster is ≥ 10%. Results FGFR1 amplification was detected in 8% (44 of 549) of ESCC. The average copy number per nucleus was 2.7 (range, 0-15.5) and the mean FGFR1/CEN8 ratio was 2.2 (range, 0-6). The 5-year disease free survival of the FGFR1 amp+ group was significantly shorter compared with that of the FGFR1amp- group (38.8% vs 63.7% P=0.012). In Cox proportional hazard model, patients with FGFR1 amp+ had a significantly greater risk of recurrence compare to amp- group after adjusting for sex, smoking status, pathologic stage, histology, and adjuvant chemotherapy (HR 1.74; 95% CI, 1.10-2.76, P=0.018). Of note, there was a trend toward worse overall survival for FGFR1 amp+ group compare to amp- group (5-year OS 32.0% vs 50.8%, P=0.11). FGFR1 amp+ group was significantly more likely to be smokers than FGFR1amp- group (97.7 % vs 2.3%, P=0.001). With increment of total cigarette smoking dosage, the incidence of FGFR1 amp+ significantly increased (P trend=0.005). Conclusions FGFR1 amplification is an independent prognostic factor for recurrence in surgically resected ESCC. FGFR1 amplification may have potential clinical application to the development of novel therapeutic strategies for ESCC Citation Format: Hyo Song Kim, Seung Eun Lee, Yoon Sung Bae, Joo Hang Kim, Hye Ryun Kim, Dae Joon Kim, Hyunki Kim, Yoon-La Choi, Byoung Chul Cho. Fibroblast growth factor receptor 1 gene amplification as an independent prognostic factor for recurrence in patients with resected squamous cell esophageal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2856. doi:10.1158/1538-7445.AM2014-2856

Influence of smoking dosage and chronic obstructive lung disease on the incidence of appropriate therapies and mortality in patients with structural heart disease and an implantable cardioverter defibrillator.

Smoking is known as a relevant risk factor for severe cardiac morbidities and mortality. This study was initiated to explore the influence of smoking dosage and presence of chronic obstructive lung disease (COPD) on the incidence of appropriate implantable cardioverter defibrillator (ICD) interventions and on mortality. Prior studies on patients equipped with an ICD suggested that nicotine consumption increases the risk of experiencing an appropriate ICD therapy. There is no substantial data regarding the influence of cigarette smoking dosage on overall mortality in such endangered patients. A total of 349 patients with structural heart disease, either coronary artery disease or nonischemic cardiomyopathy equipped with an ICD, were included. Every patient answered a questionnaire regarding his smoking status and performed a spirometry and body plethysmography. A total of 104 patients (30%) suffered from COPD. Fifty-eight patients (17%) were "current smokers," 196 patients (56%) were revealed as "former smokers," while 93 (27%) patients were registered as "never smokers." A total of 163 patients (47%) received at least one appropriate ICD intervention during follow-up (median 48 ± 8 months). Twenty-three patients died during this study (6.6%). There was no association of COPD with the incidence of appropriate ICD therapies or mortality. Smoking dosage revealed as a significant risk factor for both appropriate ICD interventions (hazard ratio [HR] 1.5 for 60 pack years [PY] P = 0.04) and mortality (HR 2.3 for 60 PY P = 0.02). This study demonstrates a dose-related increased risk of smokers for appropriate ICD interventions and mortality. The results of this trail urge a strict nicotine abstinence, especially in patients with a structural heart disease undergoing ICD therapy.