Lung cancer risk test trial: study design, participant baseline characteristics, bronchoscopy safety, and establishment of a biospecimen repository.

BACKGROUND: The Lung Cancer Risk Test (LCRT) trial is a prospective cohort study comparing lung cancer incidence among persons with a positive or negative value for the LCRT, a 15 gene test measured in normal bronchial epithelial cells (NBEC). The purpose of this article is to describe the study design, primary endpoint, and safety; baseline characteristics of enrolled individuals; and establishment of a bio-specimen repository. METHODS/DESIGN: Eligible participants were aged 50-90 years, current or former smokers with 20 pack-years or more cigarette smoking history, free of lung cancer, and willing to undergo bronchoscopic brush biopsy for NBEC sample collection. NBEC, peripheral blood samples, baseline CT, and medical and demographic data were collected from each subject. DISCUSSION: Over a two-year span (2010-2012), 403 subjects were enrolled at 12 sites. At baseline 384 subjects remained in study and mean age and smoking history were 62.9 years and 50.4 pack-years respectively, with 34% current smokers. Obstructive lung disease (FEV1/FVC <0.7) was present in 157 (54%). No severe adverse events were associated with bronchoscopic brushing. An NBEC and matched peripheral blood bio-specimen repository was established. The demographic composition of the enrolled group is representative of the population for which the LCRT is intended. Specifically, based on baseline population characteristics we expect lung cancer incidence in this cohort to be representative of the population eligible for low-dose Computed Tomography (LDCT) lung cancer screening. Collection of NBEC by bronchial brush biopsy/bronchoscopy was safe and well-tolerated in this population. These findings support the feasibility of testing LCRT clinical utility in this prospective study. If validated, the LCRT has the potential to significantly narrow the population of individuals requiring annual low-dose helical CT screening for early detection of lung cancer and delay the onset of screening for individuals with results indicating low lung cancer risk. For these individuals, the small risk incurred by undergoing once in a lifetime bronchoscopic sample collection for LCRT may be offset by a reduction in their CT-related risks. The LCRT biospecimen repository will enable additional studies of genetic basis for COPD and/or lung cancer risk. TRIAL REGISTRATION: The LCRT Study, NCT 01130285, was registered with Clinicaltrials.gov on May 24, 2010.

History of childhood maltreatment is associated with comorbid depression in women with migraine.

BACKGROUND: A bidirectional relationship between migraine and depression suggests a neurobiological link. Adverse experiences, particularly childhood maltreatment, may alter neurobiological systems, and predispose to a multiplicity of adult chronic disorders. Our objective is to determine, within a headache clinic population of women, if depression moderates the abuse-migraine relationship. METHODS: At six headache specialty clinics, women with migraine were diagnosed using ICHD-II criteria, and frequency was recorded. A questionnaire regarding maltreatment history, headache characteristics, current depression, and somatic symptoms was completed. RESULTS: A total of 949 women with migraine completed the survey: 40% had chronic headache (> or =15 headache days/month) and 72% had "very severe" headache-related disability. Major depression was recorded in 18%. Physical or sexual abuse was reported in 38%, and 12% reported both physical and sexual abuse in the past. Migraineurs with current major depression reported physical (p < 0.001) and sexual (p < 0.001) abuse in higher frequencies compared to those without depression. Women with major depression were more likely to report sexual abuse occurring before age 12 years (OR = 2.30, 95% CI: 1.14 to 4.77), and the relationship was stronger when abuse occurred both before and after age 12 years (OR = 5.08, 95% CI: 2.15 to 11.99). Women with major depression were also twice as likely to report multiple types of maltreatment (OR = 2.07, 95% CI: 1.27 to 3.35) compared to those without depression. CONCLUSIONS: Childhood maltreatment was more common in women with migraine and concomitant major depression than in those with migraine alone. The association of childhood sexual abuse with migraine and depression is amplified if abuse also occurs at a later age.

High prevalence of somatic symptoms and depression in women with disabling chronic headache.

OBJECTIVE: To better define, in women with headache, the relationship of depression and somatic symptoms to headache, characterized by diagnoses, frequency, and disability. METHODS: At six headache specialty clinics, women with headache were classified using ICHD-II criteria, and frequency was recorded. A questionnaire addressing demographics, age at onset of headache, headache-related disability, somatic symptom, and depression severity was completed. Logistic regression was performed to measure the associations of headache frequency and headache-related disability with somatic symptom and depression severity. RESULTS: A total of 1,032 women with headache completed the survey, 593 with episodic (96% with migraine) and 439 with chronic headache (87% with migraine). Low education and household income was more common in chronic headache sufferers and in persons with severe headache disability. Somatic symptom prevalence and severity was greater in persons with chronic headache and with severe headache-related disability. Significant correlation was observed between PHQ-9 and PHQ-15 scores (r = 0.62). Chronic headache, severe disability, and high somatic symptom severity were associated with major depressive disorder (OR = 25.1, 95% CI: 10.9 to 57.9), and this relationship was stronger in the subgroup with a diagnosis of migraine (OR = 31.8, 95% CI: 12.9 to 78.5). CONCLUSIONS: High somatic symptom severity is prevalent in women with chronic and severely disabling headaches. Synergistic relationship to major depression exists for high somatic symptom severity, chronic headache, and disabling headache, suggesting a psychobiological underpinning of these associations.

Effect of smoking cessation on major histologic types of lung cancer.

STUDY OBJECTIVES: It is well-recognized that the risk of lung cancer declines after smoking cessation. However, the degree of decline in different histologic types of lung cancer is not well understood. We conducted a meta-analysis of peer-reviewed studies to assess the effect of smoking cessation on rates of major histologic types of lung cancer. DESIGN: Studies published in English between 1970 and 1999 were identified through searches of computerized databases (ie, MEDLINE and CANCERLIT). Combined estimates of relative risk and 95% confidence intervals were calculated for 27 studies using fixed and random effects models. Separate analyses were conducted for men and women. RESULTS: Smoking cessation was associated with a reduction in the risk of all the major histologic types of lung cancer. The highest reduction was in small cell lung carcinoma (SCLC) and squamous cell carcinoma (SQC), and the lowest reduction was seen in large cell cancer and adenocarcinoma. In women, the combined risks for SQC and SCLC were higher than those in men. The dose-response curve for intensity of smoking was steeper in women. CONCLUSION: The findings of this study suggest that smoking cessation results in the greatest reductions for SCLC and SQC. This effect is most marked in heavy smokers, particularly among women.

Meta-analysis of systemic sclerosis and exposure to solvents.

BACKGROUND: Although systemic sclerosis is a rare disease, incidence rates have increased recently in the United States. This study investigated the association between systemic sclerosis and exposure to solvents. METHODS: A Medline search of articles published between 1966 and 2000 dealing with solvent exposure and systemic sclerosis identified eight studies that met inclusion criteria of the meta-analysis. The studies included seven case-control studies and one cohort study published between 1989 and 1998. A series of meta-analyses of studies on systemic sclerosis and solvent exposure were performed for all studies and for case-control studies. A random effect model was used to calculate a combined estimator of relative risk. RESULTS: The combined estimator of relative risk for all studies was 2.91, with a 95% confidence interval (CI) of 1.60 to 5.30. The combined estimator of relative risk for the seven case-control studies was 3.14 (95% CI, 1.56-6.33). CONCLUSIONS: A statistically significant increased relative risk for all studies and for case-control studies suggests that exposure to organic solvent may be a risk factor for developing systemic sclerosis. Further studies using other study designs and better control of confounders are needed.

Environmental risk factors and Parkinson's disease: a metaanalysis.

The study aim was to examine the association between Parkinson's disease (PD) and exposure to environmental factors such as living in a rural area, well water use, farming, exposure to farm animals, or living on a farm, and pesticides. A series of metaanalyses of peer-reviewed studies were performed, using 16 studies for living in rural area, 18 studies for well water drinking, 11 studies for farming, and 14 studies for pesticides. Prior to the metaanalyses, all studies were reviewed and evaluated for heterogeneity and publication bias. Significant heterogeneity among studies was detected and combined odds ratio (OR) was calculated using the random and the fixed-effect models. The majority of the studies reported consistent elevation in the risk of PD with exposure to environmental factors such as rural living and farming. The combined OR for rural residence was 1.56 [95% confidence interval (95% CI) 1.18-2.07] for all the studies, and 2.17(95% CI 1.54-3.06) for studies performed in United States. The combined OR for well water use was 1.26 (95% CI 0.97-1.64) for all the studies, and 1.44(95% CI 0.92-2.24) for studies done in United States. The combined OR for farming, exposure to farm animals, or living on a farm was 1.42 (95% CI 1.05-1.91) for all studies, and 1.72(95% CI 1.20-2.46) for studies done in United States. The combined OR for pesticides exposure was 1.85(95% CI 1.31-2.60) for all studies, and 2.16(95% CI 1.95-2.39) for studies done in United States. Dose-response relationships could not be established due to the imprecise nature of the reported data. Our findings suggest that living in a rural area, drinking well water, farming, and exposure to pesticides may be a risk factor for developing PD.

Increased von Willebrand factor in migraine.

The authors determined von Willebrand factor (vWF) in 63 persons with migraine, 11 persons with migraine and prior stroke, and 35 frequency-matched controls. Additional studies were done in a subset with migraine without aura who were headache free for >7 days. Migraineurs with prior stroke had significantly higher vWF antigen (170% versus 106%) and activity (162% versus 108%) than the control group. vWF antigen (126%) and activity (130%) were also significantly higher in migraineurs without stroke. Multimers and protease activity were normal in the interictal subset.

Breast cancer and NSAID use: a meta-analysis.

Recent epidemiological studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of several cancers including breast cancer. This meta-analysis examined the studies on NSAID use and breast cancer. The estimators of relative risk and associated variances, which have been adjusted for the greatest number of confounders, were abstracted and included in the meta-analysis. Combined estimators of relative risk (RR) were calculated using either fixed or random effect models. Meta-analyses were performed on 6 cohort studies (number of cases ranged from 14 to 2414) and 8 case-control studies (number of cases ranged from 252 to 5882). The combined estimate of relative risk was 0.82 (95% confidence interval [CI] = 0.75-0.89). The combined estimate for cohort studies was 0.78 (95% CI = 0.62-0.99) and was 0.87 (95% CI = 0.84-0.91) for case-control studies. The findings of this meta-analysis suggest that NSAID use may be associated with a small decrease in the risk of breast cancer. However, the available data are insufficient to estimate the dose-response effect for duration and frequency of use of any particular types of NSAID.

Effect of cigarette smoking on major histological types of lung cancer: a meta-analysis.

Although cigarette smoking is an established risk factor for lung cancer, the strength of association with different histologic types is not well understood. This meta-analyses of peer-reviewed studies was conducted to assess the effect of cigarette smoking on major histologic types of lung cancer. Studies were identified through MEDLINE and CANCERLIT searches. A total of 48 studies published between 1970 and 1999 were identified. Combined estimates of relative risks (OR) and 95% confidence intervals (CI) were calculated using fixed and random effect models. Separate analyses were conducted by study design and gender. A linear dose-response was fit to studies reporting data on intensity and duration of smoking. All histologic types of lung cancer were significantly associated with cigarette smoking. The association was stronger with squamous cell carcinoma (SQC) and small cell carcinoma (SCLC) than with large cell cancer (LGC) and adenocarcinoma (ADC). The combined OR for heaviest smoking intensity (30+ cigarettes per day) ranged from 4.10 (CI 3.16-5.31) for ADC to 18.3 (CI 9.26-36.4) for SCLC. The combined OR for longest duration of smoking (40+ years) ranged from 3.80 (CI 2.35-6.16) for ADC to 38.6 (CI 11.9-125) for SCLC. In women, the combined OR for SQC and SCLC were higher than those in men. The dose response curve for intensity of smoking was steeper in women. The findings of this study provide additional evidence for a causal relationship between smoking and all histologic types of lung cancer.

Smoking and breast cancer: a meta-analysis.

Epidemiological studies have implicated smoking as a possible risk factor in the etiology of breast cancer, yet the evidence is not conclusive. We conducted meta-analyses of peer-reviewed studies published between 1984 and 2001 to assess the relation between smoking and breast cancer. The studies were located by searching the MEDLINE (1966 to 2001) and Cancer Abstracts (1980 to 2001) databases. Combined estimators of relative risk (RR) were calculated using fixed and random effect models. The combined RR for ever smokers was 1.10 (95% CI = 1.02-1.18). The association was stronger in premenopausal cases (RR = 1.21, CI = 1.08-1.36). The dose-response trend was significant but weak for the number of cigarettes smoked per day and for the duration of smoking. Early age at the start of smoking was associated with elevated risk (RR = 1.14, CI = 1.06-1.23). Our results suggest that smoking is a weak risk factor for breast cancer and the risk is higher in the premenopausal period and in those who started smoking at an early age.

Reproducible gene expression measurement among multiple laboratories obtained in a blinded study using standardized RT (StaRT)-PCR.

BACKGROUND: A method that provides standardized data and is relatively inexpensive and capable of high throughput is a prerequisite to the development of a meaningful gene expression database suitable for conducting multi-institutional clinical studies based on expression measurement. Standardized RT (StaRT)-PCR has all these characteristics. In addition, the method must be reproducible. StaRT-PCR has high intralaboratory reproducibility. The purpose of this study is to determine whether StaRT-PCR provides similar interlaboratory reproducibility. METHODS AND RESULTS: In a blinded interlaboratory study, expression of ten genes was measured by StaRT-PCR in a complementary DNA sample provided to each of four laboratories. The average coefficient of variation for interlaboratory comparison of the nine quantifiable genes was 0.48. In all laboratories, expression of one of the genes was too low to be measured. CONCLUSION: Because StaRT-PCR data are standardized and numerical and the method is reproducible among multiple laboratories, it will allow development of a meaningful gene expression database.

Evaluation of safety orientation and training programs for reducing injuries in the plumbing and pipefitting industry.

Construction workers are at increased risk for fatal and non-fatal injuries. This study examined the effectiveness of employee orientation and training in reducing injuries among plumbers and pipefitters. We searched the Occupational Safety and Health Administration's "recordable" injury data and "documentable" safety and training records for six plumbing and pipefitting employers in northwestern Ohio. During the period 1996 to 1998, 133 injuries were recorded with the duration of 2,541,432 working hours. The most common types of injuries were cuts, lacerations, and abrasions. The majority of injuries resulted from workers being struck by objects. The injury rate was significantly higher for small companies and longer working hours. No difference was found between traveling and local workers. Seventy-five percent of workers received safety orientations on injury prevention. Among workers who received safety orientations, only 3.4% experienced injuries, compared with 11.1% of workers without orientations. Safety orientations were associated with a significant reduction in injuries (odds ratio, 0.23; 95% confidence interval, 0.15 to 0.35). Proper safety orientation and training could reduce the risks for occupational injuries in construction workers.

A meta-analysis of Parkinson's disease and exposure to pesticides.

This study examined the association between Parkinson's disease (PD) and exposure to pesticides. A series of meta-analysis of peer-reviewed studies were performed, using 19 studies published between 1989 and 1999. Prior to the meta-analysis, all studies were reviewed and evaluated for heterogeneity and publication bias. Significant heterogeneity among studies was detected and combined odds ratio (OR) was calculated using the random effect model. The majority of the studies reported consistent elevation in the risk of PD with exposure to pesticides. The combined OR studies was 1.94 [95% confidence interval (95% CI) 1.49-2.53] for all the studies, and 2.15 (95% CI 1.14-4.05) for studies performed in United States. Although the risk of PD increased with increased duration of exposure to pesticides, no significant dose-response relation was established, and no specific type of pesticide was identified. Our findings suggest that exposure to pesticides may be a significant risk factor for developing PD.

Normal bronchial epithelial cell expression of glutathione transferase P1, glutathione transferase M3, and glutathione peroxidase is low in subjects with bronchogenic carcinoma.

Normal bronchial epithelial cells (NBECs) are at risk for damage from inhaled and endogenous oxidative species and from epoxide metabolites of inhaled polycyclic aromatic hydrocarbons. Epidemiological and in vitro data suggest that interindividual variation in this risk may result from variation in NBEC expression of enzymes that inactivate reactive species by conjugating them to glutathione. Quantitative competitive reverse transcription-PCR was used to measure mRNA levels of glutathione transferases (GSTs) and glutathione peroxidases (GSHPxs) in primary NBECs from subjects with or without bronchogenic carcinoma. Mean expression levels (mRNA/10(3) beta-actin mRNA) in NBECs from 23 subjects without bronchogenic carcinoma compared to those from 11 subjects with bronchogenic carcinoma respectively (in parentheses) were: mGST (26.0, 6.11), GSTM3 (0.29, 0.09), combined GSTM1,2,4,5 (0.98, 0.60), GSTT1 (0.84, 0.76), GSTP1 (287, 110), GSHPx (140, 62.1), and GSHPxA (0.43, 0.34). Levels of GSTP1, GSTM3, and GSHPx were significantly (P < 0.05) lower in NBECs from subjects with bronchogenic carcinoma. Further, the gene expression index formed by multiplying the values for mGST x GSTM3 x GSHPx x GSHPxA x GSTP1 had a sensitivity (90%) and specificity (76%) for detecting NBECs from bronchogenic carcinoma subjects that was better than any individual gene. In cultured NBECs derived from eight individuals without bronchogenic carcinoma and incubated under identical conditions such that environmental effects were minimized, the mean level of expression and degree of interindividual variation for each gene evaluated was less than that observed in primary NBECs. Data from these studies support the hypotheses that (a) interindividual variation in risk for bronchogenic carcinoma results in part from interindividual variation in NBEC expression of antioxidant genes; (b) gene expression indices will better identify individuals at risk for bronchogenic carcinoma than individual gene expression values; and (c) both hereditary and environmental exposures contribute to the level of and interindividual variation in gene expression observed in primary NBECs. Many epidemiological studies have been designed to evaluate risk associated with polymorphisms or gene expression levels of putative susceptibility genes based on measurements in surrogate tissues, such as peripheral blood lymphocytes. Based on data presented here, it will be important to include the assessment of NBECs in future studies. Measurement of antioxidant gene expression in NBECs may identify the 5-10% of individuals at risk for bronchogenic carcinoma. Bronchoscopic sampling of NBECs from smokers and ex-smokers then will allow susceptible individuals to be entered into surveillance and/or chemoprevention studies.

Is there an association between passive smoking and breast cancer?

Recent epidemiological studies have suggested passive smoking as possible risk factors in breast cancer etiology. However, the evidence is not conclusive. We conducted a meta-analysis of the risk of breast cancer associated with passive smoking. Eleven studies were identified through Medline, Cancer Abstracts and abstract presented at related scientific meetings. Combined estimates of relative risks (RR) were calculated using fixed and random effect models. Significant heterogeneity was detected among the studies (chi2 = 34.6, p < 0.01). The combined estimate of RR for ever exposure to passive smoking was 1.41 (95% confidence interval (CI): 1.14-1.75). The combined estimate for published studies was 1.43 (95% CI: 1.10-1.85). Only two studies reported significant dose-response relation between level of passive smoking and premenopausal breast cancer. Our analysis suggests a possible weak association between passive smoking and breast cancer. More studies are needed to establish whether the observed association is causal.

Meta-analysis of Hodgkin's disease among farmers.

OBJECTIVES: This study examined the association between Hodgkin's disease and farming. METHODS: A series of meta-analyses of peer-reviewed studies was performed, using 30 studies published between 1981 and 1998. Prior to the meta-analyses, all the studies were reviewed and evaluated for heterogeneity and publication bias. Combined relative risks (RR) were calculated using the random effect model. RESULTS: The combined RR was 1.25 [95% confidence interval (95% CI) 1.11-1.42] for all the studies, and 1.08 (95% CI 0.91-1.29) for the studies involving female farmers. Significant heterogeneity among the studies was detected, and a stratified analysis was carried out by study design, country of study, and time of publication. Significantly elevated RR values were obtained for the case-referent studies (odds ratio 1.53, 95% CI 1.18-1.98) and proportionate mortality studies (PMR)(PMR 1.18, 95% CI 1.02-1.36). A decrease in risk was eminent in the more recent studies. CONCLUSIONS: The findings suggest that male farmers have a slightly elevated risk of developing Hodgkin's disease. No specific etiologic exposure was identified, but exposures commonly experienced by farmers (infectious microorganisms, herbicides and insecticides) may contribute to the occurrence of the disease.

Age at smoking onset and its effect on smoking cessation.

The aim of this study was to examine the relationship between cessation and age at which person starts smoking. Data from a survey of nine neighborhoods in Philadelphia (1985-1987) were analyzed. Interviews were conducted in the home using a structured questionnaire. Participants were from a probability sample (n = 1,700) of males aged 35 years or older. Sixty-six percent of the smokers in this series started smoking before 18 years of age. Smoking cessation rate was 58.1% in Whites and 38.8% in Blacks. Age, race, marital status, education, health condition, amount smoked, and duration of smoking were significant predictors of smoking cessation. Age at initiation of smoking was a significant factor for continuation of smoking. Men who started smoking before 16 years of age had an odds ratio of 2.1 (95% confidence interval: 1.4-3.0) for not quitting smoking compared to those who started at a later age. These findings emphasize the need for prevention program targeted to children below 16 years of age.

Assessment of complete blood count variations among workers exposed to low levels of benzene.

The effect of benzene on white blood cell and red blood cell counts, hemoglobin level, mean corpuscular volume (MCV), and platelet count was investigated among workers in a small petroleum company. The investigated cohort consisted of 105 workers exposed to low levels of benzene between 1967 and 1994. The average level of benzene exposure per year ranged between 0.14 parts per million and 2.08 parts per million (8-hour time-weighted average). The mean complete blood count (CBC) demonstrated values within normal ranges. With the exception of white blood cells, all other CBC values were significantly reduced during the follow-up period. Length of employment was significantly related to the changes in MCV and platelet counts. The reductions in MCV were significant only among workers who had been employed for more than 10 years at this particular company. The findings of this study suggest that low levels of benzene may affect CBC values. CBC values may serve as a useful tool for biological monitoring for workers with low-level benzene exposure.