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In view of the 2013 American Thyroid Association consensus statement on outpatient thyroidectomy, the present study assessed the trends and factors associated with thyroid cancer surgery setting in older adults, using the New York Statewide Planning and Research Cooperative System database.There were 14,495 patients with surgically treated thyroid cancer in New York State between 2007 and 2017. Trends were plotted over time and stratified by surgery type. Significance of the trend was assessed using the Mann-Kendall test. Multivariable logistic regression was used to assess independent associations with surgical setting.The overall outpatient surgery rate significantly increased over time (correlation coefficient 0.82; P 0.001), for both total thyroidectomy (P 0.001) and lobectomy (P 0.001). Factors associated with increased odds of inpatient surgery were medium- and high-volume hospitalization (adjusted odds ratio [ORThe present study shows that outpatient thyroidectomy is increasingly favored over inpatient thyroidectomy over time in an older patient population. A clear changepoint following 2011 preceded the publication of the American Thyroid Association statement on outpatient thyroidectomy in 2013 and was likely associated with multiple publications reporting safety of outpatient thyroid surgery and clear economic benefits.

Introduction Computed tomography (CT) and fluorodeoxyglucose-positron-emission-tomography (FDG-PET) measurements of mediastinal lymph nodes (MLNs) of patients with non-small-cell-lung-cancers (NSCLCs) ≤ 30 mm in maximum diameter are recommended for pre-surgical prediction of MLN metastases. Methods We reviewed all patients at Mount Sinai Health System enrolled in the Initiative for Early Lung Cancer Research on Treatment (IELCART), prospective cohort between 2016 and 2020, who had pre-surgical FDG-PET and underwent surgery with MLN resection and/or pre-operative endobronchial ultrasound (EBUS) for a first primary NSCLC ≤ 30 mm in maximum diameter on pre-surgical CT. Results Among 470 patients, none with part-solid (n = 63) or nonsolid (n = 23) NSCLCs had MLN metastases. Solid NSCLCs were identified in 384 patients, none in typical carcinoid (n = 48) or NSCLC ≤ 10 mm in maximum diameter (n = 47, including 8 typical carcinoids) had MLN metastases. Among the remaining 297 patients with solid NSCLCs 10.1–30.0 mm, 7 (2.4%) had MLN metastases. Area-under-the-curve (AUC) for predicting MLN metastases in solid NSCLCs 10.1–30.0 mm, using the CT maximum short-axis MLN diameter was 0.62 (95% CI:0.44–0.81, p = 0.18) and using the highest SUVmax of any MLN, AUC was 0.58 (95% CI:0.39–0.78,p = 0.41). Neither AUCs were significantly different from chance alone. Optimal cutoff for prediction of MLN metastases was ≥ 18.9 mm for CT maximum short-axis diameter [sensitivity 14.3% (95%CI:0.0%–57.9%); specificity 100.0% (95%CI:98.9%-100.0%)] and for highest SUVmax was ≥ 11.7 [sensitivity 14.3% (95%CI:0.0%-57.9%) and specificity 99.7% (95%CI:98.3%-100.0%)]. Conclusions CT and SUVmax had low sensitivity but high specificity for predicting MLN metastases in solid NSCLCs 10.1–30.0 mm. Clinical Stage IA NSCLCs ≤ 30 mm should be based on CT maximum tumor diameter and MLN maximum short-axis diameter ≤ 20 mm.

Background Self-reported smoking behavior is widely used in identifying the eligibility for lung cancer screening (LCS). In clinical trials, self-reported smoking status was shown to be a reliable measure, while its effectiveness outside of trial settings remains to be clarified. We aimed to verify self-reported smoking status with serum cotinine levels among LCS-eligible adults from the National Health and Nutrition Examination Survey (NHANES). Methods From the combined 1999-2018 NHANES data, we selected adults (aged ≥18 years) with complete data on serum cotinine and smoking behavior, and determined their LCS eligibility according to the United States Preventive Services Task Force recommendation. Using established race/ethnicity specific cotinine cutpoints as the gold standard, we verified self-reported current smoking status with five measures: sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV), and reliability Kappa. We also compared these performance measures in subgroups stratified by sex, race/ethnicity, education, family income to poverty ratio, health insurance, and secondhand smoking exposure (SHS) at home. All analyses took into account the complex survey design. Results Approximately 9.3% (n = 2335, equivalent to 8.82 million weighted population) of all adults who currently smoke or formerly smoked were eligible for LCS. The prevalence of current smoking was 52.6% and 60.8% based on self-report and cotinine, respectively. The Se and Sp were 86.4% (95%CI: 83.9%-88.9%) and 99.7% (95%CI: 99.4%-100%), respectively; PPV and NPV were 99.8% (95%CI: 99.6%-100%) and 82.6% (95%CI: 79.4%-85.7%), respectively; and Kappa was 0.83 (95%CI: 0.80-0.86). The reliability Kappa was higher among females than males (0.87 (95%CI: 0.82-0.93)) vs 0.80 (95%CI: 0.77-0.84), the lowest among non-Hispanic white (0.82 (95%CI: 0.78-0.86)), and higher among those with SHS (0.72 (95%CI: 0.63-0.80) vs (0.68 (95%CI: 0.61-0.76)). Conclusion Self-reported smoking status is reasonably reliable among adults with high risk for developing lung cancer in the general population.

Background Lung cancer screening (LCS) is an important secondary prevention measure to reduce lung cancer mortality. The goal of this study was to assess state-level variations in LCS among the US elderly during the first 3 years since Medicare began its LCS reimbursement policy in 2015. Methods This ecological study examined the relations between LCS utilization density, defined as the number of low-dose CT (LDCT) or shared decision-making and counseling (SDMC) services per 1,000 Medicare fee-for-service (FFS) beneficiaries derived from the Medicare Provider Utilization and Payment Data: Physician and Other Supplier public use file, and state-level factors from several publicly available data sources. The study included Kruskal-Wallis tests and a cluster analysis. Results In 2017, the median utilization density per 1,000 Medicare FFS beneficiaries was 3.32 for LDCT and 0.46 for SDMC, which was 24 and 13 times the 2015 level, respectively. From 2015 to 2017, the total number of unique providers billed for LCS increased from 222 to 3,444 for LDCT imaging and from 20 to 523 for SDMC. Higher utilizations for both LDCT and SDMC services tended to concentrate in the northeastern and upper Midwest states than in the southwest states. The cluster of states with high utilization density did not include those states with the most lung cancer mortality and/or smoking prevalence. Conclusions A steady increase was noted in LCS utilization since Medicare began its reimbursement policy. The utilization and its growth varied across the United States and differed between LDCT imaging and SDMC, indicating large growth potentials for LCS and for states with high lung cancer mortality and smoking prevalence.

The accurate diagnosis of mesothelioma is critical for the appropriate clinical management of this cancer. Many issues complicate making the diagnosis of mesothelioma including the presence of reactive mesothelial cells in benign pleural effusions, the heterogeneity of mesothelioma histopathology, the relatively high incidence of other epithelial malignancies that metastasize to the pleura, and primary sarcomas that arise within the pleura. Given the rapidly evolving field of molecular profiling and the need for translational correlates in mesothelioma clinical trials, the National Cancer Institute (NCI)-International Association for the Study of Lung Cancer-Mesothelioma Applied Research Foundation Clinical Trials Planning Meeting was convened in March 2017 to develop a consensus on standard pathology guidelines for future NCI-sponsored clinical trials in mesothelioma. This consensus statement covers recommendations for specimen handling, pathologic classification and diagnosis, biobanking, and tissue correlative studies.

Destruction caused by natural disasters compromises medical providers' and hospitals' abilities to administer care. Hurricane Sandy was particularly devastating, resulting in massive disruptions of medical care in the region. This study aimed to determine whether a lack of access to medical care during Hurricane Sandy was associated with posttraumatic stress disorder (PTSD) symptoms and other mental health/substance abuse outcomes. A secondary aim was to examine whether having a chronic illness moderates those associations. Self-reported medical access and mental health symptomatology were obtained from New York City and Long Island residents (n = 1669) following Hurricane Sandy under the Leaders in Gathering Hope Together project (10/23/2013–2/25/2015) and Project Restoration (6/5/2014–8/9/2016). Multivariable logistic regressions were utilized to determine the relationship between lack of access to medical care and mental health outcomes. Of the 1669 participants, 994 (59.57%) were female, 866 (51.89%) were white, and the mean age was 46.22 (SD = 19.2) years old. Those without access to medical care had significantly higher odds of showing symptoms of PTSD (AOR = 2.71, CI = [1.77–4.16]), as well as depression (AOR = 1.94, CI = [1.29–2.92]) and anxiety (AOR = 1.61, CI = [1.08–2.39]) compared to those with access. Lack of access to care was associated with a 2.12 point increase in perceived stress scale score (SE = 0.63). The interaction between having a chronic illness and lack of access to medical care was not significantly associated with any outcomes. The findings emphasize the importance of making medical care more accessible to patients, both chronically and acutely ill, during natural disasters to benefit their physical as well as their mental health., Highlights • Individuals without access to medical care had asignificantly higher odds of showing symptoms of mental health difficulties. • Chronic illness did not moderate the relationship between a lack of access to care and mental health outcomes. • Access to medical care during natural disasters may benefit the mental health of survivors with and without chronic illness.

Purpose Lung cancer screening with low-dose computed tomography has been shown to significantly reduce lung cancer–related mortality in high-risk patients. However, patients diagnosed with lung cancer are typically older and often have multiple age- and smoking-related comorbidities. As a result, cancer screening in older adults remains a complex decision, requiring careful consideration of patients' risk characteristics and life expectancy to ensure that the benefits outweigh the risks of screening. In this review, we evaluate the evidence regarding lung cancer screening, with a focus on older patients. Methods PubMed was searched to identify relevant studies evaluating the clinical outcomes of lung cancer screening. The key words used in our search included non–small cell lung cancer (NSCLC), screening, older, comorbidities, computed tomography, and survival. While we primarily looked for articles specific to older patients, we also focused on subgroup analysis in older patients in larger studies. Finally, we reviewed all relevant guidelines regarding lung cancer screening. Findings Guidelines recommend that lung cancer screening be considered in adults aged 55 to 80 years who are at high risk based on smoking history (ie, 30-pack–year smoking history; having smoked within the past 15 years). Patients who fit these criteria have been shown to have a 20% reduction in lung cancer–related mortality with the use of low-dose computed tomography versus chest radiography. High rates of false-positive results and potential overdiagnoses were also observed. Therefore, screening is generally not recommended in adults with severe comorbidities or short life expectancy, who may experience limited benefit and higher risks with screening. However, several studies have shown a benefit with continued lung cancer screening with appropriate selection of older individuals at the highest risk and with the lowest comorbidities. Implications Older patients experience the highest risk for lung cancer incidence and mortality, and stand to be the most likely to benefit from lung cancer screening. However, careful consideration must be given to higher rates of false-positives and overdiagnosis in this population, as well as tolerability of surgery and competing risks for death from other causes. The appropriate selection of older individuals for lung cancer screening can be greatly optimized by using validated risk-based targeting.

Background It has been difficult to determine the individual impact of prenatal and postnatal tobacco smoke exposure (TSE) on childhood lung function, as children are often exposed to both. Objective The goal of this study was to determine the association between current TSE and airflow obstruction while adjusting for self-reported prenatal TSE. Methods Children aged 6 to 11 years who participated in the National Health and Nutrition Examination Survey (2007-2012) who had serum cotinine levels measured and spirometry performed were included. Logistic regression was used to determine the association between log-transformed serum cotinine level and airflow obstruction while adjusting for confounders; the analysis was then stratified according to asthma status. The final model included both log-transformed serum cotinine level and prenatal exposure as covariates. Results The sample consisted of 2,070 children; 9.6% had airflow obstruction. The association between cotinine levels and airflow obstruction was significant in an unadjusted analysis (OR, 1.12 [95% CI, 1.02-1.23]). In the multivariate analysis with both exposures included as covariates, serum cotinine level was not significantly associated with airflow obstruction (OR adj , 1.07 [95% CI, 0.94-1.21]), and no association was seen in children with asthma and nonasthmatic children. Prenatal smoking was associated with airflow obstruction in children with asthma (OR adj , 2.51 [95% CI, 1.08-5.79]) but not in nonasthmatic children (OR adj , 1.08 [95% CI, 0.53-2.18]). Conclusions Current TSE was not independently associated with airflow obstruction in school-aged children. Prenatal TSE was associated with airflow obstruction in children with asthma. Repeated studies into potential mediators and confounders of this relationship are needed.

Background Lobectomy is the recommended treatment for early-stage lung cancer. Little is known about variations of access to health service areas and hospital types for lobectomy overall and according to specific surgical techniques, such as the video-assisted thoracoscopic surgery (VATS). Methods The New York Statewide Planning and Research Cooperative System (2007-2012) was queried for lung cancer patients who underwent elective lobectomy. Hospitals were defined as nearest high-volume hospital (nHVH, reference), distant HVH (dHVH), close or distant low-volume hospital (cLVH or dLVH) using lobectomy volume and travel burden by the distance to nHVH. Results Utilization of hospitals within patients' health service areas ranged between 44% and 82% for three different geographic units. Approximately 26%, 34%, 31%, and 9% of the 9099 lobectomies were performed in nHVH, dHVH, cLVH, and dLVH, respectively. Patients in nHVH were older and more likely to have private insurance. Patients in dHVH were treated more with VATS and by higher volume surgeons, opposite of what observed in cLVH and dLVH. The use of dHVH was associated with more comorbidities and higher income. The use of dLVH was higher in Hispanics and non-Hispanic blacks than that in non-Hispanic whites. The odds of adverse postoperative events were higher in cLVH and dLVH but lower for patients treated with VATS and by high-volume surgeons. Conclusions Multiple factors likely resulted in differences in patterns of elective lobectomy among lung cancer patients. These variations should be taken into account when accessing and planning specialized health care delivery services.

This is a comprehensive review and re-analysis of available literature to assess the outcome of lung cancer presenting as nonsolid nodules (NSNs), a more indolent form of cancer. PubMed and EMBASE were searched for articles reporting on CT-detected lung cancers manifesting as NSNs published in English on or before July 17, 2015. Only studies including clinicopathologic data, lung cancer-specific survival, or overall survival were included. Data extraction was performed by three independent reviewers using prespecified criteria. Twenty-four articles from 5 countries met criteria and they included 704 subjects with 712 lung cancers manifesting as NSNs. Each article reported from 2 to 100 lung cancer cases with a median follow up of 18-51 months. All NSNs were Stage I adenocarcinoma without pathologic nodal involvement upon resection, except for one case in which the NSN progressed to become part-solid nodule after 6 years of follow-up. The five-year lung cancer-specific survival rate was 100%. These findings suggest an indolent course for lung cancers manifesting as NSNs.

Introduction Surgery is the treatment of choice for early-stage lung cancer (LC). Although lobectomy (L) is the historic standard treatment, the issue of whether long-term outcomes of sublobar resection (SL) are comparable is still under debate. The objective of this study was to perform a review of the literature on 5-year survival rates after SL compared to L for patients with early-stage LC. Methods A priori inclusion criteria were as follows: (1) observational studies, (2) L compared to SL for early-stage LC, (3) radiographic staging by computed tomography scan, and (4) 5-year survival reported. A Medline search through January 2015 resulted in 31 studies representing 23 distinct datasets. The absolute difference in 5-year survival was calculated and plotted for each study. Results L was performed in 4564 patients and SL in 2287 patients. Of 19 studies reporting the reason for SL, 11 indicated that SL was performed because of comorbidities or impaired cardiopulmonary function. Four studies showed no difference in 5-year survival, 13 favored L, and six favored SL. One propensity score study favored L and the other favored SL. Of 20 studies reporting recurrence rate, 11 favored L and nine favored SL. Conclusions Studies comparing 5-year survival rates of SL to L are sufficiently heterogeneous to prevent carrying out traditional meta-analysis. SL survival is often similar to L when adjustments are made for age, comorbidities, or impaired cardiopulmonary function. New approaches are needed for the comparison of L to SL.

Previous studies have reported that higher C-reactive protein (CRP) levels are significantly associated with worse outcome in prostate cancer patients. The size of each individual study was not large enough to allow sufficient statistical power to draw conclusions. We conducted a pooled analysis of individual data of published studies to evaluate the association between increased CRP level and risk of death in prostate cancer, and to find the best CRP cutoff that could predict mortality.Original research studies on prostate cancer survival and CRP levels were identified (n = 6). Corresponding authors were contacted and invited to share individual data. Two data sets were received (235 patients). The combined hazard ratio (HR) was calculated and adjusted for age, prostate-specific antigen, hemoglobin, and alkaline phosphatase. The best cutoff of CRP was explored using X-title software version 3.6.1.High CRP level was statistically significantly associated with mortality (meta-HR, 1.83 [95% confidence interval (CI), 1.51-2.21]), without evidence of heterogeneity among studies. At pooled analysis, adjusted pooled HR for CRP 5 versus ≥ 5 mg/L was 1.44 (95% CI, 1.02-20.4). The best CRP cutoff was 12 mg/L: the adjusted HRpooled for CRP 12 versus ≥ 12 mg/L was 1.53 (95% CI, 1.01-2.32).Increased CRP levels are associated with overall survival in prostate cancer patients. Because CRP is an affordable and readily available assay, it might hold promise in improving prognostication and potentially to predict the activity of specific therapeutic agents.

Background This comprehensive meta-analysis was conducted to answer the question as to which procedure, pleurectomy decortication (P/D) or extrapleural pneumonectomy (EPP) is more beneficial to malignant pleural mesothelioma patients' outcome. Methods Original research studies that evaluated long-term outcomes of P/D versus EPP were identified, from January 1990 to January 2014. The combined percent perioperative and 2-year mortality, and median survival were calculated according to both a fixed and a random effect model. The Q statistics and I 2 statistic were used to test for heterogeneity between the studies. Results There were 24 distinct data sets, for a total of 1,512 patients treated with P/D, and 1,391 treated with EPP. There was a significantly higher proportion of short-term deaths in the EPP group versus the P/D group (percent mortality meta estimate; 4.5% vs 1.7%; p Conclusions The reanalysis of the large number of studies comparing P/D to EPP suggests that P/D is associated with a 2 ½-fold lower short-term mortality (perioperatively and within 30 days) than EPP. Pleurectomy decortication should therefore be preferred when technically feasible.

BACKGROUND: A previous pilot study found that men with a positive prostate biopsy had low numbers of circulating natural killer (NK) cells, compared to biopsy negative men. METHODS: To confirm these data, we analyzed differences in NK cells from 94 men undergoing prostate biopsy to determine whether NK cells could predict for a positive biopsy. NK cells activity (NKA) was measured by an in vitro diagnostic system, with a pre-defined cut-off value for NKA at 200 pg/mL. Logistic regression and receiver operator characteristics (Area Under the Curve (AUC)) analyses were used to test the diagnostic value of NKA. RESULTS: The NKA test performance showed specificity of 88%, positive predictive value of 84%, sensitivity of 34%, and a negative predictive value of 41%. Among the 94 men analyzed, NKA was not significantly linked with age, race, digital rectal examination (DRE), prostate volume, PSA or biopsy grade group (all P ≥ 0.14). In multivariable logistic regression analysis, the odds ratio (OR) of low NKA (< 200 pg/mL) for the detection of PC was 4.89, 95%CI 1.34–17.8, with a ROC area under the curve of 0.79 in all participants and increasing to 0.83 and 0.85 for the detection of PC and high-grade PC, respectively, among men with a normal DRE. CONCLUSIONS: Men with a low NKA value had five-times higher odds of PC at biopsy. The implementation of this NKA assay in the clinic together with PSA may help to advise patients with the highest risk of PC whether, or not, to undergo a prostate biopsy.

Men are much more likely than women to develop head and neck squamous cell carcinoma (HNSCC), a discrepancy that is insufficiently explained by gender differences in smoking and alcohol consumption. It has been hypothesized that differential hormonal exposures may account for some of this risk but thus far the literature on female reproductive factors and HNSCC risk has been sparse. To address the association of HNSCC with female hormonal and reproductive factors, a case-control study was conducted on 149 women with head and neck cancer and 158 controls. After adjusting for potential confounding, postmenopausal women using female hormones for more than 5 years showed a borderline protective effect for HNSCC (adjusted OR = 0.47, 95% CI: 0.20-1.08), with a borderline trend across duration of use categories (P = 0.06). There was no association of HNSCC with age at menarche, hysterectomy/oophorectomy status, oral contraceptive use, history of fertility medication, or number of pregnancies, parity, or age at first pregnancy or live birth. The findings of this study do not support a link between HNSCC and reproductive factors, although the borderline association with HRT warrants further investigation.

Genetic polymorphisms described for a number of enzymes involved in the metabolism of tobacco carcinogens and alcohol have been linked to increase cancer risk. Racial disparities in cancer between whites and populations of African descent are well documented. In addition to differences in access to health care, both environment and genetic factors and their interaction may contribute to the increased cancer risk in minority populations. We reviewed the literature to identify case-control studies that included subjects of African descent. Meta-analyses investigating the association of genetic polymorphisms in tobacco metabolic genes and cancer were performed. Although several genes and cancers have been studied, only one or two studies per gene for each cancer site have been published, with the exception of breast (CYP1A1 and CYP1B1), lung (GSTM1, CYP1A1, and NQO1), and prostate (CYP3A4 A293G and CYP17). Marginal statistically significant associations were observed for CYP3A4 A293G and CYP17 5'UTR polymorphisms and prostate cancer. Our findings support the need for additional genetic association studies of breast, prostate, and lung cancers that include a larger number of minority participants. Because incidence and mortality rates for these cancers rank highest among populations of African descent, concentrated research in these areas are warranted.

Background Benzene is a ubiquitous toxic environmental pollutant. Biological effects have been detected as a result of low-level environmental exposures, suggesting that a large proportion of the population may potentially suffer ill health effects. Polymorphisms in genes involved in benzene metabolism are thought to influence individual susceptibility to various levels of benzene exposure. Methods Medline literature database search for articles relating to benzene exposure and polymorphisms in genes known to be involved in benzene metabolism (NQO1, CYP2E1, GSTT1, GSTM1 and MPO). Twenty-two reports were included in this review. Results A modest effect of the studied gene polymorphisms on the analyzed biomarkers was observed. GSTM1 and GSTT1 showed some consistent associations with both biomarkers of exposure and effect. Conclusion Genetic polymorphisms on the benzene metabolism pathway should be taken into account when studying the biological effects of benzene exposure. Unique combinations of genetic polymorphisms may increase susceptibility of individuals and/or population subgroups. However, gene–gene interactions, and the biological effects of long-term and low-level exposure to benzene are not yet analyzed with well-designed studies that incorporate multiple biological end-points and multiple genes.

Polycyclic aromatic hydrocarbons (PAHs) appear to be significant contributors to the genotoxicity and carcinogenicity of air pollution present in the urban environment for humans. Populations exposed to environmental air pollution show increased levels of PAH DNA adducts and it has been postulated that another contributing cause of carcinogenicity by environmental air pollution may be the production of reactive oxygen species following oxidative stress leading to oxidative DNA damage. The antioxidant status as well as the genetic profile of an individual should in theory govern the amount of protection afforded against the deleterious effects associated with exposure to environmental air pollution. In this study we investigated the formation of total PAH (bulky) and B[a]P DNA adducts following exposure of individuals to environmental air pollution in three metropolitan cities and the effect on endogenously derived oxidative DNA damage. Furthermore, the influence of antioxidant status (vitamin levels) and genetic susceptibility of individuals with regard to DNA damage was also investigated. There was no significant correlation for individuals between the levels of vitamin A, vitamin E, vitamin C and folate with M(1)dG and 8-oxodG adducts as well as M(1)dG adducts with total PAH (bulky) or B[a]P DNA adducts. The interesting finding from this study was the significant negative correlation between the level of 8-oxodG adducts and the level of total PAH (bulky) and B[a]P DNA adducts implying that the repair of oxidative DNA damage may be enhanced. This correlation was most significant for those individuals that were non smokers or those unexposed to environmental air pollution. Furthermore the significant inverse correlation between 8-oxodG and B[a]P DNA adducts was confined to individuals carrying the wild type genotype for both the GSTM1 and the GSTT1 gene (separately and interacting). This effect was not observed for individuals carrying the null variant.

Modification of DNA is believed to be a key step in carcinogenesis, and therefore DNA adducts have been proposed as predictive biomarkers of human cancer. Smoked and grilled foods are important contributors of PAH-DNA adduct levels, while the consumption of flavonoids and other antioxidants seems to decrease the level of DNA adducts. The aim of this study was to assess the effect of each group of foods and of different dietary profiles on the DNA adducts levels and on oxidative damage to DNA. Occupationally exposed men were recruited in Czech Republic, Slovak Republic and Bulgaria. Non-occupationally exposed subjects were matched on age and gender to PAH-exposed workers. Three hundred and fifty-six subjects who completed the questionnaire for dietary information and had a measurement of DNA adduct levels and oxidative damage to DNA were included in this study. No food item seemed to be individually associated with markers of exposure or DNA damage. Total DNA adducts levels were significantly higher for subjects who had eaten, in the previous 24 h, smoked or fried food. A Principal Components Analysis was performed to identify groups of subjects with similar dietary profiles: no significant differences in biomarker levels were observed among the groups defined according to dietary profiles. In conclusion, this study did not show any significant association between diet and biomarkers of DNA damage, oxidative damage to DNA and chromosomal aberrations, neither when each food was considered separately, nor when the effect of different dietary profiles was tested. The recent consumption of smoked or fried food was associated with an increase in total DNA adducts levels.

Data from the EXPAH project on PAH exposure and intermediary biomarkers were analyzed with respect to individual genotypes at seven metabolic gene loci. The GSTM1 null allele was associated with significantly higher levels of two biomarkers, malondialdehyde-2′-deoxyguanosine and benzo[a]pyrene DNA adducts in the total population from three Central and Eastern European countries. The CYP1B1 Leu/Val variant demonstrated effects on both markers of oxidative DNA damage in opposite directions, producing a higher level of M1dG with a trend from wild type (Leu/Leu) to heterozygotes to homozygous (Val/Val) variants, whereas the effects of these variants were reversed for 8-oxodG. Cluster Analysis was used to group composite genotypes in order to determine if combined genotypes of multiple loci could explain some of the variation seen with the biomarkers, expressed per unit of exposure, referred to as a sensitivity index. This analysis revealed two closely related genotypes each involving four of the loci (GSTM1*0/*0, CYP1A1*1*1, CYP1B1*1/*2, GSTP1*1/*1 and GSTT1*0/*0, CYP1A1*1*1, CYP1B1*1/*2, GSTP1*1/*1.) that conferred significant resistance to the DNA damaging effects of benzo[a]pyrene, measured as the level of a benzo[a]pyrene-like adduct per unit of benzo[a]pyrene exposed.

Myeloperoxidase is a phase I metabolic enzyme that converts the metabolites of benzo[a]pyrene from tobacco smoke into highly reactive epoxides. A polymorphism in the promoter region of myeloperoxidase (463G-->A) has been found to be inversely associated with lung cancer; differences in the association with age and gender have been suggested. We conducted a pooled analysis of individual data from 10 studies (3688 cases and 3874 controls) from the Genetic Susceptibility to Environmental Carcinogens database. The odds ratio for lung cancer was 0.88 (95% confidence interval: 0.80-0.97) for the AG variant of myeloperoxidase G-463A polymorphism, and 0.71 (95% confidence interval: 0.57-0.88) for the AA variant after adjusting for smoking, age, gender, and ethnicity. The inverse association between lung cancer and myeloperoxidase G-463A polymorphism was equally found in males and females (odds ratio for the AA genotype 0.73 [95% confidence interval: 0.56-0.96] and 0.67 [95% confidence interval: 0.46-0.98], respectively), without differences in the association according to age in the two genders. The myeloperoxidase G-463A polymorphism was significantly protective in "ever" smokers but not in "never" smokers. Myeloperoxidase is a key enzyme in tobacco-induced carcinogenesis.

Tobacco smoking is a major risk factor for lung cancer causing, among other effects, oxidative stress and lipid peroxidation. Malondialdehyde (MDA)–DNA adducts can be induced by direct DNA oxidation and by lipid peroxidation. We measured the relationship between bronchial MDA–DNA adducts and tobacco smoking, cancer status, and selected polymorphisms in 43 subjects undergoing a bronchoscopic examination for diagnostic purposes. MDA–DNA adducts were higher in current smokers than in never smokers (frequency ratio (FR) = 1.51, 95% confidence interval (CI) 1.01–2.26). MDA–DNA adducts were also increased in lung cancer cases with respect to controls, but only in smokers (FR = 1.70, 95% CI 1.16–2.51). Subjects with GA and AA cyclin D1 (CCND1) genotypes showed higher levels of MDA–DNA adducts than those with the wild-type genotype (FR = 1.51 (1.04–2.20) and 1.45 (1.02–2.07)). Lung cancer cases with levels of MDA–DNA adducts over the median showed a worse, but not statistically significant, survival, after adjusting for age, gender, and packyears (hazard ratio = 2.48, 95% CI 0.65–9.44). Our findings reinforce the role of smoking in lung carcinogenesis through oxidative stress. Subjects who carry at least one variant allele of the CCND1 gene could accumulate DNA damage for altered cell-cycle control and reduced DNA repair proficiency.

Background Since genetic factors may play an important role in lung cancer development at low dose carcinogen exposure, non-smokers are a good model to study genetic susceptibility and its interaction with environmental factors. Materials and methods We evaluated the role of the metabolic gene polymorphisms CYP1A1MspI, CYP1A1Ile462Val, GSTM1, and GSTT1 in non-smoker lung cancer patients from the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens (GSEC). Non-smokers (defined as subjects who never smoked on a regular basis) were selected from the GSEC database. We pooled the raw data from 21 case-control studies for a total of 2764 Caucasians (555 cases and 2209 controls) and 383 Asians (113 cases and 270 controls). Tests of heterogeneity and of inclusion bias were performed. Results A significant association between lung cancer and CYP1A1Ile462Val polymorphism was observed in Caucasians (adjusted OR = 2.04, 95% CI 1.17–3.54). GSTT1 deletion seems to be a risk factor for lung cancer in Caucasian non smokers only when the analysis was restricted to studies including healthy controls (adjusted OR = 1.66, 95% CI 1.12–2.46). A protective effect on lung cancer was observed with the combination of CYP1A1 wild type, GSTM1 null, and GSTT1 non-null genotypes. None of the analysed polymorphisms were associated with lung cancer in Asian non-smokers. Discussion Our analysis confirms previous findings that CYP1A1Ile462Val polymorphism may play a role in lung carcinogenesis in Caucasian non-smokers.

DNA adducts measured in tissues are promising markers for identifying damage in organs that could be a target for carcinogens. Polymorphisms in genes involved in polycyclic aromatic hydrocarbons (PAHs) metabolism have been shown to modify the levels of PAH-DNA adducts in target tissues. In order to study the role of metabolic gene polymorphisms on DNA-adduct formation in sperm, we determined the GSTM1 genotype in a group of men in whom PAH-DNA adducts in sperm had been previously measured by immunofluorescence. The mean level of adducts in sperm was significantly higher in subjects carrying the homozygous deletion variant of GSTM1 than in subjects with a functional GSTM1 (mean fluorescence staining intensity: 1.62+/-0.62 versus 1.33+/-0.55; p=0.02). With respect to environmental factors, subjects who reported occupational exposure to PAHs and who carried the GSTM1 deletion had a significant increase in PAH-DNA adducts in sperm in comparison with subjects who were not exposed and had a functional GSTM1 (mean staining intensity: 1.83+/-0.67 versus 1.30+/-0.53; p=0.05), although among GSTM1-null subjects there was no significant difference with or without occupational exposure. This study presents for the first time the effect of a common polymorphism in a gene that metabolizes PAHs on DNA-adduct levels in sperm.

Biomarkers of benzene exposure and effect were evaluated in 158 Bulgarian petrochemical workers and 50 matched controls. Air exposures to benzene averaged about 1.8 ppm, for workers and 0.02 ppm for controls. Urinary trans,trans-muconic acid, and S-phenylmuconic acid, showed dose response relationships with benzene air exposure. The dose response curve for DNA single strand breaks (SSB), but not for the metabolites, showed a saturation effect. NQO1 genotype had a significant effect on SSB. We conclude that the pathways for these metabolites may be distinct from those involved in some forms of genotoxic damage induced by benzene.

Primary vesicoureteral reflux (VUR), one of the principal causes of chronic renal failure (CRF), occurs as a result of two distinct and sex-related mechanisms: congenital renal hypoplasia, which is prevalent in males, and acquired renal scarring in females. We used data from the ItalKid Project, a prospective population-based CRF registry of patients undergoing conservative treatment, to evaluate the gender distribution and severity of primary VUR, the age at diagnosis, and the diagnostic and therapeutic methods adopted in children with CRF. The prevalence of males (77.5%), the severity of VUR (grade IV-V), and the early age at diagnosis (18% prenatally) seem to suggest that congenital renal damage is the major cause of pediatric CRF.

Exposure to high levels of environmental air pollution is known to be associated with an increased carcinogenic risk. The individual contribution to this risk derived from specific carcinogenic chemicals within the complex mixture of air pollution is less certain, but may be explored by the use of molecular epidemiological techniques. Measurements of biomarkers of exposure, of effect and of susceptibility provide information of potential benefit for epidemiological and cancer risk assessment. The application of such techniques has been mostly concerned in the past with the carcinogenic polycyclic aromatic hydrocarbons (c-PAHs) that are associated with particulate matter in air pollution, and has showed clear evidence of genotoxic effects, such as DNA adducts, chromosome aberrations (CA) and ras oncogene overexpression, in environmentally exposed Czech and Polish populations. We are currently extending these studies by an investigation of populations exposed to environmental pollution in three European countries, Czech Republic, Slovak Republic and Bulgaria. This pays particular attention to PAHs, but also investigates the extent of radically induced (oxidative) DNA damage in the exposed populations. Policemen, bus drivers and controls, who carried personal monitors to determine their exposures to PAHs have been studied, and blood and urine were collected. Antioxidant and dietary status were assessed in these populations. Stationary monitors were also used for ambient air monitoring. Amongst the parameters studied in the biological samples were: (a) exposure biomarkers, such

Background. Insulin resistance is a key feature of nonalcoholic fatty liver disease. Patients with hereditary hemochromatosis, a disease characterized by progressive iron overload due, in most cases, to homozygosity for C282Y mutation in the HFE gene, have often decreased insulin sensitivity and release. Aims. To determine whether increased iron parameters/heterozygosity for the mutations of the HFE gene confer susceptibility to nonalcoholic fatty liver disease. Patients. One hundred and thirty-four consecutive Italian patients with clinical and ultrasonographic diagnosis of nonalcoholic fatty liver disease (82 with hyperferritinemia), half confirmed by liver biopsy. Methods. Insulin was determined by radioimmunoassay. HFE gene mutations were determined by polymerase chain reaction and restriction fragment length polymorphism analysis. Results. (1) Prevalence of C282Y HFE mutation was significantly higher in patients with nonalcoholic fatty liver disease compared to controls, the difference being more striking in patients with hyperferritinemia than in those without. (2) The presence of mild iron overload was associated with a lower insulin release. (3) Carriers of C282Y mutation developed nonalcoholic fatty liver disease despite lower body mass index and triglycerides. Conclusion. The mild iron overload associated with heterozygosity for C282Y HFE mutation confers susceptibility to nonalcoholic fatty liver disease, causing relative insulin deficiency.