Real-world study of patients with locally advanced HNSCC in the community oncology setting.

Introduction: There is a need to understand the current treatment landscape for LA HNSCC in the real-world setting. Methods: This retrospective study assessed real-world outcomes and treatment patterns of 1,158 adult patients diagnosed with locally advanced (stage III-IVB) HNSCC initiating chemoradiotherapy (CRT) within the period January 2015 to December 2017 in a large network of US community oncology practices. Structured data were abstracted from electronic health records. Demographic, clinical and treatment characteristics were analyzed descriptively overall and stratified by index treatment (cisplatin + radiotherapy [RT], cisplatin + other chemotherapy + RT, or cetuximab + RT). Time to next treatment (TTNT) and overall survival (OS) were measured using the Kaplan-Meier method, and median duration of treatment was assessed. OS was compared across treatment cohorts using multinomial logistic regression with inverse probability treatment weighting. To identify covariates associated with OS, a multivariable adjusted Cox proportional hazard model was used. Results: This study examined 22,782 records, of which 2124 had stage III to stage IVB and no other cancers, and 1158 met all eligibility criteria. Among the treatment cohorts analyzed (cisplatin + RT, cisplatin + other chemotherapy + RT, or cetuximab + RT), cisplatin + RT was the most common concurrent chemotherapy (65.8%). Among 1158 patients, 838 (72.4%) did not initiate subsequent treatment and 139 (12.0%) died. The median TTNT and median OS were only reached by the cetuximab + RT cohort. Among patients with oropharynx primary tumor location, patients with human papilloma virus (HPV) positive status had the longest time on treatment and highest survival at 60 months. Covariates associated with improved survival were never/former tobacco use, HPV positive status, and overweight or obese body mass index. Covariates associated with poorer survival were age of 60+ years, primary tumor location of hypopharynx or oral cavity and Eastern Cooperative Oncology Group performance status score of 2+. Conclusion: These data describe real-world treatment patterns in locally advanced head and neck squamous cell cancer and sets the baseline to assess outcomes for future studies on the community oncology population.

An interdisciplinary framework for derivation of occupational exposure limits.

Protecting the health and safety of workers in industrial operations is a top priority. One of the resources used in industry to ensure worker safety is the occupational exposure limit (OEL). OELs are derived from the assessment and interpretation of empirical data from animal and/or human studies. There are various guidelines for the derivation and implementation of OELs globally, with a range of stakeholders (including regulatory bodies, governmental agencies, expert groups and others). The purpose of this manuscript is to supplement existing guidance with learnings from a multidisciplinary team approach within an industry setting. The framework we present is similar in construct to other risk assessment frameworks and includes: (1) problem formulation, (2) literature review, (3) weight of evidence considerations, (4) point of departure selection/derivation, (5) application of assessment factors, and the final step, (6) derivation of the OEL. Within each step are descriptions and examples to consider when incorporating data from various disciplines such as toxicology, epidemiology, and exposure science. This manuscript describes a technical framework by which available data relevant for occupational exposures is compiled, analyzed, and utilized to inform safety threshold derivation applicable to OELs.

Mortality of 196,826 Men and Women Working in U.S.-Based Petrochemical and Refinery Operations: Update 1979 to 2010.

OBJECTIVE: To describe mortality trends of men and women working in various petrochemical and refinery operations of a U.S.-based company. METHODS: The cohort consists of full-time employees with at least 1 day of service during 1979 through 2010. Standardized mortality ratios (SMRs) and 95% confidence intervals (CIs) were calculated for 111 possible causes of death studied. RESULTS: SMRs for malignant mesothelioma and asbestosis were highest for the 1940s decade of hire. Increased SMRs were observed for malignant melanoma and motor neuron disease with no obvious work patterns. Decreasing mortality patterns were observed for aplastic anemia and acute nonlymphocytic leukemia. CONCLUSIONS: Mortality surveillance of this large established cohort aids in assessing the chronic health status of the workforce. Identifying methods for incorporating job-exposure matrices and nonoccupational risk factors could further enhance interpretations for some findings such as motor neuron disease.

Tumour size and overall survival among surgically treated patients with non-metastatic colon cancer in the U.S. Military Health System.

AIM: Larger tumour size and lymph node involvement traditionally predict poorer survival in colon cancer patients. However, it has been recently suggested that very small tumours (<5 mm) may be a predictor of poor prognosis in colon cancer patients when lymph nodes are involved. This study investigated whether node-positive colon cancer patients with small tumours had worse survival compared to those with larger tumours in the Department of Defense's (DoD) Military Health System (MHS), a universal health care system. METHODS: Surgically treated colon cancer patients were identified from the DoD's Automated Central Tumour Registry (ACTUR). These patients were diagnosed with Stage I-III colon cancer between 1989 and 2010, had one or more lymph nodes examined, did not receive pre-operative radiotherapy and were followed through 2013 to determine vital status. Multivariable Cox models were used to examine survival differences according to tumour size, and data were stratified by lymph node status and age. RESULTS: There were no differences in overall survival according to tumour size in the study population. These findings remained similar in analyses stratified by lymph node status and age. CONCLUSION: In a universal healthcare system, small tumour size is not associated with worse prognosis in node-positive colon cancer patients.

Age and Lymph Node Positivity in Patients With Colon and Rectal Cancer in the US Military Health System.

BACKGROUND: Young age may be associated with an increased risk of lymph node involvement at diagnosis of colorectal cancer. Accessibility to care, which is related to cancer detection, tumor stage, and therefore lymph node positivity, may vary by age and thus influence research results. OBJECTIVE: The purpose of this study was to investigate whether young patients had an increased risk of lymph node-positive colon and rectal cancers in the Department of Defense Military Health System, which provides universal health care to its beneficiaries. DESIGN: This was a retrospective, cross-sectional study. SETTINGS: Patients were identified from the US Department of Defense Automated Central Tumor Registry. PATIENTS: Included patients were diagnosed with histologically confirmed primary stage I to III colon and rectal adenocarcinomas between 1989 and 2013, had surgery and ≥1 lymph node examined, and did not receive preoperative radiotherapy. Logistic regression was used to examine the relationships between age at diagnosis (18-49, 50-59, 60-69, and ≥70 y) and lymph node positivity overall and stratified by tumor T stage and number of lymph nodes examined. MAIN OUTCOME MEASURES: Lymph node positivity of colon and rectal cancers was measured. RESULTS: The youngest patients (aged 18-49 y) were more likely to have lymph node-positive colon and rectal cancers compared with those who were aged ≥70 years after adjustment for potential confounders (OR = 2.04 and 95% CI, 1.63-2.56 for colon cancer; OR = 1.73 and 95% CI, 1.11-2.70 for rectal cancer). A similar tendency was shown in most colon and rectal cancer subgroups stratified by tumor T stage and number of lymph nodes examined. LIMITATIONS: This study was limited by its small sample size for certain subgroup analyses. No information on comorbidities, BMI, or other indicators of health status was available. CONCLUSIONS: In a universal healthcare system, young age was associated with increased lymph node positivity of colon and rectal cancers, suggesting that factors other than access to care may play a role in this association. See Video Abstract at http://links.lww.com/DCR/B90. EDAD Y POSITIVIDAD DE GANGLIOS LINFÁTICOS EN PACIENTES CON CÁNCER DEL COLON Y EL RECTO EN EL SISTEMA DE SALUD MILITAR DE EE UU: La edad temprana puede estar asociada con un mayor riesgo de compromiso de los ganglios linfáticos en el momento del diagnóstico de cáncer colorrectal. La accesibilidad a la atención medica, que está relacionada con la detección del cáncer, el estadio del tumor y, por lo tanto, la positividad de los ganglios linfáticos, puede variar según la edad y, por lo tanto, influir en los resultados de la investigación.Investigar si los pacientes jóvenes tenían un mayor riesgo de cáncer del colon y el recto con ganglios linfáticos positivos en el Sistema de Salud Militar del Departamento de Defensa, que brinda atención médica universal a sus beneficiarios.Estudio transversal retrospectivo.Se identificaron pacientes del Registro Automático Central de Tumores del Departamento de Defensa de los Estados Unidos.Fueron diagnosticados con adenocarcinomas del colon y el recto en estadio I-III confirmados histológicamente entre 1989-2013, se les realizó una cirugía y se examinaron ≥ 1 ganglio linfático, y no recibieron radioterapia preoperatoria. La regresión logística se utilizó para examinar las relaciones entre la edad al momento del diagnóstico (18-49, 50-59, 60-69 y ≥70 años) y la positividad de los ganglios linfáticos en general y fue estratificada por el estadio T tumoral y el número de ganglios linfáticos examinados.Positividad de ganglios linfáticos de cáncer del colon y el recto.Los pacientes más jóvenes (18-49 años) tenían más probabilidades de tener cáncer del colon y el recto con ganglios linfáticos positivos en comparación con aquellos que tenían 70 años o más después del ajuste por posibles factores de confusión (odds ratio: 2.04, intervalo de confianza del 95%: 1.63 -2.56 para el cáncer de colon; odds ratio: 1.73, intervalo de confianza del 95%: 1.11-2.70 para el cáncer de recto). Se mostró una tendencia similar en la mayoría de los subgrupos de cáncer del colon y el recto estratificados por el estadio T tumoral y el número de ganglios linfáticos examinados.Tamaño de muestra pequeño para ciertos análisis de subgrupos. No hay información sobre comorbilidades, índice de masa corporal u otros indicadores del estado de salud.En un sistema de salud universal, la edad joven se asoció con un aumento de la positividad de los ganglios linfáticos del cáncer del colon y el recto, lo que sugiere que otros factores además del acceso a la atención medica pueden desempeñar un papel en esta asociación. Consulte Video Resumen en http://links.lww.com/DCR/B90.

Race and overall survival in men diagnosed with prostate cancer in the Department of Defense Military Health System, 1990-2010.

BACKGROUND: In the U.S. general population, black men experience poorer survival after prostate cancer (CaP) diagnosis compared to white men, and findings may be impacted by unequal access to healthcare. The objective of the study is to investigate racial differences in overall survival (OS) among Department of Defense beneficiaries diagnosed with CaP. METHODS: A retrospective cohort study was conducted utilizing the Automated Central Tumor Registry within the Military Healthcare System, a system designed to provide equal access. Men diagnosed with primary prostate adenocarcinomas between 1990 and 2010 [n = 18,484; 24% Non-Hispanic black (NHB), 76% Non-Hispanic white (NHW)] were followed through 2013 for vital status. Unadjusted Kaplan-Meier estimation curves and multivariable Cox proportional hazards (PH) regression models were used to examine racial differences in OS. RESULTS: Age-specific Kaplan-Meier analyses showed equivalent OS for NHW and NHB men in all age groups, except for 75+, where NHB had poorer OS (p = 0.0048). Multivariable Cox PH models revealed no significant differences in OS for race (HR 1.02; 95% CI 0.95-1.08), except in men aged ≥ 75 years, where NHB men had poorer OS (HR 1.27; 95% CI 1.08-1.49). CONCLUSIONS: Findings suggest that in a healthcare system designed for equal access, disparities in OS among men diagnosed with CaP may not exist.

The deepwater horizon oil spill coast guard cohort study: A cross-sectional study of acute respiratory health symptoms.

INTRODUCTION: Over 8500 United States Coast Guard (USCG) personnel were deployed in response to the Deepwater Horizon (DWH) oil spill; however, human respiratory effects as a result of spill-related exposures are relatively unknown. METHODS: USCG personnel who responded to the DWH oil spill were queried via survey on exposures to crude oil and oil dispersant, and acute respiratory symptoms experienced during deployment. Adjusted log binomial regressions were used to calculate prevalence ratios (PRs) and 95% confidence intervals (CI), investigating the associations between oil spill exposures and respiratory symptoms. RESULTS: 4855 USCG personnel completed the survey. More than half (54.6%) and almost one-fourth (22.0%) of responders were exposed to crude oil and oil dispersants, respectively. Coughing was the most prevalent symptom (19.4%), followed by shortness of breath (5.5%), and wheezing (3.6%). Adjusted analyses showed an exposure-response relationship between increasing deployment duration and likelihood of coughing, shortness of breath, and wheezing in the pre-capping period. A similar pattern was observed in the post-capping period for coughing and wheezing. Adjusted analyses revealed increased PRs for coughing (PR=1.92), shortness of breath (PR=2.60), and wheezing (PR=2.68) for any oil exposure. Increasing frequency of inhalation of oil was associated with increased likelihood of all three respiratory symptoms. A similar pattern was observed for contact with oil dispersants for coughing and shortness of breath. The combination of both oil and oil dispersants presented associations that were much greater in magnitude than oil alone for coughing (PR=2.72), shortness of breath (PR=4.65), and wheezing (PR=5.06). CONCLUSIONS: Results from the present study suggested strong relationships between oil and oil dispersant exposures and acute respiratory symptoms among disaster responders. Future prospective studies will be needed to confirm these findings.

The Deepwater Horizon Oil Spill Coast Guard Cohort study.

OBJECTIVES: Long-term studies of oil spill responders are urgently needed as oil spills continue to occur. To this end, we established the prospective Deepwater Horizon (DWH) Oil Spill Coast Guard Cohort study. METHODS: DWH oil spill responders (n=8696) and non-responders (n=44 823) who were members of the US Coast Guard (20 April-17 December 2010) were included. This cohort uses both prospective, objective health data from military medical encounters and cross-sectional survey data. Here, we describe the cohort, present adjusted prevalence ratios (PRs) estimating cross-sectional associations between crude oil exposure (none, low/medium, high) and acute physical symptoms, and present adjusted relative risks (RRs) based on longitudinal medical encounter data (2010-2012) for responders/non-responders and responders exposed/not exposed to crude oil. RESULTS: Responders and non-responders in this large cohort (n=53 519) have similar characteristics. Crude oil exposure was reported by >50% of responders. We found statistically significant associations for crude oil exposure with coughing (PRhigh=1.78), shortness of breath (PRhigh=2.30), wheezing (PRhigh=2.32), headaches (PRhigh=1.46), light-headedness/dizziness (PRhigh=1.96), skin rash/itching (PRhigh=1.87), diarrhoea (PRhigh=1.76), stomach pain (PRhigh=1.67), nausea/vomiting (PRhigh=1.48) and painful/burning urination (PRhigh=2.89) during deployment. Longitudinal analyses revealed that responders had elevated RRs for dermal conditions (RR=1.09), as did oil-exposed responders for chronic respiratory conditions (RR=1.32), asthma (RR=1.83) and dermal conditions (RR=1.21). CONCLUSIONS: We found positive associations between crude oil exposure and various acute physical symptoms among responders, as well as longer term health effects. This cohort is well positioned to evaluate both short-term and long-term effects of oil spill exposures using both self-reported and clinical health data.

Mortality among Coast Guard Shipyard workers: A retrospective cohort study of specific exposures.

In a previous analysis of a cohort of shipyard workers, we found excess mortality from all causes, lung cancer, and mesothelioma for longer work durations and in specific occupations. Here, we expand the previous analyses by evaluating mortality associated with 5 chemical exposures: asbestos, solvents, lead, oils/greases, and wood dust. Data were gathered retrospectively for 4,702 workers employed at the Coast Guard Shipyard, Baltimore, MD (1950-1964). The cohort was traced through 2001 for vital status. Associations between mortality and these 5 exposures were calculated via standardized mortality ratios (SMRs). We found all 5 substances to be independently associated with mortality from mesothelioma, cancer of the respiratory system, and lung cancer. Findings from efforts to evaluate solvents, lead, oils/greases, and wood dust in isolation of asbestos suggested that the excesses from these other exposures may be due to residual confounding from asbestos exposure.

Pesticide use and LINE-1 methylation among male private pesticide applicators in the Agricultural Health Study.

Cancer risk may be associated with DNA methylation (DNAm) levels in Long Interspersed Nucleotide Element 1 (LINE-1), a surrogate for global DNAm. Exposure to certain pesticides may increase risk of particular cancers, perhaps mediated in part through global DNAm alterations. To date, human data on pesticide exposure and global DNAm alterations are limited. The goal of this study was to evaluate alterations of LINE-1 DNAm by pesticides in a variety of classes. Data from 596 cancer-free male participants enrolled in the Agricultural Health Study (AHS) were used to examine associations between use of 57 pesticides and LINE-1 DNAm measured via Pyrosequencing in peripheral blood leucocytes. Participants provided information on pesticide use at three contacts between 1993 and 2010. Associations of ever/never pesticide use and lifetime days of application (years of use × days per year) and LINE-1 DNAm level were assessed using linear regression, adjusting for potential confounders (race, age at blood draw, and frequency of drinking alcohol) and other moderately correlated pesticides. After adjustment, ever application of 10 pesticides was positively associated and ever application of eight pesticides was negatively associated with LINE-1 DNAm. In dose-response analyses, increases in five pesticides (imazethapyr, fenthion, EPTC, butylate, and heptachlor) were associated with increasing LINE-1 DNAm (ptrend < 0.05) and increases in three pesticides (carbaryl, chlordane, and paraquat) were associated with decreasing LINE-1 DNAm (ptrend < 0.05). This study provides some mechanistic insight into the pesticide-cancer relationship, which may be mediated in part by epigenetics.

High pesticide exposure events and DNA methylation among pesticide applicators in the agricultural health study.

Pesticide exposure has been associated with acute and chronic adverse health effects. DNA methylation (DNAm) may mediate these effects. We evaluated the association between experiencing unusually high pesticide exposure events (HPEEs) and DNAm among pesticide applicators in the Agricultural Health Study (AHS), a prospective study of applicators from Iowa and North Carolina. DNA was extracted from whole blood from male AHS pesticide applicators (n = 695). Questionnaire data were used to ascertain the occurrence of HPEEs over the participant's lifetime. Pyrosequencing was used to quantify DNAm in CDH1, GSTp1, and MGMT promoters, and in the repetitive element, LINE-1. Linear and robust regression analyses evaluated adjusted associations between HPEE and DNAm. Ever having an HPEE (n = 142; 24%) was associated with elevated DNAm in the GSTp1 promoter at CpG7 (chr11:67,351,134; P < 0.01) and for the mean across the CpGs measured in the GSTp1 promoter (P < 0.01). In stratified analyses, elevated GSTP1 promoter DNAm associated with HPEE was more pronounced among applicators >59 years and those with plasma folate levels ≤16.56 ng/mL (p-interaction <0.01); HPEE was associated with reduced MGMT promoter DNAm at CpG2 (chr10:131,265,803; P = 0.03), CpG3 (chr10:131,265,810; P = 0.05), and the mean across CpGs measured in the MGMT promoter (P = 0.03) among applicators >59 years and reduced LINE-1 DNAm (P = 0.05) among applicators with ≤16.56 ng/mL plasma folate. Non-specific HPEEs may contribute to increased DNAm in GSTp1, and in some groups, reduced DNAm in MGMT and LINE-1. The impacts of these alterations on disease development are unclear, but elevated GSTp1 promoter DNAm and subsequent gene inactivation has been consistently associated with prostate cancer. Environ. Mol. Mutagen. 58:19-29, 2017. © 2016 Wiley Periodicals, Inc.

The National Veteran Sleep Disorder Study: Descriptive Epidemiology and Secular Trends, 2000-2010.

STUDY OBJECTIVES: A large proportion of individuals affected by sleep disorders are untreated and susceptible to accidents, injuries, long-term sequelae (e.g., risk of cardiovascular disease, cancer, psychiatric disorders), and increased mortality risk. Few studies have examined the scope and magnitude of sleep disorder diagnoses in the United States (US) or factors influencing them. Veterans are particularly vulnerable to factors that elicit or exacerbate sleep disorders. METHODS: This serial cross-sectional study characterized secular trends in diagnosed sleep disorders among veterans seeking care in US Veterans Health Administration facilities over an eleven-year span (FY2000-2010, n = 9,786,778). Electronic medical records from the national Veterans Administration Informatics and Computing Infrastructure database were accessed. Cases were defined using diagnostic codes specified by the American Academy of Sleep Medicine. Age-adjusted annual prevalence was summarized by sex, race, combat exposure, body mass index, and comorbid diagnoses (cardiovascular disease, cancer, mental disorders). RESULTS: Sleep apnea (47%) and insomnia (26%) were the most common diagnoses among patients with any sleep disorder. There was a six-fold relative increase in total sleep disorder prevalence over the study period. Posttraumatic stress disorder, which tripled over the same time period, was associated with the highest prevalence of sleep disorders (16%) among the comorbid conditions evaluated. CONCLUSIONS: The results indicate a growing need for integration of sleep disorder management with patient care and health care planning among US veterans. COMMENTARY: A commentary on this article appears in this issue on page 1331.

Case-control study of the PERIOD3 clock gene length polymorphism and colorectal adenoma formation.

Clock genes are expressed in a self-perpetuating, circadian pattern in virtually every tissue including the human gastrointestinal tract. They coordinate cellular processes critical for tumor development, including cell proliferation, DNA damage response and apoptosis. Circadian rhythm disturbances have been associated with an increased risk for colon cancer and other cancers. This mechanism has not been elucidated, yet may involve dysregulation of the 'period' (PER) clock genes, which have tumor suppressor properties. A variable number tandem repeat (VNTR) in the PERIOD3 (PER3) gene has been associated with sleep disorders, differences in diurnal hormone secretion, and increased premenopausal breast cancer risk. Susceptibility related to PER3 has not been examined in conjunction with adenomatous polyps. This exploratory case-control study was the first to test the hypothesis that the 5-repeat PER3 VNTR sequence is associated with increased odds of adenoma formation. Information on demographics, medical history, occupation and lifestyle was collected prior to colonoscopy. Cases (n=49) were individuals with at least one histopathologically confirmed adenoma. Controls (n=97) included patients with normal findings or hyperplastic polyps not requiring enhanced surveillance. Unconditional multiple logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs), after adjusting for potential confounding. Adenomas were detected in 34% of participants. Cases were more likely to possess the 5-repeat PER3 genotype relative to controls (4/5 OR, 2.1; 95% CI, 0.9-4.8; 5/5 OR, 5.1; 95% CI, 1.4-18.1; 4/5+5/5 OR, 2.5; 95% CI, 1.7-5.4). Examination of the Oncomine microarray database indicated lower PERIOD gene expression in adenomas relative to adjacent normal tissue. Results suggest a need for follow-up in a larger sample.

A healthy lifestyle index is associated with reduced risk of colorectal adenomatous polyps among non-users of non-steroidal anti-inflammatory drugs.

In a Columbia, South Carolina-based case-control study, we developed a healthy lifestyle index from five modifiable lifestyle factors (smoking, alcohol intake, physical activity, diet, and body mass index), and examined the association between this lifestyle index and the risk of colorectal adenomatous polyps (adenoma). Participants were recruited from a local endoscopy center and completed questionnaires related to lifestyle behaviors prior to colonoscopy. We scored responses on each of five lifestyle factors as unhealthy (0 point) or healthy (1 point) based on current evidence and recommendations. We added the five scores to produce a combined lifestyle index for each participant ranging from 0 (least healthy) to 5 (healthiest), which was dichotomized into unhealthy (0-2) and healthy (3-5) lifestyle scores. We used logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) for adenoma with adjustment for multiple covariates. We identified 47 adenoma cases and 91 controls. In the main analyses, there was a statistically nonsignificant inverse association between the dichotomous (OR 0.54; 95% CI 0.22, 1.29) and continuous (OR 0.75; 95% CI 0.51, 1.10) lifestyle index and adenoma. Odds of adenoma were significantly modified by the use of non-steroidal anti-inflammatory drugs (NSAIDs) (p(interaction) = 0.04). For participants who reported no use of NSAIDs, those in the healthy lifestyle category had a 72% lower odds of adenoma as compared to those in the unhealthy category (OR 0.28; 95% CI 0.08, 0.98), whereas a one-unit increase in the index significantly reduced odds of adenoma by 53% (OR 0.47; 95% CI 0.26, 0.88). Although these findings should be interpreted cautiously given our small sample size, our results suggest that higher scores from this index are associated with reduced odds of adenomas, especially in non-users of NSAIDs. Lifestyle interventions are required to test this approach as a strategy to prevent colorectal adenomatous polyps.

Effect of GSTM2-5 polymorphisms in relation to tobacco smoke exposures on lung function growth: a birth cohort study.

BACKGROUND: Genetic variation within GSTM2-5 genes may interfere with detoxification of environmental compounds, thereby having a detrimental effect on lung function following exposures such as tobacco smoke. We aim to investigate the influence of variants and associated methylation in the GSTM gene cluster with changes in lung function growth during adolescence. METHODS: Growth in forced expiratory volume (FEV1), forced vital capacity (FVC), and change in FEV1/FVC ratio measures were obtained from children in the Isle of Wight birth cohort at ages 10 and 18. Illumina GoldenGate assays were used to genotype 10 tagging polymorphisms from GSTM2 (rs574344 and rs12024479), GSTM3 (rs1537236, rs7483, and rs10735234), GSTM4 (rs668413, rs560018, and rs506008), and GSTM5 (rs929166 and rs11807) genes. Diplotypes were generated in the software Phase 3.0.2. DNA methylation was measured in over 450,000 CpG sites using the Infinium HumanMethylation450 BeadChip (Illumina 450K) in a subsample of 245 18-year olds from the Isle of Wight birth cohort. Gender, age, in utero smoke exposure, secondhand smoke exposure (SHS), and current smoking status were assessed via questionnaire; smoke exposures were validated with urine cotinine. We used linear mixed models to estimate the effect of GSTM diplotypes on lung function across time and examine interactions with tobacco smoke. RESULTS: 1,121 (77%) out of 1,456 children had information on lung function at ages 10 or 18. After adjustment for false discovery rate, one diplotype in GSTM3 had a detrimental effect on changes in FEV1 (p=0.03), and another diplotype in GSTM3 reduced FVC (p=0.02) over time. No significant interactions with smoking were identified. SHS significantly modified the relationship between diplotypes and methylation levels in one GSTM2 CpG site; however, this site did not predict lung function outcomes at age 18. Joint effects of GSTM loci and CpG sites located within these loci on adolescent lung growth were detected. CONCLUSIONS: Diplotypes within GSTM2-5 genes are associated with lung function growth across adolescence, but do not appear to modify the effect of tobacco smoke exposures on adolescent lung growth. Interactions between DNA methylation and diplotypes should be taken into account to gain further understanding on lung function in adolescence.