Epigenome-wide association study of lung cancer among never smokers in two prospective cohorts in Shanghai, China.

BACKGROUND: The aetiology of lung cancer among individuals who never smoked remains elusive, despite 15% of lung cancer cases in men and 53% in women worldwide being unrelated to smoking. Epigenetic alterations, particularly DNA methylation (DNAm) changes, have emerged as potential drivers. Yet, few prospective epigenome-wide association studies (EWAS), primarily focusing on peripheral blood DNAm with limited representation of never smokers, have been conducted. METHODS: We conducted a nested case-control study of 80 never-smoking incident lung cancer cases and 83 never-smoking controls within the Shanghai Women's Health Study and Shanghai Men's Health Study. DNAm was measured in prediagnostic oral rinse samples using Illumina MethylationEPIC array. Initially, we conducted an EWAS to identify differentially methylated positions (DMPs) associated with lung cancer in the discovery sample of 101 subjects. The top 50 DMPs were further evaluated in a replication sample of 62 subjects, and results were pooled using fixed-effect meta-analysis. RESULTS: Our study identified three DMPs significantly associated with lung cancer at the epigenome-wide significance level of p<8.22×10-8. These DMPs were identified as cg09198866 (MYH9; TXN2), cg01411366 (SLC9A10) and cg12787323. Furthermore, examination of the top 1000 DMPs indicated significant enrichment in epithelial regulatory regions and their involvement in small GTPase-mediated signal transduction pathways. Additionally, GrimAge acceleration was identified as a risk factor for lung cancer (OR=1.19 per year; 95% CI 1.06 to 1.34). CONCLUSIONS: While replication in a larger sample size is necessary, our findings suggest that DNAm patterns in prediagnostic oral rinse samples could provide novel insights into the underlying mechanisms of lung cancer in never smokers.

Exposure to fibres and risk of pleural mesothelioma in the Norwegian Offshore Petroleum Workers cohort.

OBJECTIVES: Pleural mesothelioma is a rare respiratory cancer, mainly caused by inhalation of asbestos fibres. Other inorganic fibres are also suggested risk factors. We aimed to investigate the association between exposure to asbestos or refractory ceramic fibres (RCFs) and pleural mesothelioma among male Norwegian offshore petroleum workers. METHODS: Among 25 347 men in the Norwegian Offshore Petroleum Workers (NOPW) cohort (1965-1998), 43 pleural mesothelioma cases were identified through the Cancer Registry of Norway (1999-2022). A case-cohort study was conducted with 2095 randomly drawn non-cases from the cohort. Asbestos and RCF exposures were assessed with expert-made job-exposure matrices (JEMs). Weighted Cox regression was used to estimate HRs and 95% CIs, adjusted for age at baseline and pre-offshore employment with likely asbestos exposure. RESULTS: An increased risk of pleural mesothelioma was indicated for the highest versus lowest tertile of average intensity of asbestos (HR=1.21, 95% CI: 0.57 to 2.54). Pre-offshore asbestos exposure (vs no such exposure) was associated with increased risk of pleural mesothelioma (HR=2.06, 95% CI: 1.11 to 3.81). For offshore workers with no pre-offshore asbestos exposure, an increased risk of pleural mesothelioma was found for the highest tertile of average intensity of asbestos (HR=4.13, 95% CI: 0.93 to 18), versus the lowest tertile. No associations were found between RCF and pleural mesothelioma. CONCLUSIONS: Associations between JEM-based offshore asbestos exposure and pleural mesothelioma were confirmed in the NOPW cohort. Pleural mesothelioma risk was also associated with asbestos exposure before work in the offshore petroleum industry.

A nested case-control study of untargeted albumin adductomics and acute myeloid leukemia.

Environmental exposures often produce reactive electrophiles in vivo, leading to oxidative stress, which plays a major role in carcinogenesis. These electrophiles frequently form adducts with human albumin, which can be measured to assess in vivo oxidative stress. Here, we aimed to examine the associations between circulatory albumin adducts and acute myeloid leukemia (AML), the most common adult myeloid leukemia that showed consistent associations with environmental exposures. We conducted a nested case-control study of 52 incident AML cases and 103 controls matched on age, sex and race within two prospective cohorts: the CLUE and PLCO studies. We measured 42 untargeted albumin adducts in prediagnostic samples using liquid chromatography-high-resolution mass spectrometry. Circulatory albumin adducts were associated with AML in conditional logistic regression models. For instance, higher levels of Cys34 disulfide adduct of the S-γ-glutamylcysteine, a precursor of the essential antioxidant, glutathione were associated with a lower risk of AML (odds ratios [95% confidence intervals]) for the 1st, 2nd and 3rd tertiles were 1.0, 0.65 (0.31-1.36) and 0.31 (0.12-0.80), respectively (P-trend = .01). These associations were largely driven by effects present among cases diagnosed at or above the median follow-up time of 5.5 years. In conclusion, applying a novel approach to characterize exposures in the prediagnostic samples, we found evidence supporting the notion that oxidative stress may play a role in the pathogenesis of AML. Our findings offer insight into AML etiology and may be relevant in identifying novel therapeutic targets.

Circulating immune markers and risks of non-Hodgkin lymphoma subtypes: A pooled analysis.

Although prediagnostic circulating concentrations of the immune activation markers soluble CD27 (sCD27), sCD30 and chemokine ligand-13 (CXCL13) have been associated with non-Hodgkin lymphoma (NHL) risk, studies have been limited by sample size in associations with NHL subtypes. We pooled data from eight nested case-control studies to investigate subtype-specific relationships for these analytes. Using polytomous regression, we calculated odds ratios (ORs) with 95% confidence intervals (CIs) relating study-specific analyte tertiles to selected subtypes vs controls (n = 3310): chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 623), diffuse large B cell lymphoma (DLBCL; n = 621), follicular lymphoma (FL; n = 398), marginal zone lymphoma (MZL; n = 138), mantle cell lymphoma (MCL; n = 82) and T cell lymphoma (TCL; n = 92). We observed associations with DLBCL for elevated sCD27 [OR for third vs first tertile (ORT3 ) = 2.2, 95% CI = 1.6-3.1], sCD30 (ORT3  = 2.0, 95% CI = 1.6-2.5) and CXCL13 (ORT3  = 2.3, 95% CI = 1.8-3.0). We also observed associations with sCD27 for CLL/SLL (ORT3  = 3.3, 95% CI = 2.4-4.6), MZL (ORT3  = 7.7, 95% CI = 3.0-20.1) and TCL (ORT3  = 3.4, 95% CI = 1.5-7.7), and between sCD30 and FL (ORT3  = 2.7, 95% CI = 2.0-3.5). In analyses stratified by time from phlebotomy to case diagnosis, the sCD27-TCL and all three DLBCL associations were equivalent across both follow-up periods (<7.5, ≥7.5 years). For other analyte-subtype comparisons, associations were stronger for the follow-up period closer to phlebotomy, particularly for indolent subtypes. In conclusion, we found robust evidence of an association between these immune markers and DLBCL, consistent with hypotheses that mechanisms related to immune activation are important in its pathogenesis. Our other findings, particularly for the rarer subtypes MZL and TCL, require further investigation.

Exposure to benzene and other hydrocarbons and risk of bladder cancer among male offshore petroleum workers.

BACKGROUND: Occupational exposures constitute the second leading cause of urinary bladder cancer after tobacco smoking. Increased risks have been found in the petroleum industry, but high-quality exposure data are needed to explain these observations. METHODS: Using a prospective case-cohort design, we analysed 189 bladder cancer cases (1999-2017) and 2065 randomly drawn non-cases from the Norwegian Offshore Petroleum Workers cohort. Cases were identified in the Cancer Registry of Norway, while work histories (1965-1998) and lifestyle factors were recorded by questionnaire at baseline (1998). Occupational petroleum-related hydrocarbon exposures were assessed by expert-developed job-exposure matrices. Hazard ratios were estimated by weighted Cox-regressions, adjusted for age, tobacco smoking, education, and year of first employment, and with lagged exposures. RESULTS: Increased risks were found in benzene-exposed workers, either long-term exposure (≥18.8 years, HR = 1.89, 95% CI: 1.14-3.13; p-trend = 0.044) or high-level cumulative benzene exposure (HR = 1.60, 95% CI: 0.97-2.63; p-trend = 0.065), compared with the unexposed. Associations persisted with 20-year exposure lag. No associations were found with skin or inhalation exposure to crude oil, mineral oil (lubrication, hydraulics, turbines, drilling), or diesel exhaust. CONCLUSIONS: The results suggest that exposures in the benzene fraction of the petroleum stream may be associated with increased bladder cancer risk.

Similar Efficacy Observed for First-Line Immunotherapy in Racial/Ethnic Minority Patients With Metastatic NSCLC.

BACKGROUND: Limited data exist on the impact of immunotherapy use in ethnic minority patients with non-small cell lung cancer (NSCLC), because they have been underrepresented in immunotherapy trials. This study aims to evaluate race/ethnicity and other demographic, socioeconomic, and clinical factors of patients with metastatic NSCLC treated with first-line immunotherapy. METHODS: A retrospective cohort study of 5,920 patients diagnosed with lung cancer treated at Montefiore Einstein Cancer Center from January 1, 2013, to June 1, 2022, was used to identify patients with metastatic NSCLC without EGFR, ALK, or ROS1 alterations who underwent first-line immunotherapy (n=248). The primary endpoint was overall survival (OS), with secondary endpoints of progression-free survival (PFS) and time to discontinuation (TTD) from the start of immunotherapy. RESULTS: Among the 248 patients, median follow-up time was 12.0 months, median age at start of treatment was 66 years, and 39.1% were non-Hispanic Black, 30.2% were Hispanic, and 30.7% were non-Hispanic White. OS (P=.39), PFS (P=.29), and TTD (P=.98) were similar among racial/ethnic groups. Patients with an ECOG performance status (PS) of <2 at the start of immunotherapy had longer OS compared with those with ECOG PS of ≥2 (P<.0001). PD-L1 expression (<50% vs ≥50%; P=.03) and body mass index (BMI) (P=.01) were also found to be associated with PFS, and ECOG PS (P<.0001) and BMI (P=.02) were associated with TTD. In a multivariate analysis of OS and PFS, ECOG PS was the only variable found to be significant. CONCLUSIONS: Our study observed similar benefits of immunotherapy in patients with metastatic NSCLC in different racial and ethnic groups. Furthermore, ECOG PS was associated with OS, and PD-L1 expression and BMI were associated with PFS and TTD. These findings help identify potential factors associated with outcomes and care while patients are undergoing immunotherapy.

Benzene exposure and risk of lung cancer in the Norwegian Offshore Petroleum Worker cohort: a prospective case-cohort study.

OBJECTIVE: The objective of our study was to examine whether occupational exposure to benzene is associated with lung cancer among males in the Norwegian Offshore Petroleum Workers cohort. METHODS: Among 25 347 male offshore workers employed during 1965-1998, we conducted a case-cohort study with 399 lung cancer cases diagnosed between 1999 and 2021, and 2035 non-cases sampled randomly by 5-year birth cohorts. Individual work histories were coupled to study-specific job-exposure matrices for benzene and other known lung carcinogens. Weighted Cox regression was used to estimate HRs and 95% CIs for the associations between benzene exposure and lung cancer, by major histological subtypes, adjusted for age, smoking and occupational exposure to welding fumes, asbestos and crystalline silica. Missing data were imputed. RESULTS: For lung cancer (all subtypes combined), HRs (95% CIs) for the highest quartiles of benzene exposure versus unexposed were 1.15 (0.61 to 2.35) for cumulative exposure, 1.43 (0.76 to 2.69) for duration, and 1.22 (0.68 to 2.18) for average intensity (0.280≤P-trend≤0.741). For 152 adenocarcinoma cases, a positive trend was observed for exposure duration (P-trend=0.044). CONCLUSIONS: In this cohort of offshore petroleum workers generally exposed to low average levels of benzene, we did not find an overall clear support for an association with lung cancer (all subtypes combined), although an association was suggested for duration of benzene exposure and adenocarcinoma. The limited evidence might be due to restricted statistical power.

Alterations to biomarkers related to long-term exposure to diesel exhaust at concentrations below occupational exposure limits in the European Union and the USA.

BACKGROUND: We previously found that occupational exposure to diesel engine exhaust (DEE) was associated with alterations to 19 biomarkers that potentially reflect the mechanisms of carcinogenesis. Whether DEE is associated with biological alterations at concentrations under existing or recommended occupational exposure limits (OELs) is unclear. METHODS: In a cross-sectional study of 54 factory workers exposed long-term to DEE and 55 unexposed controls, we reanalysed the 19 previously identified biomarkers. Multivariable linear regression was used to compare biomarker levels between DEE-exposed versus unexposed subjects and to assess elemental carbon (EC) exposure-response relationships, adjusted for age and smoking status. We analysed each biomarker at EC concentrations below the US Mine Safety and Health Administration (MSHA) OEL (<106 µg/m3), below the European Union (EU) OEL (<50 µg/m3) and below the American Conference of Governmental Industrial Hygienists (ACGIH) recommendation (<20 µg/m3). RESULTS: Below the MSHA OEL, 17 biomarkers were altered between DEE-exposed workers and unexposed controls. Below the EU OEL, DEE-exposed workers had elevated lymphocytes (p=9E-03, false discovery rate (FDR)=0.04), CD4+ count (p=0.02, FDR=0.05), CD8+ count (p=5E-03, FDR=0.03) and miR-92a-3p (p=0.02, FDR=0.05), and nasal turbinate gene expression (first principal component: p=1E-06, FDR=2E-05), as well as decreased C-reactive protein (p=0.02, FDR=0.05), macrophage inflammatory protein-1ß (p=0.04, FDR=0.09), miR-423-3p (p=0.04, FDR=0.09) and miR-122-5p (p=2E-03, FDR=0.02). Even at EC concentrations under the ACGIH recommendation, we found some evidence of exposure-response relationships for miR-423-3p (ptrend=0.01, FDR=0.19) and gene expression (ptrend=0.02, FDR=0.19). CONCLUSIONS: DEE exposure under existing or recommended OELs may be associated with biomarkers reflective of cancer-related processes, including inflammatory/immune response.

Drivers of Differential Time to Diagnosis in Pediatric ALL Tied to Race and Ethnicity.

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, with diagnosis preceded by symptoms that may include fever, weight loss, fatigue, bleeding, and bruising. Timely diagnosis and treatment of ALL may lead to improved outcomes and reduced morbidity from associated complications, including tumor lysis syndrome, hyperviscosity, and stroke. We performed a retrospective cohort analysis of 274 pediatric pre-B cell ALL and acute lymphoblastic lymphoma patients within Montefiore Health System to determine whether there were factors associated with time from symptom onset to diagnosis. The median time to diagnosis for all patients was 11.5 days (interquartile range: 7.8, 14.3). Those with Medicaid insurance (n=189) were diagnosed sooner than those with private/self-pay insurance (n=85) (median of 10 vs. 16 days; P =0.05). English and other language speakers experienced fewer median days from symptom onset to diagnosis date compared with Spanish speakers (11 vs. 7 vs. 14; P =0.05). Insurance status may impact the time to diagnosis to a greater degree in non-Hispanic patients, while the English language and female sex may represent a greater advantage to Hispanic patients. Insurance status and language preference may impact the time to diagnosis of pediatric ALL. There is a further need to confirm our findings and to study possible causes driving these disparities.

Factors Influencing the Referral of Patients with Prediabetes to a Diabetes Prevention Program in the Bronx, New York.

INTRODUCTION: Disparate engagement in the Diabetes Prevention Program (DPP) may occur as early as the point of referral for certain subgroups, including Black and Hispanic men. We aimed to determine patient demographic and provider characteristics associated with referrals to a health system DPP in the Bronx, New York. METHODS: Patient and health system characteristics for DPP-eligible patients seen in primary care between July 1, 2015, and December 31, 2017, were obtained through the electronic health record. Generalized mixed-effects modeling was used to test the association between referral rate and clinical and sociodemographic variables. RESULTS: Of 26,727 eligible patients, 66% were female, 46% were Hispanic, and 39% were non-Hispanic Black. Only 10% (n = 2,785) of eligible patients were referred to DPP. In the adjusted analyses, lower odds of referral were observed for men versus women (OR = 0.60; 95% CI, 0.52-0.66), for non-Hispanic White versus Hispanic patients (OR = 0.53; 95% CI, 0.40-0.71), and for uninsured patients versus Medicaid patients (OR = 0.66; 95% CI, 0.54-0.80). The odds were higher for patients in the highest versus lowest hemoglobin A1c (OR = 2.49; 95% CI, 2.27-2.72) category; for those in the highest versus lowest body mass index categories (OR = 1.61; 95% CI, 1.45-1.79); for middle-aged patients (aged 45-64 y) versus those aged 18-26 y (OR =1.63; 95% CI, 1.33-2.00); and for patients being seen by a family versus an internal medicine physician (OR = 1.65; 95% CI, 1.22-2.22). CONCLUSION: We identified under-referral for men and highlighted other patient and health system factors associated with referral rates. Interventions to address bias in referrals and increase referrals for men at high risk for diabetes, not typically represented in DPP, are recommended.

Efficacy and Patient Satisfaction Associated With Intramuscular Triamcinolone Therapy for Acute Flares of Hidradenitis Suppurativa.

BACKGROUND: A lack of consensus exists regarding acute flare management in hidradenitis suppurativa (HS). Intramuscular triamcinolone (IMTAC) therapy is useful in numerous inflammatory conditions; however, it has not been investigated for acute HS flares. OBJECTIVE: To evaluate the efficacy and patient experience associated with IMTAC therapy for acute, severe HS flares. METHODS: Retrospective analysis and surveys of 45 HS patients were conducted at Albert Einstein College of Medicine/ Montefiore HS Center, Bronx, NY, USA. RESULTS: Follow-up visits 6.77 (4.45) weeks after IMTAC therapy revealed significant reductions in mean HS-Physician Global Assessment (PGA) (P < .001), C-Reactive Protein (CRP) (P = .03), increased hemoglobin (P = .004), and improved pain scores (P < .001). Adjusting for age, sex and concomitant medications, multivariate analysis yielded significantly reduced pain (P = .02) and increased hemoglobin (P = .03). Patient surveys indicate that IMTAC was well-tolerated, as reflected in positive mean responses for satisfaction (29 [64%]) and willingness to receive IMTAC injections again (42 [93%]). CONCLUSIONS: These novel findings demonstrate that IMTAC is a safe, effective, and well accepted adjunct for acute HS management.

Association between diesel exhaust exposure and mitochondrial DNA methylation.

OBJECTIVES: Diesel exhaust is an established human carcinogen, however the mechanisms by which it leads to cancer development are not fully understood. Mitochondrial dysfunction is an established contributor to carcinogenesis. Recent studies have improved our understanding of the role played by epigenetic modifications in the mitochondrial genome on tumorigenesis. In this study, we aim to evaluate the association between diesel engine exhaust (DEE) exposure with mitochondrial DNA (mtDNA) methylation levels in workers exposed to DEE. METHODS: The study population consisted of 53 male workers employed at a diesel engine manufacturing facility in Northern China who were routinely exposed to diesel exhaust in their occupational setting, as well as 55 unexposed male control workers from other unrelated factories in the same geographic area. Exposure to DEE, elemental carbon, organic carbon, and particulate matter (PM2.5) were assessed. mtDNA methylation for CpG sites (CpGs) from seven mitochondrial genes (D-Loop, MT-RNR1, MT-CO2, MT-CO3, MT-ATP6, MT-ATP8, MT-ND5) was measured in blood samples. Linear regression models were used to estimate the associations between DEE, elemental carbon, organic carbon and PM2.5 exposures with mtDNA methylation levels, adjusting for potential confounders. RESULTS: DEE exposure was associated with decreased MT-ATP6 (difference = -35.6%, P-value = 0.019) and MT-ATP8 methylation (difference = -30%, P-value = 0.029) compared to unexposed controls. Exposures to elemental carbon, organic carbon, and PM2.5 were also significantly and inversely associated with methylation in MT-ATP6 and MT-ATP8 genes (all P-values < 0.05). CONCLUSIONS: Our findings suggest that DEE exposure perturbs mtDNA methylation, which may be of importance for tumorigenesis.

Variation in oral microbiome is associated with future risk of lung cancer among never-smokers.

OBJECTIVE: To prospectively investigate whether diversity in oral microbiota is associated with risk of lung cancer among never-smokers. DESIGN AND SETTING: A nested case-control study within two prospective cohort studies, the Shanghai Women's Health Study (n=74 941) and the Shanghai Men's Health Study (n=61 480). PARTICIPANTS: Lifetime never-smokers who had no cancer at baseline. Cases were subjects who were diagnosed with incident lung cancer (n=114) and were matched 1:1 with controls on sex, age (≤2 years), date (≤30 days) and time (morning/afternoon) of sample collection, antibiotic use during the week before sample collection (yes/no) and menopausal status (for women). MAIN OUTCOMES AND MEASURES: Metagenomic shotgun sequencing was used to measure the community structure and abundance of the oral microbiome in pre-diagnostic oral rinse samples of each case and control. Multivariable logistic regression models were used to estimate the association of lung cancer risk with alpha diversity metrics and relative abundance of taxa. The Microbiome Regression-Based Kernel Association Test (MiRKAT) evaluated the association between risk and the microbiome beta diversity. RESULTS: Subjects with lower microbiota alpha diversity had an increased risk of lung cancer compared with those with higher microbial alpha diversity (Shannon: ptrend=0.05; Simpson: ptrend=0.04; Observed Species: ptrend=0.64). No case-control differences were apparent for beta diversity (pMiRKAT=0.30). After accounting for multiple comparisons, a greater abundance of Spirochaetia (ORlow 1.00 (reference), ORmedium 0.61 (95% CI 0.32 to 1.18), ORhigh 0.42 (95% CI 0.21 to 0.85)) and Bacteroidetes (ORlow 1.00 (reference), ORmedium 0.66 (95% CI 0.35 to 1.25), ORhigh 0.31 (95% CI 0.15 to 0.64)) was associated with a decreased risk of lung cancer, while a greater abundance of the Bacilli class (ORlow 1.00 (reference), ORmedium 1.49 (95% CI 0.73 to 3.08), ORhigh 2.40 (95% CI 1.18 to 4.87)) and Lactobacillales order (ORlow 1.00 (reference), ORmedium 2.15 (95% CI 1.03 to 4.47), ORhigh 3.26 (95% CI 1.58 to 6.70)) was associated with an increased risk of lung cancer. CONCLUSIONS: Our prospective study of never-smokers suggests that lower alpha diversity was associated with a greater risk of lung cancer and the abundance of certain specific taxa was associated with altered risk, providing further insight into the aetiology of lung cancer in the absence of active tobacco smoking.

Tuberculosis infection and lung adenocarcinoma: Mendelian randomization and pathway analysis of genome-wide association study data from never-smoking Asian women.

We investigated whether genetic susceptibility to tuberculosis (TB) influences lung adenocarcinoma development among never-smokers using TB genome-wide association study (GWAS) results within the Female Lung Cancer Consortium in Asia. Pathway analysis with the adaptive rank truncated product method was used to assess the association between a TB-related gene-set and lung adenocarcinoma using GWAS data from 5512 lung adenocarcinoma cases and 6277 controls. The gene-set consisted of 31 genes containing known/suggestive associations with genetic variants from previous TB-GWAS. Subsequently, we followed-up with Mendelian Randomization to evaluate the association between TB and lung adenocarcinoma using three genome-wide significant variants from previous TB-GWAS in East Asians. The TB-related gene-set was associated with lung adenocarcinoma (p = 0.016). Additionally, the Mendelian Randomization showed an association between TB and lung adenocarcinoma (OR = 1.31, 95% CI: 1.03, 1.66, p = 0.027). Our findings support TB as a causal risk factor for lung cancer development among never-smoking Asian women.

Prediagnostic blood levels of organochlorines and risk of non-Hodgkin lymphoma in three prospective cohorts in China and Singapore.

Specific organochlorines (OCs) have been associated with non-Hodgkin lymphoma (NHL) with varying degrees of evidence. These associations have not been evaluated in Asia, where the high exposure and historical environmental contamination of certain OC pesticides (e.g., dichlorodiphenyltrichloroethane [DDT], hexachlorocyclohexane [HCH]) are different from Western populations. We evaluated NHL risk and prediagnostic blood levels of OC pesticides/metabolites and polychlorinated biphenyl congeners in a case-control study of 167 NHL cases and 167 controls nested within three prospective cohorts in Shanghai and Singapore. Conditional logistic regression was used to analyze lipid-adjusted OC levels and NHL risk. Median levels of p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE), the primary DDT metabolite, and ß-HCH were up to 12 and 65 times higher, respectively, in samples from the Asian cohorts compared to several cohorts in the United States and Norway. An increased risk of NHL was observed among those with higher ß-HCH levels both overall (3rd vs. 1st tertile OR = 1.8, 95%CI = 1.0-3.2; ptrend = 0.049) and after excluding cases diagnosed within 2 years of blood collection (3rd vs. 1st tertile OR = 2.0, 95%CI = 1.1-3.9; ptrend = 0.03), and the association was highly consistent across the three cohorts. No significant associations were observed for other OCs, including p,p'-DDE. Our findings provide support for an association between ß-HCH blood levels and NHL risk. This is a concern because substantial quantities of persistent, toxic residues of HCH are present in the environment worldwide. Although there is some evidence that DDT is associated with NHL, our findings for p,p'-DDE do not support an association.

High-dose, high-frequency infliximab: A novel treatment paradigm for hidradenitis suppurativa.

BACKGROUND: The permanent disfigurement associated with hidradenitis suppurativa (HS) necessitates early aggressive disease intervention. Although limited data support the use of infliximab (IFX) in HS, the efficacy of high-dose, high-frequency IFX has yet to be defined. OBJECTIVE: To evaluate the efficacy of IFX 7.5 to 10 mg/kg, with a maintenance frequency every 4 weeks. METHODS: Prospective analysis of 42 patients initiating IFX 7.5 mg/kg every 4 weeks (IFX 7.5) and 16 patients receiving dose escalation to IFX 10 mg/kg every 4 weeks (IFX 10) between March 1, 2018, and February 28, 2019. The primary outcome measure (clinical response) was the proportion of patients with Physician Global Assessment of clear, minimal, or mild (score of 0-2) HS with at least a 2-grade improvement from baseline scores. RESULTS: The proportion of patients achieving a clinical response after initiating IFX 7.5 was 20 of 42 (47.6%) at week 4 and 17 of 24 (70.8%) at week 12. For patients receiving dose escalation to IFX 10 because of incomplete initial response, 6 of 16 (37.5%) achieved clinical response at week 4 and 6 of 12 (50%) at week 12. CONCLUSIONS: Initiation of IFX 7.5 every 4 weeks, with possible dose escalation to IFX 10, if needed, provides optimal mitigation of HS-related disease activity.

Environmental health literacy and household air pollution-associated symptoms in Kenya: a cross-sectional study.

BACKGROUND: Household air pollution (HAP) is a significant source of the global burden of disease. Our objective was to evaluate the association between environmental health literacy (EHL), a domain of health literacy (HL) that describes the ability to use environmental health information to reduce health risks, and symptoms associated with HAP. METHODS: We performed a cross-sectional population-based study of 353 households in Kasarani, Kenya. One individual from each household was surveyed using our novel EHL survey tool. Baseline characteristics were compared between individuals who were symptomatic (i.e., experiencing cough, shortness of breath, phlegm production, wheeze, chest tightness, headache, eye irritation, or burns from cooking at least 5 times per month) versus individuals who were asymptomatic (i.e., experiencing none or symptoms no more than once per month). Multivariate logistic regression was used to determine the odds ratios (OR) of self-reported symptoms associated with HL, stratified by median EHL, adjusting for education, self-perceived health and solid fuel use. RESULTS: A total of 100 individuals (28%) reported experiencing one or more symptoms at least 5 times per month, including 31.2% of solid fuel users and 30.3% of non-solid fuel users. Among individuals with high EHL, higher HL was associated with lower risk of experiencing symptoms (OR = 0.26; 95% CI 0.10-0.67), however, there was no association among individuals with low EHL (OR = 0.85; 95% CI 0.34-2.13). Among solid fuel users, the association between HL and risk of experiencing symptoms was driven by individuals with high EHL (OR = 0.30; 95% CI 0.05-1.84), rather than those with low EHL (OR = 1.22; 95% CI 0.36-4.16). CONCLUSIONS: To the best of our knowledge, this was the first study to assess the association between EHL, HL, and HAP-associated symptoms. Our findings highlight the potential importance of EHL in promoting sustainable interventions to reduce symptoms associated with HAP from solid fuel use among communities in Kenya.

Reproductive factors and lung cancer risk: a comprehensive systematic review and meta-analysis.

BACKGROUND: A number of studies have investigated the association between reproductive factors and lung cancer risk, however findings are inconsistent. This meta-analysis aimed to evaluate the association between female reproductive factors and lung cancer risk. METHODS: We conducted a comprehensive systematic search to identify relevant and eligible studies published before 18th December 2019. Inter-study heterogeneity was assessed using the Q test and I2 statistic. Based on the heterogeneity of each reproductive factor, fixed or random effects models were used to calculate the summary odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup analyses by study design, lung cancer subtypes, smoking status, and ethnicity were also performed. RESULTS: A total of 66 studies with 20 distinct reproductive factors were included in this meta-analysis. Comparing the highest and lowest categories (reference) of each reproductive factor, parity (OR = 0.83, 95% CI = 0.72-0.96), menstrual cycle length (OR = 0.79, 95% CI = 0.65-0.96), and age at first birth (OR = 0.85, 95% CI = 0.74-0.98), were significantly associated with a lower risk of overall lung cancer. On the contrary, non-natural menopause was significantly associated with higher lung cancer risk (OR = 1.52, 95% CI = 1.25-1.86). Among never-smokers, a significant negative association was found between parity and lung cancer risk. Both parity and non-natural menopause were statistically significant in case-control studies. CONCLUSION: These results suggest that certain reproductive factors may be associated with lung cancer risk. Future studies should further validate the associations, and investigate the underlying mechanisms.

Variation in ribosomal DNA copy number is associated with lung cancer risk in a prospective cohort study.

Disruption of ribosomal DNA (rDNA) has been linked to a variety of diseases in humans, including carcinogenesis. To evaluate the associations between rDNA copy number (CN) and risk of lung cancer, we measured 5.8S and 18S rDNA CN in the peripheral blood of 229 incident lung cancer cases and 1:1 matched controls from a nested case-control study within a prospective cohort of male smokers. There was a dose-response relationship between quartiles of both 18S and 5.8S rDNA CN and risk of lung cancer (odds ratio [OR], 95% confidence interval [CI]: 18S: 1.0 [ref]; 1.2 [0.6-2.1]; 1.8 [1.0-3.4]; 2.3 [1.3-4.1; Ptrend = 0.0002; 5.8S: 1.0 [ref]; 1.6 [0.8-2.9]; 2.2 [1.1-4.2]; 2.6 [1.3-5.1]; Ptrend = 0.0001). The associations between rDNA CN and lung cancer risk were similar when excluding cases diagnosed within 5 years of follow-up, and when stratifying by heavy (>20 cigarettes per day) and light smokers (≤20 cigarettes per day). We are the first to report that rDNA CN may be associated with future risk of lung cancer. To further elucidate the relationship between rDNA and lung cancer, replication studies are needed in additional populations, particularly those that include non-smokers.

Association between GWAS-identified lung adenocarcinoma susceptibility loci and EGFR mutations in never-smoking Asian women, and comparison with findings from Western populations.

To evaluate associations by EGFR mutation status for lung adenocarcinoma risk among never-smoking Asian women, we conducted a meta-analysis of 11 loci previously identified in genome-wide association studies (GWAS). Genotyping in an additional 10,780 never-smoking cases and 10,938 never-smoking controls from Asia confirmed associations with eight known single nucleotide polymorphisms (SNPs). Two new signals were observed at genome-wide significance (P < 5 × 10-8), namely, rs7216064 (17q24.3, BPTF), for overall lung adenocarcinoma risk, and rs3817963 (6p21.3, BTNL2) which is specific to cases with EGFR mutations. In further sub-analyses by EGFR status, rs9387478 (ROS1/DCBLD1) and rs2179920 (HLA-DPB1) showed stronger estimated associations in EGFR-positive compared to EGFR-negative cases. Comparison of the overall associations with published results in Western populations revealed that the majority of these findings were distinct, underscoring the importance of distinct contributing factors for smoking and non-smoking lung cancer. Our results extend the catalogue of regions associated with lung adenocarcinoma in non-smoking Asian women and highlight the importance of how the germline could inform risk for specific tumour mutation patterns, which could have important translational implications.