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AbstractObjectiveTo evaluate the associations between personal use of permanent hair dyes and cancer risk and mortality.DesignProspective cohort study.Setting and participants117 200 women enrolled in the Nurses’ Health Study, an ongoing prospective cohort study of female nurses in the United States. The women were free of cancer at baseline, reported information on personal use of permanent hair dyes, and were followed for 36 years.ExposureStatus, duration, frequency, and integral use (cumulative dose calculated from duration and frequency) of permanent hair dyes. Age at first use and time since first use of permanent hair dyes.Main outcome measuresAssociations of personal use of permanent hair dyes with risk of overall cancer and specific cancers, and cancer related death. Age and multivariable adjusted hazard ratios and 95% confidence intervals were estimated by using Cox proportional hazard models.ResultsEver users of permanent hair dyes had no significant increases in risk of solid cancers (n=20 805, excluding non-melanoma skin cancers; hazard ratio 0.98, 95% confidence interval 0.96 to 1.01) or hematopoietic cancers overall (n=1807; 1.00, 0.91 to 1.10) compared with non-users. Additionally, ever users did not have an increased risk of most specific cancers (cutaneous squamous cell carcinoma, bladder cancer, melanoma, estrogen receptor positive breast cancer, progesterone receptor positive breast cancer, hormone receptor positive breast cancer, brain cancer, colorectal cancer, kidney cancer, lung cancer, and most of the major subclasses and histological subtypes of hematopoietic cancer) or cancer related death (n=4860; 0.96, 0.91 to 1.02). Basal cell carcinoma risk was slightly increased for ever users (n=22 560; 1.05, 1.02 to 1.08). Cumulative dose was positively associated with risk of estrogen receptor negative breast cancer, progesterone receptor negative breast cancer, hormone receptor negative breast cancer, and ovarian cancer. An increased risk of Hodgkin lymphoma was observed only for women with naturally dark hair (based on 70 women, 24 with dark hair), and a higher risk of basal cell carcinoma was observed for women with naturally light hair.ConclusionNo positive association was found between personal use of permanent hair dye and risk of most cancers and cancer related mortality. The increased risk of basal cell carcinoma, breast cancer (estrogen receptor negative, progesterone receptor negative, hormone receptor negative) and ovarian cancer, and the mixed findings in analyses stratified by natural hair color warrant further investigation.

Background: Childhood brain tumors are associated with high mortality and morbidity but little is known about its causes. About half of women use medicines when pregnant and some of the medicines commonly used might be carcinogenic. Objective: The aim with this population-based case–control study was to analyze associations between specific groups of medicines taken during pregnancy and the risk of brain tumor in the offspring. Methods: All children, up to 15 years of age, born in Sweden between 1975 and 1984 were eligible for the study. Cases ( N = 512) were children diagnosed with brain tumor and controls ( N = 525) were randomly selected from the Medical Birth Register. Exposure data on medicines was extracted blindly from antenatal medical records and grouped according to Anatomical Therapeutic Chemical (ATC) code. Information on maternal reproductive history was received from the Medical Birth Register. We used logistic regression to estimate associations between fetal exposure to medicines and childhood brain tumor. Results: No significant changes in risk were noted after exposure to iron supplementation, antiemetics, analgesics, antibiotics or any other main ATC group. A tendency of protective effect was seen for prenatal exposure to folic acid (adjusted OR 0.6, 95% CI 0.3–1.1). Ten children with a diagnosis of brain tumor had been exposed to β-blocking agents in fetal life as compared to two children without brain tumor (adjusted OR 5.3, 95% CI 1.2–24.8). Conclusions: In this case–control study, an increased risk of brain tumor was seen in children exposed to β-blocking agents during fetal life. However, due to the low number of exposed the interpretation of this finding should be made with caution.

Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation is brain metastasis (BM)-prone. We determined the impact of this hallmark, along with EGFR subtype and generation of tyrosine kinase inhibitor (TKI) treatment, on patients’ outcome. 553 metastatic EGFR -mutant NSCLC patients received front-line EGFR-TKI treatment. Progression-free survival (PFS), overall survival (OS) and secondary T790M rate were analysed. BM was observed in 211 (38.2%) patients. BM (HR 1.20 [95% CI 0.99–1.48]; p = 0.053), ECOG PS 0–1 (HR 0.71 [95% CI 0.54–0.93]; p = 0.014) and afatinib treatment (HR 0.81 [95% CI 0.66–0.99]; p = 0.045) were associated with PFS. Afatinib-treated patients without BM demonstrated a significantly longer PFS (16.3 months) compared to afatinib-treated patients with BM (13.7 months) and to gefitinib/erlotinib-treated patients with (11.1 months) or without BM (14.2 months; p < 0.001). CNS-only progression trended higher in afatinib-treated patients. ECOG PS 0–1 (HR 0.41 [95% CI 0.31–0.56]; p < 0.001) and EGFR L858R mutation (HR 1.46 [95% CI 1.13–1.88]; p = 0.003), but not BM, were the predictors for OS. BM (OR 2.02 [95% CI 1.02–4.08]; p = 0.040), afatinib treatment (OR 0.26 [95% CI 0.12–0.50]; p < 0.001) and EGFR L858R mutation (OR 0.55 [95% CI 0.28–1.05]; p = 0.070) were associated with secondary T790M rate. In BM patients, gefitinib/erlotinib-treated ones with 19 deletion mutation and afatinib-treated ones with L858R mutation had the highest and the lowest T790M rate (94.4% vs. 27.3%, p < 0.001), respectively. BM and generation of EGFR-TKI jointly impact PFS and secondary T790M rate in patients with EGFR -mutant NSCLC, whereas OS was mainly associated with EGFR subtype.

Rhabdoid tumours (RTs) are highly aggressive tumours of infancy, frequently localized in the central nervous system (CNS) where they are termed atypical teratoid/rhabdoid tumours (AT/RTs) and characterized by bi-allelic inactivation of the SMARCB1 tumour suppressor gene. In this study, by temporal control of tamoxifen injection in Smarcb1 flox/flox ;Rosa26-Cre ERT2 mice, we explore the phenotypes associated with Smarcb1 inactivation at different developmental stages. Injection before E6, at birth or at 2 months of age recapitulates previously described phenotypes including embryonic lethality, hepatic toxicity or development of T-cell lymphomas, respectively. Injection between E6 and E10 leads to high penetrance tumours, mainly intra-cranial, with short delays (median: 3 months). These tumours demonstrate anatomical, morphological and gene expression profiles consistent with those of human AT/RTs. Moreover, intra- and inter-species comparisons of tumours reveal that human and mouse RTs can be split into different entities that may underline the variety of RT cells of origin. SMARCB1 inactivation is prevalent in human atypical teratoid/rhabdoid tumours but a mouse model that accurately phenocopies the human disease is lacking. Here, the authors show that inactivation of SMARCB1 between E6 and E10 in mice results in tumours that better recapitulate the human phenotype, compared to previously reported models.

Air pollution is linked to brain inflammation, which accelerates tumorigenesis and neurodegeneration. The molecular mechanisms that connect air pollution with brain pathology are largely unknown but seem to depend on the chemical composition of airborne particulate matter (PM). We sourced ambient PM from Riverside, California, and selectively exposed rats to coarse (PM 2.5–10 : 2.5–10 µm), fine (PM <2.5 : <2.5 µm), or ultrafine particles (UFPM: <0.15 µm). We characterized each PM type via atomic emission spectroscopy and detected nickel, cobalt and zinc within them. We then exposed rats separately to each PM type for short (2 weeks), intermediate (1–3 months) and long durations (1 year). All three metals accumulated in rat brains during intermediate-length PM exposures. Via RNAseq analysis we then determined that intermediate-length PM 2.5–10 exposures triggered the expression of the early growth response gene 2 (EGR2), genes encoding inflammatory cytokine pathways (IL13-Rα1 and IL-16) and the oncogene RAC1. Gene upregulation occurred only in brains of rats exposed to PM 2.5–10 and correlated with cerebral nickel accumulation. We hypothesize that the expression of inflammation and oncogenesis-related genes is triggered by the combinatorial exposure to certain metals and toxins in Los Angeles Basin PM 2.5–10 .

Background We conducted this meta-analysis to investigate the potential association between maternal smoking, alcohol and caffeinated beverages consumption during pregnancy and the risk of childhood brain tumors (CBTs). Methods A thorough search was carried out on PubMed, Embase, Web of Science, Cochrane Library, and China National Knowledge Internet to identify pertinent articles. Fixed or random effects model was applied to meta-analyze the data. Results The results suggested a borderline statistically significant increased risk of CBTs associated with maternal smoking during pregnancy (OR 1.04, 95% CI 0.99–1.09). We found that passive smoking (OR 1.12, 95% CI 1.03–1.20), rather than active smoking (OR 1.00, 95% CI 0.93–1.07), led to an increased risk of CBTs. The results suggested a higher risk in 0–1 year old children (OR 1.21, 95% CI 0.94–1.56), followed by 0–4 years old children (OR 1.12, 95% CI 0.97–1.28) and 5–9 years old children (OR 1.11, 95% CI 0.95–1.29). This meta-analysis found no significant association between maternal alcohol consumption during pregnancy and CBTs risk (OR 1.00, 95% CI 0.80–1.24). An increased risk of CBTs was found to be associated with maternal consumption of caffeinated beverages (OR 1.16, 95% CI 1.07–1.26) during pregnancy, especially coffee (OR 1.18, 95% CI 1.00–1.38). Conclusions Maternal passive smoking, consumption of caffeinated beverages during pregnancy should be considered as risk factors for CBTs, especially glioma. More prospective cohort studies are warranted to provide a higher level of evidence.

Epigenetic alterations have emerged as critical factors in the pathogenesis of brain cancer, particularly gliomas. This article explores the impact of organochlorine pesticides (OCPs) on the hypermethylation of key tumor suppressor genes, and some histone modifications in primary brain tumor (PBT) patients. This study involved 73 patients diagnosed with PBT and 15 non-cancerous brain tissue samples as contol. DNA extracted from tumor specimens was used to evaluate the methylation status of tumor suppressor genes, P16 and RRP22 , using the methylation-specific PCR (MSP) technique and four histone marks (H4K16ac, H3K9ac, H4K20me3, and H3k4me2) to investigate by western blotting. The results of MSP revealed the methylation of RRP22 and P16 promoter regions and western blot analysis demonstrated significantly low levels of H3K9ac, H4K20me3, and H3K4me2 in PBT patients in comparison with the controls. The results of regression analysis revealed direct and significant correlations between serum OCPs concentration and methylation of RRP22 and P16 . Furthermore, a direct and significant association was observed between hypomethylation of histones H3K4 and H4K20, as well as hypoacetylation of H3K9, with OCPs levels. This study revealed that epigenetic modifications play a significant role in the development of brain tumors, with OCPs identified as key contributors to these changes. Our research indicated that in patients with PBT, hypermethylation of the RRP22 and P16 gene and histone modifications correlates directly and significantly with the levels of OCPs found in their serum. Graphical Abstract Organochlorine pesticides exposure and epigenetic modifications in brain cancer: This study reveals that pesticide exposure may significantly induce the epigenetic modifications and by this way, participate in primary brain cancer development.

ObjectivesIn absence of clear evidence regarding possible effects of occupational chemical exposures on brain tumour aetiology, it is worthwhile to explore the hypothesis that such exposures might act on brain tumour risk in interaction with occupational exposure to extremely low frequency magnetic fields (ELF).MethodsINTEROCC is a seven-country (Australia, Canada, France, Germany, Israel, New Zealand and UK), population-based, case–control study, based on the larger INTERPHONE study. Incident cases of primary glioma and meningioma were ascertained from 2000 to 2004. Job titles were coded into standard international occupational classifications and estimates of ELF and chemical exposures were assigned based on job-exposure matrices. Dichotomous indicators of cumulative ELF (≥50th vs <50th percentile, 1–4 year exposure time window) and chemical exposures (ever vs never, 5-year lag) were created. Interaction was assessed on both the additive and multiplicative scales.ResultsA total of 1939 glioma cases, 1822 meningioma cases and 5404 controls were included in the analysis, using conditional logistic regression. There was no clear evidence for interactions between ELF and any of the chemical exposures assessed for either glioma or meningioma risk. For glioma, subjects in the low ELF/metal exposed group had a lower risk than would be predicted from marginal effects. Results were similar according to different exposure time windows, to cut-points of exposure or in exposed-only analyses.ConclusionsThere was no clear evidence for interactions between occupational ELF and chemical exposures in relation to glioma or meningioma risk observed. Further research with more refined estimates of occupational exposures is recommended.

•EGFR mutation is associated with higher incidence of brain metastases for patients with advanced non-squamous NSCLC.•The use of a TKI is associated with higher incidence of brain metastases for patients with advanced non-squamous NSCLC.•For patients with brain metastases, the survival was significantly longer in EGFR+ patients than in EGFR- patients. Brain metastases remain lethal in lung cancer patients. The impacts of epidermal growth factor receptor (EGFR) mutations and EGFR tyrosine kinase inhibitors (TKIs) on the incidence of brain metastases in patients with advanced non-squamous non-small cell lung cancer (NSCLC) are still uncertain. A total of 1672 patients with advanced non-squamous NSCLC with a definitive report on EGFR mutation status between January 2005 and June 2013 were retrospectively analyzed. The impacts of EGFR mutation status and EGFR TKIs use on the incidence of brain metastases and survival were investigated. Of the 1672 patients, 465 (27.8%) had an EGFR mutation, and 1207 (72.2%) did not. Four hundred and eighteen (25.0%) patients had baseline brain metastases. The cumulative incidence of brain metastases for patients in EGFR+ group was significantly higher than patients in EGFR- group (HR, 1.27; 95% CI 1.06–1.52; P=0.008). The cumulative incidence of brain metastases was also higher for patients who received an EGFR-TKI as their first-line treatment than those who received other first-line treatment (HR, 1.36; 95% CI 1.14–1.64; P=0.001). Patients harboring EGFR mutations had prolonged overall survival (OS) than patients with wild-type EGFR (HR, 0.47; 95% CI 0.41–0.54; P<0.001; median, 25.2 vs. 12.9 months). Both the EGFR mutation-positive status and the use of a TKI are associated with higher incidence of brain metastases for patients with advanced non-squamous NSCLC.

Background: The risk of benign brain tumors (BBT) associated with metformin use has not received much attention. Therefore, a retrospective cohort study was designed to investigate such an association in patients with type 2 diabetes mellitus (T2DM). Methods: We used the database of Taiwan’s National Health Insurance to enroll 152,176 ever users and 16,120 never users of metformin for the follow-up of incidence of BBT and a more specific outcome of cerebral meningioma. The patients were newly diagnosed with T2DM between 1999 and 2005; and they were followed up from 1 January 2006 until 31 December 2011. Hazard ratios were estimated by Cox regression incorporated with the inverse probability of treatment weighting using propensity score. Results: During follow-up, 111 never users and 557 ever users were diagnosed with BBT. For BBT, the respective incidence rates for never users and ever users were 153.95 per 100,000 person-years and 77.61 per 100,000 person-years. While ever users were compared to never users, the hazard ratio was 0.502 (95% confidence interval: 0.409–0.615). A dose-response pattern was seen when ever users were categorized into tertiles of cumulative duration of metformin therapy (cutoffs: <27.10 months, 27.10–58.27 months and >58.27 months) with respective hazard ratios of 0.910 (0.728–1.138), 0.475 (0.375–0.602) and 0.243 (0.187–0.315). For cerebral meningioma, the overall hazard ratio was 0.506 (0.317–0.808); and the hazard ratios comparing the respective tertiles to never users were 0.895 (0.531–1.508), 0.585 (0.346–0.988) and 0.196 (0.104–0.369). Conclusions: A reduced risk of BBT and cerebral meningioma is observed in metformin users in patients with T2DM.