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We previously identified five single nucleotide polymorphisms (SNPs) at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate two loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5662 cases and 9237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF] = 0.40) was associated with DLBCL risk [odds ratio (OR) = 0.83, P = 3.62 × 10−13]. rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5510 cases and 12 817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF = 0.45) was also associated with DLBCL risk (OR = 1.20, P = 2.31 × 10−12). This SNP is 29 426-bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.

Background: A previous International Lymphoma Epidemiology (InterLymph) Consortium evaluation of joint associations between five immune gene variants and autoimmune conditions reported interactions between B-cell response-mediated autoimmune conditions and the rs1800629 genotype on risk of B-cell non–Hodgkin lymphoma (NHL) subtypes. Here, we extend that evaluation using NHL subtype-specific polygenic risk scores (PRS) constructed from loci identified in genome-wide association studies of three common B-cell NHL subtypes. Methods: In a pooled analysis of NHL cases and controls of Caucasian descent from 14 participating InterLymph studies, we evaluated joint associations between B-cell–mediated autoimmune conditions and tertile (T) of PRS for risk of diffuse large B-cell lymphoma (DLBCL; n = 1,914), follicular lymphoma (n = 1,733), and marginal zone lymphoma (MZL; n = 407), using unconditional logistic regression. Results: We demonstrated a positive association of DLBCL PRS with DLBCL risk [T2 vs. T1: OR = 1.24; 95% confidence interval (CI), 1.08–1.43; T3 vs. T1: OR = 1.81; 95% CI, 1.59–2.07; P-trend (Ptrend) < 0.0001]. DLBCL risk also increased with increasing PRS tertile among those with an autoimmune condition, being highest for those with a B-cell–mediated autoimmune condition and a T3 PRS [OR = 6.46 vs. no autoimmune condition and a T1 PRS, Ptrend < 0.0001, P-interaction (Pinteraction) = 0.49]. Follicular lymphoma and MZL risk demonstrated no evidence of joint associations or significant Pinteraction. Conclusions: Our results suggest that PRS constructed from currently known subtype-specific loci may not necessarily capture biological pathways shared with autoimmune conditions. Impact: Targeted genetic (PRS) screening among population subsets with autoimmune conditions may offer opportunities for identifying those at highest risk for (and early detection from) DLBCL.

A few reports have described increasing trends and spatial distribution of multiple myeloma (MM). We used a validated database including the 1606 cases of MM diagnosed in Sardinia in 1974–2003 to explore its time trend, and we applied Bayesian methods to plot MM probability by administrative unit on the regional map. Over the 30 years of observation, the MM standardized incidence rate (standard world population, all ages) was 2.17 x 10− 5 (95% CI 2.01–2.34), 2.29 (95% CI 2.06–2.52) among men, and 2.06 (95% CI 1.83–2.28) among women. MM incidence increased by 3.3%/year in 1974–2003, in both males and females, particularly among the elderly and in the high incidence areas. Areas at risk tended to cluster in the north-eastern part of the region. A higher proportion of elderly in the resident population, but not socioeconomic factors, nor livestock farming, was associated with higher incidence rates. The steep upward time trend and the spatial clustering of MM suggest interactions between genetic and environmental determinants that might be more efficiently investigated in the areas at risk.

Evidence for the human health effects of pesticides is needed to inform risk assessment. We studied the relationship between occupational insecticide use and risk of non-Hodgkin lymphoma (NHL) by pooling data from nine case-control studies participating in the InterLymph Consortium, including 7909 cases and 8644 controls from North America, the European Union, and Australia. Insecticide use was coded using self-report or expert assessment, for insecticide groups (e.g., organophosphates, pyrethroids) and active ingredients (e.g., malathion, permethrin). Associations with insecticides were estimated using logistic regression to produce odds ratios (ORs) and 95% confidence intervals (CI) for all NHL and NHL subtypes, with adjustment for study site, demographic factors, and use of other pesticides. Occupational insecticide use, overall, was not associated with risk of NHL. Use of organophosphate insecticides was associated with increased risk of all NHL and the subtype follicular lymphoma, and an association was found with diazinon, in particular (ever use: OR=2.05, 95% CI: 1.24-3.37). The carbamate insecticide, carbaryl, was associated with risk of all NHL, and the strongest associations were found with T-cell NHL for ever-use (OR=2.44, 95% CI: 1.13-5.28) and longer duration (>8 years vs. never: OR=2.90, 95% CI: 1.02-8.25). There was no association of NHL with other broad groups of insecticides, including organochlorine and pyrethroids, and some inverse associations were estimated in relation to historical DDT use. Our findings contribute to the totality of evidence available to help inform risk decisions by public health and regulatory agencies - of importance given continued, widespread use of organophosphate and carbamate insecticides. This article is protected by copyright. All rights reserved.

Background The International Agency for Research on Cancer (IARC) recently classified glyphosate, the most used herbicide worldwide, as a probable human carcinogen. We inquired into the association between occupational exposure to glyphosate and risk of lymphoma subtypes in a multicenter case-control study conducted in Italy. Methods The Italian Gene-Environment Interactions in Lymphoma Etiology (ItGxE) study took place in 2011–17 in six Italian centres. Overall, 867 incident lymphoma cases and 774 controls participated in the study. Based on detailed questionnaire information, occupational experts classified duration, confidence, frequency, and intensity of exposure to glyphosate for each study subject. Using unconditional regression analysis, we modelled risk of major lymphoma subtypes associated with exposure to glyphosate adjusted by age, gender, education, and study centre. Results Very few study subjects (2.2%) were classified as ever exposed to glyphosate. Risk of follicular lymphoma (FL) was elevated 7-fold in subjects classified as ever exposed to glyphosate with medium-high confidence, 4.5-fold in association with medium-high cumulative exposure level, 12-fold with medium-high exposure intensity, and 6-fold with exposure for 10 days or more per year. Significant upward trends were detected with all the exposure metrics, but duration. The overall p-value for an upward trend with four independent metrics was 1.88 × 10− 4. There was no association with risk of lymphoma (any subtype), Non Hodgkin Lymphoma, B-cell lymphoma, or the major lymphoma subtypes other than FL. Conclusions Our findings provide limited support to the IARC decision to classify glyphosate as Group 2A human carcinogen.

The causes of the peculiar time trend in the incidence of non-Hodgkin’s lymphoma (NHL) in most parts of the world and of its geographic distribution are still unknown. We used the data base of 1974–2003 incident cases of hematological malignancies to explore the time trend of NHL incidence in the region of Sardinia, Italy, and we used Bayesian methods to plot the probability of NHL incidence by residential unit on the regional map. In 1974–2003, 4109 NHL cases were diagnosed among resident adults in Sardinia, with an incidence rate of 13.38 x 10−5 (95% CI 12.97–13.80). NHL incidence showed an upward trend along the study period with an average annual percent change (APC) of 4.94 (95% CI -5.39–16.4), which did not vary by gender or by age-group. Cancer registry data, covering part of the region starting from 1993, suggest that the increasing trend did not persist in the subsequent years. Areas with the highest probability of an excess incidence tended to cluster in the north-eastern part of the region and in two major urban centers, with the low incidence areas located in the south, confirming previous observations. Prevalence of viral infections, environmental and occupational exposures, or socio-economic deprivation would not explain the peculiar geographic distribution we observed. These findings provide convincing arguments for extending the coverage of routine cancer registration over the whole Sardinian population, while prompting further research on the genetic and environmental determinants of NHL in the risk areas.

Aim: Recessive genetic variation is thought to play a role in non-Hodgkin lymphoma (NHL) etiology. Runs of homozygosity (ROH), defined based on long, continuous segments of homozygous SNPs, can be used to estimate both measured and unmeasured recessive genetic variation. We sought to examine genome-wide homozygosity and NHL risk.Methods: We used data from eight genome-wide association studies of four common NHL subtypes: 3061 chronic lymphocytic leukemia (CLL), 3814 diffuse large B-cell lymphoma (DLBCL), 2784 follicular lymphoma (FL), and 808 marginal zone lymphoma (MZL) cases, as well as 9374 controls. We examined the effect of homozygous variation on risk by: (1) estimating the fraction of the autosome containing runs of homozygosity (FROH); (2) calculating an inbreeding coefficient derived from the correlation among uniting gametes (F3); and (3) examining specific autosomal regions containing ROH. For each, we calculated beta coefficients and standard errors using logistic regression and combined estimates across studies using random-effects meta-analysis.Results: We discovered positive associations between FROH and CLL (β = 21.1, SE = 4.41, P = 1.6 × 10 -6) and FL (β = 11.4, SE = 5.82, P = 0.02) but not DLBCL ( P = 1.0) or MZL ( P = 0.91). For F3, we observed an association with CLL (β = 27.5, SE = 6.51, P = 2.4 × 10 -5). We did not find evidence of associations with specific ROH, suggesting that the associations observed with FROH and F3 for CLL and FL risk were not driven by a single region of homozygosity. Conclusion: Our findings support the role of recessive genetic variation in the etiology of CLL and FL; additional research is needed to identify the specific loci associated with NHL risk.

Objectives: This study aimed to estimate the risk of lymphoma and its major subtypes in relation to occupational exposure to specific organic dusts. Methods: We explored the association in 1853 cases and 1997 controls who participated in the EpiLymph case–control study, conducted in six European countries in 1998–2004. Based on expert assessment of lifetime occupational exposures, we calculated the risk of the major lymphoma subtypes associated with exposure to six specific organic dusts, namely, flour, hardwood, softwood, natural textile, synthetic textile, and leather, and two generic (any types) groups: wood and textile dusts. Risk was predicted with unconditional regression modeling, adjusted by age, gender, study center, and education. Results: We observed a 2.1-fold increase in risk of follicular lymphoma associated with ever exposure to leather dust [95% confidence interval (CI) 1.01–4.20]. After excluding subjects who ever worked in a farm or had ever been exposed to solvents, risk of B-cell lymphoma was elevated in relation to ever exposure to leather dust [odd ratio (OR) 2.2, 95% CI 1.00–4.78], but it was not supported by increasing trends with the exposure metrics. Risk of Hodgkin lymphoma was elevated (OR 2.0, 95% CI 0.95–4.30) for exposure to textile dust, with consistent upward trends by cumulative exposure and three independent exposure metrics combined (P=0.023, and P=0.0068, respectively). Conclusions: Future, larger studies might provide further insights into the nature of the association we observed between exposure to textile dust and risk of Hodgkin lymphoma.

BackgroundThe International Agency for Research on Cancer (IARC) recently classified glyphosate, the most used herbicide worldwide, as a probable human carcinogen. We inquired into the association between occupational exposure to glyphosate and risk of lymphoma subtypes in a multicenter case-control study conducted in Italy. MethodsThe Italian Gene-Environment Interactions in Lymphoma Etiology (ItGxE) study took place in 2011-17 in six Italian centres. Overall, 867 incident lymphoma cases and 774 controls participated in the study. Based on detailed questionnaire information, occupational experts classified duration, confidence, frequency, and intensity of exposure to glyphosate for each study subject. Using unconditional regression analysis, we modelled risk of major lymphoma subtypes associated with exposure to glyphosate adjusted by age, gender, education, and study centre. ResultsVery few study subjects (2.2%) were classified as ever exposed to glyphosate. Risk of follicular lymphoma (FL) was elevated 7-fold in subjects classified as ever exposed to glyphosate with medium-high confidence, 4.5-fold in association with medium-high cumulative exposure level, 12-fold with medium-high exposure intensity, and 6-fold with exposure for 10 days or more per year. Significant upward trends were detected with all the exposure metrics, but duration. The overall p-value for an upward trend with four independent metrics was 1.88 x 10-4. There was no association with risk of lymphoma (any subtype), Non Hodgkin Lymphoma, B-cell lymphoma, or the major lymphoma subtypes other than FL. ConclusionsOur findings provide limited support to the IARC decision to classify glyphosate as Group 2A human carcinogen.

In these days of 2020, tests for the diagnosis of SARS-CoV-2, and their use in the context of health surveillance of workers, are becoming popular. Nevertheless, their sensitivity and specificity could vary on the basis of the type of test used and on the moment of infection of the subject tested. The aim of this viewpoint paper is to make employers, workers, occupational physicians, and public health specialists think about the limits of diagnostic tests currently available, and the possible implication related to the erroneous and incautious assignment of “immunity passports” or “risk-free certificates” to workers during screening campaigns in workplaces.

International audience; Medical diagnostic X-rays are an important source of ionizing radiation (IR) exposure in the general population; however, it is unclear if the resulting low patient doses increase lymphoma risk. We examined the association between lifetime medical diagnostic X-ray dose and lymphoma risk, taking into account potential confounding factors, including medical history. The international Epilymph study (conducted in the Czech-Republic, France, Germany, Ireland, Italy, and Spain) collected self-reported information on common diagnostic X-ray procedures from 2,362 lymphoma cases and 2,465 frequency-matched (age, sex, country) controls. Individual lifetime cumulative bone marrow (BM) dose was estimated using time period-based dose estimates for different procedures and body parts. The association between categories of BM dose and lymphoma risk was examined using unconditional logistic regression models adjusting for matching factors, socioeconomic variables, and the presence of underlying medical conditions (atopic, autoimmune, infectious diseases, osteoarthritis, having had a sick childhood, and family history of lymphoma) as potential confounders of the association. Cumulative BM dose was low (median 2.25 mGy) and was not positively associated with lymphoma risk. Odds ratios (ORs) were consistently less than 1.0 in all dose categories compared to the reference category (less than 1 mGy). Results were similar after adjustment for potential confounding factors, when using different exposure scenarios, and in analyses by lymphoma subtype and by type of control (hospital-, population-based). Overall no increased risk of lymphoma was observed. The reduced ORs may be related to unmeasured confounding or other sources of systematic bias.We found little evidence that chronic medical conditions confound lymphoma risk and medical radiation associations.

Introduction Oral health-related quality of life is a reflection of general health and wellbeing; related problems stand as major public health issues. Aim To investigate the potential association between dental caries and quality of life (QoL) among children aged 5-6 years old. Materials and methods Oral examination of 310 children admitted to a paediatric dentistry clinic was performed by using the International Caries Detection and Assessment System II (ICDAS-II) and the QoL was assessed using the Early Childhood Oral Health Impact Scale. A nested case-control study was conducted with all 104 QoL-unaffected children as the controls and a random sample of 104 QoL-affected children as the cases. Relative risk (RR) and its 95% confidence interval (CI) values were calculated to interpret potential associations. Results Gender distribution was similar by case controls (52.9% vs 51.0% were females, respectively). Early childhood caries (ECC) was detected in 78.8% of cases and 19.2% of controls. In binary analysis of the QoL (with a cutpoint of 2), low parental education, having a sibling, dental visit history for complaints and irregular/no toothbrushing were detected as significant predictors of poor QoL (p value

Background Evidence linking risk of lymphoma and B-cell lymphoma subtypes to ionizing radiation is inconclusive, particularly at low exposure levels. Methods We investigated risk of lymphoma (all subtypes), B-cell lymphomas, and its major subtypes, associated with low-level occupational exposure to ionizing radiation, in 2346 lymphoma cases and 2463 controls, who participated in the multicenter EpiLymph case-control study. We developed a job-exposure matrix to estimate exposure to ionizing radiation, distinguishing between internal and external radiation, and we applied it to the lifetime occupational history of study subjects, We calculated the Odds Ratio (OR) and its 95% confidence interval (95% CI) for lymphoma (all subtypes combined), B-cell lymphoma, and its major subtypes using unconditional, polytomous logistic regression adjusting for age, gender, and education. Results We did not observe an association between exposure metrics of external and internal radiation and risk of lymphoma (all subtypes), nor with B-cell lymphoma, or its major subtypes, at the levels regularly experienced in occupational settings. An elevated risk of diffuse large B cell lymphoma was observed among the most likely exposed study subjects with relatively higher exposure intensity, which would be worth further investigation. Conclusions Further investigation is warranted on risk of B cell lymphoma subtypes associated with low-level occupational exposure to external ionizing radiation, and to clarify whether lymphoma should be included among the cancer outcomes related to ionizing radiation.

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of “heterozygote advantage” regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06–1.60; OR MZL = 1.45, 95% CI = 1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24–3.55; OR MZL = 2.10, 95% CI = 0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes. Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086–96. ©2018 AACR.

To assess the predictive power of the comet assay in the context of occupational exposure to pesticides.The recruited subjects completed a structured questionnaire and gave a blood sample. Exposure to pesticides was measured by means of an algorithm based on Dosemeci's work (Agricultural Health Study). Approximately 50 images were analyzed for each sample via fluorescence microscopy. The extent of DNA damage was estimated by tail moment (TM) and is the product of tail DNA (%) and tail Length.Crude significant risks (odds ratios, ORs) for values higher than the 75th percentile of TM were observed among the exposed subjects (score 1). The frequency of some confounding factors (sex, age and smoking) was significantly higher among the exposed workers. A significant dose-effect relationship was observed between TM and exposure score. Significant high-risk estimates (ORs), adjusted by the studied confounding factors, among exposure to pesticides and TM, % tail DNA and tail length were confirmed using unconditional logistic regression models.The adjusted associations (ORs) between the comet parameters and exposure to pesticides were significant. The sensitivity of the comet test was low (41%), the specificity (89%) and the predictive positive value (0.77) were found acceptable.

Objective Using a quantitative diary design, the purpose of this paper is to gain insight in the workplace violence phenomenon by examining whether within-person fluctuations in fear of future violence is linked to within-person levels of burnout. In addition, authors investigated whether this relationship was stronger for those low in job control. Finally, psychological violence was proposed as a cross-level moderator of the relation between fear of future violent events at work and burnout. Methods A diary study was conducted among 40 doctors on duty. Participants completed a general questionnaire and a diary booklet (one diary every 10-working days; 40 × 5 = 200 occasions). Results Multilevel analyses showed that fear of future violence was linked to emotional exhaustion and cynicism. Job control did not moderate the relationship between fear of future violence and cynicism but moderated the relationship between fear of future violence and emotional exhaustion. In addition, the experience of psychological violence did not moderate the relationships of fear of future violence with either emotional exhaustion or cynicism. Conclusions Our findings provided additional evidence that not only being the target of violent behaviors may take an emotional toll. When a worker experiences fear of future violent events at work, he\she tends to experience stronger levels of emotional exhaustion and cynicism. Job control plays a fundamental role, buffering the way that a person perceives workplace conditions and the choice of coping strategy.

Background: Work-related stress is a potential cardiovascular risk factor, but the underlying mechanism is not fully explained. The autonomic nervous system control of cardiac function might play a specific role, therefore, monitoring the QT interval in the electrocardiogram can highlight an autonomic imbalance induced by occupational stressors. The aim of our study was to explore the QT interval parameters as early indicators of imbalance of the autonomic cardiac function in relation to work-related stress. Methods: During 2015&ndash, 2016 annual workplace health surveillance, we measured work-related stress in 484 workers of a logistic support company using the Health and Safety Executive (HSE) tool. We assessed the frequency-corrected QT (QTc) interval and the QT index (QTi) on the electrocardiogram of each participant, and collected demographic and clinical data. We compared the QTc values by the four Karasek&rsquo, s categories (active/passive jobs, low/high strain job), and by job support (present/lacking), and conducted multivariate analysis to adjust for possible confounders. Results: The results of the multivariate regression analysis showed that QTc was prolonged among workers operating at a specific site where stress level was found to be elevated. Regular physical activity showed a beneficial effect against QTc prolongation. We did not observe an effect on QTc length by the cross-combined Karasek&rsquo, s categories of job control, job demand, and job support. Conclusions: Our study suggests subclinical effects of conditions associated with work-related stress on the autonomic regulation of cardiac function. Further research is warranted to elucidate the combined effect of work organization and lifestyle factors on autonomic cardiac function.

International audience; Epidemiologic studies show an increased risk of non-Hodgkin lymphoma (NHL) in patients with autoimmune disease (AD), due to a combination of shared environmental factors and/or genetic factors, or a causative cascade: chronic inflammation/antigen-stimulation in one disease leads to another. Here we assess shared genetic risk in genome-wide-association-studies (GWAS). Secondary analysis of GWAS of NHL subtypes (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and ADs (rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Shared genetic risk was assessed by (a) description of regional genetic of overlap, (b) polygenic risk score (PRS), (c)"diseasome", (d)meta-analysis. Descriptive analysis revealed few shared genetic factors between each AD and each NHL subtype. The PRS of ADs were not increased in NHL patients (nor vice versa). In the diseasome, NHLs shared more genetic etiology with ADs than solid cancers (p = .0041). A meta-analysis (combing AD with NHL) implicated genes of apoptosis and telomere length. This GWAS-based analysis four NHL subtypes and three ADs revealed few weakly-associated shared loci, explaining little total risk. This suggests common genetic variation, as assessed by GWAS in these sample sizes, may not be the primary explanation for the link between these ADs and NHLs.

Background Clustered protocadherins (PCDHs) map in tandem at human chromosome 5q31 and comprise three multi-genes clusters: α-, β- and γ-PCDH. The expression of this cluster consists of a complex mechanism involving DNA hub formation through DNA-CCTC binding factor (CTCF) interaction. Methylation alterations can affect this interaction, leading to transcriptional dysregulation. In cancer, clustered PCDHs undergo a mechanism of long-range epigenetic silencing by hypermethylation. Results In this study, we detected frequent methylation alterations at CpG islands associated to these clustered PCDHs in all the solid tumours analysed (colorectal, gastric and biliary tract cancers, pilocytic astrocytoma), but not hematologic neoplasms such as chronic lymphocytic leukemia. Importantly, several altered CpG islands were associated with CTCF binding sites. Interestingly, our analysis revealed a hypomethylation event in pilocytic astrocytoma, suggesting that in neuronal tissue, where PCDHs are highly expressed, these genes become hypomethylated in this type of cancer. On the other hand, in tissues where PCDHs are lowly expressed, these CpG islands are targeted by DNA methylation. In fact, PCDH-associated CpG islands resulted hypermethylated in gastrointestinal tumours. Conclusions Our study highlighted a strong alteration of the clustered PCDHs methylation pattern in the analysed solid cancers and suggested these methylation aberrations in the CpG islands associated with PCDH genes as powerful diagnostic biomarkers. Electronic supplementary material The online version of this article (10.1186/s13148-019-0695-0) contains supplementary material, which is available to authorized users.

Lymphoma defines a group of different diseases. This study examined pre-treatment plasma samples from 66 adult patients (aged 20&ndash, 74) newly diagnosed with any lymphoma subtype, and 96 frequency matched population controls. We used gas chromatography-mass spectrometry (GC-MS) to compare the metabolic profile by case/control status and across the major lymphoma subtypes. We conducted univariate and multivariate analyses, and partial least square discriminant analysis (PLS-DA). When compared to the controls, statistically validated models were obtained for diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and Hodgkin lymphoma (HL), but not follicular lymphoma (FL). The metabolomic analysis highlighted interesting differences between lymphoma patients and population controls, allowing the discrimination between pathologic and healthy subjects: Important metabolites, such as hypoxanthine and elaidic acid, were more abundant in all lymphoma subtypes. The small sample size of the individual lymphoma subtypes prevented obtaining PLS-DA validated models, although specific peculiar features of each subtype were observed, for instance, fatty acids were most represented in MM and HL patients, while 2-aminoadipic acid, 2-aminoheptanedioic acid, erythritol, and threitol characterized DLBCL and CLL. Metabolomic analysis was able to highlight interesting differences between lymphoma patients and population controls, allowing the discrimination between pathologic and healthy subjects. Further studies are warranted to understand whether the peculiar metabolic patterns observed might serve as early biomarkers of lymphoma.

Background Risk factors associated with non-Hodgkin lymphoma (NHL) remain unknown, but certain occupational contexts (OCs) have been implicated. The objective of this study was to inventory, from the accumulated knowledge, associations between OCs and NHL risk. Methods Literature was used to identify the NHL-associated OCs. For each context, items were ranked both by scientific interest and the association strength. Results Three ranked lists of OCs related to NHL were constructed. We found that NHL was associated with 31 occupational activities, 91 occupational exposures, and 35 occupational activity–exposure combinations. Among them, 5 activities, 2 exposures, and 3 combinations, involving agricultural or industrial sector and solvents or pesticides, were highlighted with the highest publications number and the strongest association with NHL risk. Conclusion These results could be useful in both providing a ranked inventory of OCs associated with NHL risk and highlighting “hot” occupational activities and exposures. Am. J. Ind. Med. © 2016 Wiley Periodicals, Inc.

Background A possible protective effect of seasonal influenza vaccination against the spread of the COVID-19 epidemic has been suggested. Methods We used publicly available data bases to explore the hypothesis as well as the effect of multiple social and environmental factors in the 20 Italian regions. Results Our results suggest that vaccination against seasonal influenza might beneficially impact on incidence and severity of the novel corona virus epidemic. Population density and vehicular traffic were also moderately associated with cumulative incidence of COVID-19. None of the other variables we considered showed an effect on cumulative incidence, case fatality rate or mortality from COVID-19. Conclusions Extending influenza vaccination coverage particularly among the elderly, vulnerable individuals with specific chronic medical conditions, health care workers, and workers in other essential services, early in the upcoming 2020 influenza season, might help reduce the health impact of a second epidemic wave of COVID-19.

We used field-emission scanning electron microscopy (FESEM) coupled with energy dispersive X-ray spectroscopy (EDS) microanalysis to determine size, shape, and elemental composition of particles in the liver and kidney autopsy of 35 subjects living in Sardinia. Particles were detected in 94% of livers and in 97% of kidney samples as aggregates, ranging between 50 nm and 100 μm. A total of 513 particle aggregates were observed in all tissues (276 in the liver and 237 in the kidney samples). Aggregates consisted of single elements (As, Ba, Cu, F, Fe, Ge, Hg, Ni, P, Pb, S, Si, Ti) or multiple association of elements, up to six. Silicon and Fe were the main element constituents (presence in 61% and 23% of the total Pags) followed by Al, Hg, Ni, Pb, and Ti (

Background: Lipid traits have been inconsistently linked to risk of non-Hodgkin lymphoma (NHL). We examined the association of genetically predicted lipid traits with risk of diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and marginal zone lymphoma (MZL) using Mendelian randomization (MR) analysis. Methods: Genome-wide association study data from the InterLymph Consortium were available for 2,661 DLBCLs, 2,179 CLLs, 2,142 FLs, 824 MZLs, and 6,221 controls. SNPs associated (P < 5 × 10−8) with high-density lipoprotein (HDL, n = 164), low-density lipoprotein (LDL, n = 137), total cholesterol (TC, n = 161), and triglycerides (TG, n = 123) were used as instrumental variables (IV), explaining 14.6%, 27.7%, 16.8%, and 12.8% of phenotypic variation, respectively. Associations between each lipid trait and NHL subtype were calculated using the MR inverse variance–weighted method, estimating odds ratios (OR) per standard deviation and 95% confidence intervals (CI). Results: HDL was positively associated with DLBCL (OR = 1.14; 95% CI, 1.00–1.30) and MZL (OR = 1.09; 95% CI, 1.01–1.18), while TG was inversely associated with MZL risk (OR = 0.90; 95% CI, 0.83–0.99), all at nominal significance (P < 0.05). A positive trend was observed for HDL with FL risk (OR = 1.08; 95% CI, 0.99–1.19; P = 0.087). No associations were noteworthy after adjusting for multiple testing. Conclusions: We did not find evidence of a clear or strong association of these lipid traits with the most common NHL subtypes. While these IVs have been previously linked to other cancers, our findings do not support any causal associations with these NHL subtypes. Impact: Our results suggest that prior reported inverse associations of lipid traits are not likely to be causal and could represent reverse causality or confounding.

ObjectivesTo investigate the association between occupational exposure to aromatic hydrocarbon solvents and risk of multiple myeloma (MM) in a large, consortium-based study.MethodsWe pooled data on 2854 cases and 10 743 controls from nine studies participating in the InterLymph consortium. Occupational exposures to benzene, toluene and xylene were assigned by a job–exposure matrix, coupled with ‘correction’ of exposure probability by self-reported or expert-assessed exposure from the individual studies. Cumulative intensity was calculated as the job-specific exposure intensity multiplied by job duration, summed across jobs. Associations were estimated using logistic regression, with inclusion of covariates for study matching factors and other potential confounders. We repeated our main analysis using random-effects meta-analysis to evaluate heterogeneity of effect.ResultsBenzene, toluene and xylene were each associated with MM. For the three solvents, the highest quartile of high-probability cumulative intensity exposure (vs unexposed) was associated with 42% to 63% increased risks of MM. Associations with toluene and xylene exposures were fairly consistent and robust to sensitivity analyses. The estimated effect for benzene was moderately heterogeneous between the studies. Each solvent’s association with MM was stronger for exposure occurring within 20 years of diagnosis than with exposure lagged by more than 20 years.ConclusionsOur study adds important evidence for a role of aromatic hydrocarbon solvents in causation of MM. The difficulty in disentangling individual compounds in this group and a lack of data on potential carcinogenicity of toluene and xylene, in widespread current use, underscore a need for further epidemiological evaluation.

IF 15.132 (2017); International audience; Inherited loci have been found to be associated with risk of chronic lymphocytic leukemia (CLL). A combined polygenic risk score (PRS) of representative single nucleotide polymorphisms (SNPs) from these loci may improve risk prediction over individual SNPs. Herein, we evaluated the association of a PRS with CLL risk and its precursor, monoclonal B-cell lymphocytosis (MBL). We assessed its validity and discriminative ability in an independent sample and evaluated effect modification and confounding by family history (FH) of hematological cancers. For discovery, we pooled genotype data on 41 representative SNPs from 1499 CLL and 2459 controls from the InterLymph Consortium. For validation, we used data from 1267 controls from Mayo Clinic and 201 CLL, 95 MBL, and 144 controls with a FH of CLL from the Genetic Epidemiology of CLL Consortium. We used odds ratios (ORs) to estimate disease associations with PRS and c-statistics to assess discriminatory accuracy. In InterLymph, the continuous PRS was strongly associated with CLL risk (OR, 2.49; P = 4.4 × 10-94). We replicated these findings in the Genetic Epidemiology of CLL Consortium and Mayo controls (OR, 3.02; P = 7.8 × 10-30) and observed high discrimination (c-statistic = 0.78). When jointly modeled with FH, PRS retained its significance, along with FH status. Finally, we found a highly significant association of the continuous PRS with MBL risk (OR, 2.81; P = 9.8 × 10-16). In conclusion, our validated PRS was strongly associated with CLL risk, adding information beyond FH. The PRS provides a means of identifying those individuals at greater risk for CLL as well as those at increased risk of MBL, a condition that has potential clinical impact beyond CLL.

Introduction Farming occupations have been reported at risk of developing non Hodgkin lymphoma. Within the EPILYMPH multicentre European case-control study on the aetiology of lymphoma, we explored the association of risk of the major lymphoma subtypes with exposure to specific classes of pesticides, contact with livestock, and exposure to organic dust. Methods In 1998–2003, 2348 cases of lymphoma (all subtypes), and 2462 controls participated in the EPILYMPH case-control study in several centres six European countries. A detailed occupational history was collected in cases and controls. Information on contact with breeding animals, exposure to five organic dusts, and to specific classes of pesticides was obtained through personal interviews. Local agronomists and occupational experts assessed likelihood, frequency and intensity of specific exposures based on the questionnaire information. Risk of the major lymphoma subtypes associated with contact with the most frequently represented species of livestock, organic dusts, and classes of pesticides was calculated with unconditional logistic regression analysis adjusting by age, gender, education, and centre. Result Exposure to organophosphate insecticides was significantly associated with an increase in risk of chronic lymphocytic leukaemia; risk of DLBCL, was significantly lower amongst subjects who started occupational contact with any species of livestock before or at age 12 (OR=0.5, 95% CI: 0.2 to 0.9), but not at older ages. A significant heterogeneity in risk of B cell lymphoma by age at first contact was detected for contact with cattle, poultry and swine. We did not find an association with exposure to any of the organic dust exposures. Discussion Agricultural exposures are numerous, and difficult to disentangle; also, the use of agrochemicals varies with time, type of crop, and location. Some exposures might be etiologically relevant, others might protect against lymphomas depending on age at first exposure, possibly in relation to the different type of immune response elicited.

Introduction To study new disease-exposure associations, we created a pilot network (namely MAREL – MAlattie e Rischi Emergenti sul Lavoro ) of occupational disease consultation centres of the Italian national health service to which patients are referred for potentially work-related diseases. Methods The MAREL network included in 2016 five occupational disease consultation centres of university hospitals located in central-northern Italy. Patients were referred to the MAREL consultation centres by their general practitioners, occupational physicians or other specialists for the investigation of the putative occupational origin of a disease. Each centre collected cases of putative occupational origin through a structured and standardised data collection form. We collected data on: diagnosis; personal habits; occupational history; exposure to risk factors; physician’s opinion on the possible causal relationship between disease and occupation. Data were coded according to national and international classifications. Results The data collection started in 2016, enrolling 1516 cases of putative occupational diseases. Musculoskeletal disorders were the most represented conditions: intervertebral lumbar disc degeneration (11.2%), spondylitis (6.3%), tendinopathies (4.9%), arthritis (4.8%), upper limb mononeuropathies (4.4%), and shoulder disorders (3.7%). The most frequently reported exposures were related to biomechanical overload: manual material handling (29.5%, out of 1811), hand-arm vibrations (13.9%), repetitive movements of the upper limb (10.9%), whole-body vibrations (7.6%), awkward posture of the upper limb (7.1%), and awkward body posture (4.5%). Discussion The exposure to biomechanical overload seems to play a role in generating potentially work-related conditions. Expanding the MAREL network to other occupational disease consultation centres in 2017 and 2018, we will contribute to already existing surveillance systems (i.e. MALPROF) by the detection of new and emerging occupational diseases and risks.

Introduction The definition of pesticide covers about 1 00 000 different chemicals, inorganic and organic, that are grouped according to their function or their chemical structure. Evidence is growing about long-term health effects following high-level, long-lasting exposure to some pesticides, including asthma and other allergic diseases, immunotoxicity, endocrine disruption, cancer, and central and peripheral nervous system effects. Identifying such specific chemicals is of paramount importance in preventing ill health in farmers, while preserving the benefits of plant protection against pests. Methods An extensive review of the literature was conducted. Result Currently, the International Agency for Research on Cancer classifies three obsolete agrochemicals as Group 1 human carcinogens (Arsenic compounds, lindane, and 1,2-dichloropropane); six are classified as probable human carcinogens, including captafol, DDT, diazinon, glyphosate, ethylene dibromide, and malathion, generating a vast controversy among the International Health and Safety Agencies and the media about the need to phase them out as some were widely used worldwide. Possibly human carcinogen pesticides are 20, and for 32 there is inadequate scientific evidence to classify their potential human carcinogenicity. The endocrine disrupting effects of numerous pesticides have also been extensively studied, but evidence of hormonal effects comes mainly from animal studies, either laboratory or wildlife animals; such results are difficult to refer to the low level long term exposure in humans. Other chronic effects repeatedly reported among users of specific pesticides include asthma and chronic bronchitis, immunosuppression, and neurodegenerative diseases, with the classical example of paraquat, but also other pesticide classes, and Parkinson’s disease. Discussion Major reasons for uncertainty in interpreting epidemiological findings of long term pesticide effects include the complex pattern of overlapping exposure due to multiple treatments applied to different crops and their frequent changes over time to overcome pest resistance. Further research will have to address specific agrochemicals with well-characterised exposure patterns.

We investigated the association between environmental exposure to radiofrequency electromagnetic fields (RF-EMF) and risk of lymphoma subtypes in a case-control study comprised of 322 patients and 444 individuals serving as controls in Sardinia, Italy in 1998-2004. Questionnaire information included the self-reported distance of the three longest held residential addresses from fixed radio-television transmitters and mobile phone base stations. We georeferenced the residential addresses of all study subjects and obtained the spatial coordinates of mobile phone base stations. For each address within a 500-meter radius from a mobile phone base station, we estimated the RF-EMF intensity using predictions from spatial models, and we performed RF-EMF measurements at the door in the subset of the longest held addresses within a 250-meter radius. We calculated risk of lymphoma and its major subtypes associated with the RF-EMF exposure metrics with unconditional logistic regression, adjusting by age, gender and years of education. In the analysis of self-reported data, risk associated with residence in proximity (within 50 meters) to fixed radio-television transmitters was likewise elevated for lymphoma overall [odds ratio = 2.7, 95% confidence interval = 1.5-4.6], and for the major lymphoma subtypes. With reference to mobile phone base stations, we did not observe an association with either the self-reported, or the geocoded distance from mobile phone base stations. RF-EMF measurements did not vary by case-control status. By comparing the self-reports to the geocoded data, we discovered that the cases tended to underestimate the distance from mobile phone base stations differentially from the controls ( P = 0.073). The interpretation of our findings is compromised by the limited study size, particularly in the analysis of the individual lymphoma subtypes, and the unavailability of the spatial coordinates of radio-television transmitters. Nonetheless, our results do not support the hypothesis of a link between environmental exposure to RF-EMF from mobile phone base stations and risk of lymphoma subtypes.

Background: A proportion of the genetic variants involved in susceptibility to Hodgkin lymphoma differ by the tumor's Epstein–Barr virus (EBV) status, particularly within the MHC region. Methods: We have conducted an SNP imputation study of the MHC region, considering tumor EBV status in 1,200 classical Hodgkin lymphoma (cHL) cases and 5,726 control subjects of European origin. Notable findings were genotyped in an independent study population of 468 cHL cases and 551 controls. Results: We identified and subsequently replicated a novel association between a common genetic variant rs6457715 and cHL. Although strongly associated with EBV-positive cHL [OR, 2.33; 95% confidence interval (CI), 1.83–2.97; P = 7 × 10–12], there was little evidence for association between rs6457715 and the EBV-negative subgroup of cHL (OR, 1.06; 95% CI, 0.92–1.21), indicating that this association was specific to the EBV-positive subgroup (Phet < P = 10−8). Furthermore, the association was limited to EBV-positive cHL subgroups within mixed cell (MCHL) and nodular sclerosis subtypes (NSHL), suggesting that the association is independent of histologic subtype of cHL. Conclusions: rs6457715, located near the HLA-DPB1 gene, is associated with EBV-positive cHL and suggests this region as a novel susceptibility locus for cHL. Impact: This expands the number of genetic variants that are associated with cHL and provides additional evidence for a critical and specific role of EBV in the etiology of this disease. Cancer Epidemiol Biomarkers Prev; 24(12); 1838–43. ©2015 AACR.

Quantification of platinum in human urine is a valuable technique for assessing occupational and environmental exposure to platinum. We hereby present a simple and sensitive method to monitor urinary platinum in hospital workers exposed to platinum-based anticancer agents. This method consists in: i) the sample digestion with an ultrapure HNO3/HCl (5:1) mixture in a sonicator for 2 h, and ii) the Inductively Coupled Plasma Mass Spectrometry (ICP–MS) platinum determination on the 1:10 diluted solutions. Sample pre-treatment is simpler and faster when compared to other published procedures, which are typically multistep and time-consuming and often require expensive equipments. The ICP–MS analysis of all pre-treated samples shows good selectivity, sensitivity, repeatability and recoveries. It is noteworthy that in the present case both standard addition mode and the direct platinum determination with reference to an external calibration curve give satisfactory results for urinary platinum, while the standard addition mode is typically required in the literature methods.

The aim of the study was to examine the relationship between role stress, emotional exhaustion, and a supportive coworker climate among health care workers, by adopting a multilevel perspective.Aggregated data of 738 health care workers nested within 67 teams of three Italian hospitals were collected. Multilevel regression analysis with a random intercept model was used.Hierarchical linear modeling showed that a lack of role clarity was significantly linked to emotional exhaustion at the individual level. At the unit level, the cross-level interaction revealed that a supportive coworker climate moderated the relationship between lack of role clarity and emotional exhaustion.This study supports previous results of single-level burnout studies, extending the existing literature with evidence on the multidimensional and cross-level interaction associations of a supportive coworker climate as a key aspect of job resources on burnout.

Introduction The association between ionising radiation and risk of solid tumours and leukaemia is well established; however, the role of low dose radiation exposure in the aetiology of lymphoma is still uncertain. We investigated the role of occupational exposure to internal and external ionising radiation in the aetiology of lymphoma and its major subtypes. Methods Between 1998 and 2004, 2348 cases and 2465 controls from six different European countries participated in the multicentre EpiLymph case-control study. A detailed occupational history was collected by questionnaire in all participants a coded using the ISCO68 occupational and NACE industrial coding systems. Based on the same coding systems, we developed a Job Exposure Matrix (JEM) to assess probability and intensity of exposure to internal and external ionising radiation. We used unconditional logistic regression to calculate Odds Ratios and their 95% Confidence Intervals for lymphoma and its major subtypes associated with the ionising radiation exposure metrics, adjusting by age, gender, education and country. Results Risk of lymphoma overall did not show an association with exposure to radiation either internal or external. Risk of Diffuse Large B-Cell Lymphoma (DLBCL) was elevated and did show an upward trend with intensity of exposure to external radiation (Low Intensity OR=2.1, 95% CI=0.97–4.46 and High Intensity OR=2.5, 95% CI=1.21–5.08). We did not observe any risk increase associated with internal exposure to ionising radiation. Conclusions Our results provide limited support to the relation between external sources of ionising radiation and risk of DLBCL. We cannot exclude the possibility of bias due to the multiple comparisons we made.

Background Detecting new disease-exposure associations is an important public health issue. We created a pilot network (MAREL - MAlattie e Rischi Emergenti sul Lavoro) of occupational disease consultation centres of Italian university hospitals to which patients are referred for potentially work-related diseases. Methods The MAREL network currently includes five occupational disease consultation centres of university hospitals located in central-northern Italy. Patients are referred to these consultation centres by their general practitioners, occupational physicians or other specialists for the investigation of the putative occupational origin of the disease. Each centre collects cases of putative occupational origin through a structured and standardised data collection form. We collect data on: diagnosis; personal habits; occupational history; exposure assessment for potentially associated risk factors; physician’s opinion on the possible causal relationship between disease and occupation. Data are coded according to national and international classifications. Results The data collection started in 2016. We collected 1516 cases of putative occupational diseases. Intervertebral lumbar disc degeneration was the most represented condition (n=170, 11.2%). Apart from musculoskeletal disorders, cases of asthma were the most frequently reported (n=59, 3.9%). About 11% of patients were construction workers. The most frequently reported exposures were: manual material handling (29.5%, out of 1811), hand-arm vibrations (13.9%), and repetitive movements of the upper limb (10.9%). Discussion The MAREL network will be expanded to other occupational disease consultation centres in 2017 with the aim to contribute to already existing surveillance systems (i.e. MALPROF) by the detection of new and emerging occupational diseases and risks.

Introduction Conflicting results have been published on the association between occupational and environmental exposure to radiofrequency (RF) and cancer risk Information bias might have played a role in some instances. Methods We geocoded fixed radio-tv transmitters and mobile phone base stations, as well as the residence of 451 cases and 603 controls who participated in a case-control study on the aetiology of lymphoma in Sardinia, Italy. A detailed residential history was available for all cases and controls, including the perceived distance from fixed radio-tv transmitters and mobile phone base stations. We applied the models used by the Regional Agency for Environmental Protection, and conducted RF measurements to estimate the RF field at the door of study subjects. We used unconditional logistic regression to calculate Odds Ratios and their 95% confidence intervals for lymphoma and its major subtypes associated with the RF exposure metrics, adjusting by age, gender, and education. Results Based on questionnaire data, risk of lymphoma overall was elevated for a cumulative exposure to fixed radio-tv transmitters above the median (OR=2.7, 95% CI=1.5–4.6). Risk was likewise elevated for all lymphoma subtypes. With reference to mobile phone base stations, we only observed a non significant excess risk of diffuse large B-cell lymphoma (DLBCL, OR=2.5, 95% CI=0.7–8.3). Such associations disappeared when we considered exposure based on the models, or the measurements. By comparing the reported distance to the geocoded data, we found out that the cases tended to underestimated the distance from the source of RF emission. Conclusions Our results do not support the hypothesis of a link between environmental exposure to RF and risk of lymphoma subtypes. Conflict of Interest statement : None of the coauthors declare any conflict of interest related to the matters discussed in this paper.

As several media reports suggested an increase in cancer mortality in the surrounding area, we investigated the mortality experience of the military personnel of the Interforce shooting range of Salto di Quirra (PISQ) in Sardinia, Italy.Based on the PISQ registers, we reconstructed the cohort of 6,828 military personnel who had been employed at PISQ for at least six months on January 1, 1990 or entered subsequently up to June 30, 2005. We searched for life status or date, place, and cause of death of each cohort member up to December 31, 2010. Based on job and operating department, we preliminarily assessed exposure of each cohort member to radiofrequencies, solvents, nanoparticles, servicing in shooting ranges, participation to peacekeeping operations abroad, and undergoing vaccination procedures while in service. For each cause of interest, we calculated the standardized mortality ratio (SMR) and its 95% confidence interval, based on the Italian and regional rates specific for age, gender and year of follow-up.Mortality from all causes showed a significant decrease over the expectation, based on the national and regional mortality rates (based on national rates: SMR=78, 95% CI 60-101; based on regional rates: SMR=66, 95% CI 52-84). Deaths from haemolymphatic malignancies matched the expectation from regional rates (7 cases vs 6,3 expected; SMR=111, 95% CI 38-326). We observed two deaths from neoplasms of the haemolymphopoietic system against 0.5 expected among solvent exposed cohort members. We did not observe any significant increase in mortality from all causes or specific causes of death in relation to the exposures we investigated.The study size was too small, and the follow-up not prolonged enough to conclude whether the operational activities at PISQ did result or not in increased risks of specific causes of death, including cancers, among the military personnel. Further follow-up will be needed before final conclusions can be drawn.

(1) Background: The assessment of airborne particulate matter (PM) and ultrafine particles (UFPs) in battlefield scenarios is a topic of particular concern; (2) Methods: Size distribution, concentration, and chemical composition of UFPs during operative military training activities (target drone launches, ammunition blasting, and inert bomb impact) were investigated using an electric low-pressure impactor (ELPI+) and a scanning electron microscope (SEM), equipped with energy-dispersive spectroscopy (EDS); (3) Results: The median of UFPs, measured for all sampling periods and at variable distance from sources, was between 1.02 × 103 and 3.75 × 103 particles/cm3 for drone launches, between 3.32 × 103 and 15.4 × 103 particles/cm3 for the ammunition blasting and from 7.9 × 103 to 1.3 × 104 particles/cm3 for inert launches. Maximum peak concentrations, during emitting sources starting, were 75.5 × 106 and 17.9 × 106 particles/cm3, respectively. Particles from the drone launches were predominantly composed of silicon (Si), iron (Fe) and calcium (Ca), and those from the blasting campaigns by magnesium (Mg), sulphur (S), aluminum (Al), iron (Fe), barium (Ba) and silicon (Si); (4) Conclusions: The investigated sources produced UFPs with median values lower than other anthropogenic sources, and with a similar chemical composition.

Background: Non-Hodgkin lymphoma (NHL), the most common hematologic malignancy, consists of numerous subtypes. The etiology of NHL is incompletely understood, and increasing evidence suggests that risk factors may vary by NHL subtype. However, small numbers of cases have made investigation of subtype-specific risks challenging. The International Lymphoma Epidemiology Consortium therefore undertook the NHL Subtypes Project, an international collaborative effort to investigate the etiologies of NHL subtypes. This article describes in detail the project rationale and design. Methods: We pooled individual-level data from 20 case-control studies (17 471 NHL cases, 23 096 controls) from North America, Europe, and Australia. Centralized data harmonization and analysis ensured standardized definitions and approaches, with rigorous quality control. Results: The pooled study population included 11 specified NHL subtypes with more than 100 cases: diffuse large B-cell lymphoma (N = 4667), follicular lymphoma (N = 3530), chronic lymphocytic leukemia/small lymphocytic lymphoma (N = 2440), marginal zone lymphoma (N = 1052), peripheral T-cell lymphoma (N = 584), mantle cell lymphoma (N = 557), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (N = 374), mycosis fungoides/Sézary syndrome (N = 324), Burkitt/Burkitt-like lymphoma/leukemia (N = 295), hairy cell leukemia (N = 154), and acute lymphoblastic leukemia/lymphoma (N = 152). Associations with medical history, family history, lifestyle factors, and occupation for each of these 11 subtypes are presented in separate articles in this issue, with a final article quantitatively comparing risk factor patterns among subtypes. Conclusions: The International Lymphoma Epidemiology Consortium NHL Subtypes Project provides the largest and most comprehensive investigation of potential risk factors for a broad range of common and rare NHL subtypes to date. The analyses contribute to our understanding of the multifactorial nature of NHL subtype etiologies, motivate hypothesis-driven prospective investigations, provide clues for prevention, and exemplify the benefits of international consortial collaboration in cancer epidemiology.

Marginal zone lymphoma (MZL), comprised of nodal, extranodal, and splenic subtypes, accounts for 5%-10% of non-Hodgkin lymphoma cases. A detailed evaluation of the independent effects of risk factors for MZL and its subtypes has not been conducted.Data were pooled from 1052 MZL cases (extranodal [EMZL] = 633, nodal [NMZL] = 157, splenic [SMZL] = 140) and 13766 controls from 12 case-control studies. Adjusted unconditional logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs).Novel findings for MZL subtypes include increased risk for B-cell activating autoimmune conditions (EMZL OR = 6.40, 95% CI = 4.24 to 9.68; NMZL OR = 7.80, 95% CI = 3.32 to 18.33; SMZL OR = 4.25, 95% CI = 1.49 to 12.14), hepatitis C virus seropositivity (EMZL OR = 5.29, 95% CI = 2.48 to 11.28), self-reported peptic ulcers (EMZL OR = 1.83, 95% CI = 1.35 to 2.49), asthma without other atopy (SMZL OR = 2.28, 95% CI = 1.23 to 4.23), family history of hematologic cancer (EMZL OR = 1.90, 95% CI = 1.37 to 2.62) and of non-Hodgkin lymphoma (NMZL OR = 2.82, 95% CI = 1.33 to 5.98), permanent hairdye use (SMZL OR = 6.59, 95% CI = 1.54 to 28.17), and occupation as a metalworker (NMZL OR = 3.56, 95% CI = 1.67 to 7.58). Reduced risks were observed with consumption of any alcohol (EMZL fourth quartile OR = 0.48, 95% CI = 0.28 to 0.82) and lower consumption of wine (NMZL first to third quartile ORs0.45) compared with nondrinkers, and occupation as a teacher (EMZL OR = 0.58, 95% CI = 0.37 to 0.88).Our results provide new data suggesting etiologic heterogeneity across MZL subtypes although a common risk of MZL associated with B-cell activating autoimmune conditions was found.

Mycosis fungoides and Sézary syndrome (MF/SS) are rare cutaneous T-cell lymphomas. Their etiology is poorly understood.A pooled analysis of 324 MF/SS cases and 17217 controls from 14 case-control studies from Europe, North America, and Australia, as part of the International Lymphoma Epidemiology Consortium (InterLymph) Non-Hodgkin Lymphoma (NHL) Subtypes Project, was carried out to investigate associations with lifestyle, medical history, family history, and occupational risk factors. Multivariate logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI).We found an increased risk of MF/SS associated with body mass index equal to or larger than 30 kg/m(2) (OR = 1.57, 95% CI = 1.03 to 2.40), cigarette smoking for 40 years or more (OR = 1.55, 95% CI = 1.04 to 2.31), eczema (OR = 2.38, 95% CI = 1.73 to 3.29), family history of multiple myeloma (OR = 8.49, 95% CI = 3.31 to 21.80), and occupation as crop and vegetable farmers (OR = 2.37, 95% CI = 1.14 to 4.92), painters (OR = 3.71, 95% CI = 1.94 to 7.07), woodworkers (OR = 2.20, 95% CI = 1.18 to 4.08), and general carpenters (OR = 4.07, 95% CI = 1.54 to 10.75). We also found a reduced risk of MF/SS associated with moderate leisure time physical activity (OR = 0.46, 95% CI = 0.22 to 0.97).Our study provided the first detailed analysis of risk factors for MF/SS and further investigation is needed to confirm these findings in prospective data and in other populations.

Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy and the fifth most common type of cancer in more developed regions of the world (1). Numerous NHL subtypes with distinct combinations of morphologic, immunophenotypic, genetic, and clinical features are currently recognized (2,3). The incidence of NHL subtypes varies substantially by age, sex, and race/ethnicity (4–7). However, the etiological implications of this biological, clinical, and epidemiological diversity are incompletely understood. The importance of investigating etiology by NHL subtype is clearly supported by research on immunosuppression, infections, and autoimmune diseases, which are the strongest and most established risk factors for NHL. Studies of solid organ transplant recipients and individuals infected with HIV demonstrate that risks are markedly increased for several—but not all—NHL subtypes (8–13). Some infections and autoimmune diseases are associated with a single specific subtype [eg, human T-cell lymphotropic virus, type I (HTLV-I) with adult T-cell leukemia/lymphoma (14), celiac disease with enteropathy-type peripheral T-cell lymphoma (PTCL) (15–17)], whereas others [eg, Epstein–Barr virus, hepatitis C virus (HCV), Sjogren’s syndrome (18–21)] have been associated with multiple subtypes. In the last two decades, reports from individual epidemiological studies of NHL have suggested differences in risks among NHL subtypes for a wide range of risk factors, but most studies have lacked the statistical power to assess any differences quantitatively and have not systematically evaluated combinations of subtypes. One study assessed multiple risk factors and found support for both etiologic commonality and heterogeneity for NHL subtypes, with risk factor patterns suggesting that immune dysfunction is of greater etiologic importance for diffuse large B-cell lymphoma (DLBCL) and marginal zone lymphoma than for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma (22). However, that analysis was limited to approximately 1300 NHL cases and considered only the four most common NHL subtypes. Pooling data from multiple studies through the International Lymphoma Epidemiology Consortium (InterLymph) have provided substantial insight into associations between specific risk factors and NHL subtypes, with evidence that family history of hematologic malignancy, autoimmune diseases, atopic conditions, lifestyle factors (smoking, alcohol, anthropometric measures, and hair dye use), and sun exposure are associated with NHL risk (19,21,23–32). However, no previous study has compared patterns of risk for a range of exposures for both common and rarer NHL subtypes. We undertook the InterLymph NHL Subtypes Project, a pooled analysis of 20 case–control studies including 17 471 NHL cases and 23 096 controls, to advance understanding of NHL etiology by investigating NHL subtype-specific risks associated with medical history, family history of hematologic malignancy, lifestyle factors, and occupation. The detailed risk factor profiles for each of 11 NHL subtypes appear in this issue (15–17,33–40). In this report, we assess risk factor heterogeneity among the NHL subtypes and identify subtypes that have similar risk factor profiles.

IntroductionIn 2010, the International Agency for Research on Cancer (IARC) classified ‘Shiftwork that involves circadian disruption’ as a probable human carcinogen (group 2A), based on limited evidence from epidemiological studies and sufficient evidence from experimental animal studies. The epidemiological results were consistent for breast cancer. More recent publications suggested an increase in risk for ovarian and endometrial cancer, prostate cancer, and colorectal cancer.Sleep deprivation is common in shift workers, and it leads to disruption of the transcription of genes implicated in the regulation of the immune response.ObjectivesAs depression of the immune system is a known risk factor for lymphomas, we explored the association between risk of lymphoma subtypes and nightshift work with a case-control study design.Materials and methodsBased on the lifetime occupational history available for 323 cases and 463 controls who participated in a case-control study on lymphoma etiology conducted in Sardinia (Italy) in 1998–2006, expert occupational physicians assessed nightshift work for each job entry of each study subject. We calculated risk of major lymphoma subtypes, namely diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, multiple myeloma and Hodgkin lymphoma, associated with cumulative days of nightshift work with unconditional logistic regression, adjusting by age, gender, and education.ResultsNone of the lymphoma subtypes we investigated showed an association with lifetime cumulative days of nightshift work. Contrary to our expectation, risk of all lymphomas combined tended to decrease with cumulative days of nightshift work.ConclusionsFurther studies are warranted to investigate in more detail whether sleep deprivation resulting from nightshift work might be implicated in lymphomagenesis. Future investigations should include information on the chronotype of study subjects, the specific shift rotation schedule applied in each workplace, usual hours of sleep per day, and occurrence of daytime sleepiness.

Kamper-Jorgensen, M Rostgaard, K Glaser, S L Zahm, S H Cozen, W Smedby, K E Sanjose, S Chang, E T Zheng, T La Vecchia, C Serraino, D Monnereau, A Kane, E V Miligi, L Vineis, P Spinelli, J J McLaughlin, J R Pahwa, P Dosman, J A Vornanen, M Foretova, L Maynadie, M Staines, A Becker, N Nieters, A Brennan, P Boffetta, P Cocco, P Hjalgrim, H eng 5 ROI CA69269/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England 2013/06/22 06:00 Ann Oncol. 2013 Sep;24(9):2245-55. doi: 10.1093/annonc/mdt218. Epub 2013 Jun 19.; International audience; BACKGROUND: The etiology of Hodgkin lymphoma (HL) remains incompletely characterized. Studies of the association between smoking and HL have yielded ambiguous results, possibly due to differences between HL subtypes. PATIENTS AND METHODS: Through the InterLymph Consortium, 12 case-control studies regarding cigarette smoking and HL were identified. Pooled analyses on the association between smoking and HL stratified by tumor histology and Epstein-Barr virus (EBV) status were conducted using random effects models adjusted for confounders. Analyses included 3335 HL cases and 14 278 controls. RESULTS: Overall, 54.5% of cases and 57.4% of controls were ever cigarette smokers. Compared with never smokers, ever smokers had an odds ratio (OR) of HL of 1.10 [95% confidence interval (CI) 1.01-1.21]. This increased risk reflected associations with mixed cellularity cHL (OR = 1.60, 95% CI 1.29-1.99) and EBV-positive cHL (OR = 1.81, 95% CI 1.27-2.56) among current smokers, whereas risk of nodular sclerosis (OR = 1.09, 95% CI 0.90-1.32) and EBV-negative HL (OR = 1.02, 95% CI 0.72-1.44) was not increased. CONCLUSION: These results support the notion of etiologic heterogeneity between HL subtypes, highlighting the need for HL stratification in future studies. Even if not relevant to all subtypes, our study emphasizes that cigarette smoking should be added to the few modifiable HL risk factors identified.

Objectives We evaluated the association between occupational exposure to trichloroethylene (TCE) and risk of non-Hodgkin lymphoma (NHL) in a pooled analysis of four international case-control studies. Methods Overall, the pooled study population included 3788 NHL cases and 4279 controls. Risk of NHL and its major subtypes associated with TCE exposure was calculated with unconditional logistic regression and polytomous regression analysis, adjusting by age, gender and study. Results Risk of follicular lymphoma (FL), but not NHL overall or other subtypes, increased by probability (p=0.02) and intensity level (p=0.04), and with the combined analysis of four exposure metrics assumed as independent (p=0.004). After restricting the analysis to the most likely exposed study subjects, risk of NHL overall, FL and chronic lymphocytic leukaemia (CLL) were elevated and increased by duration of exposure (p=0.009, p=0.04 and p=0.01, respectively) and with the combined analysis of duration, frequency and intensity of exposure (p=0.004, p=0.015 and p=0.005, respectively). Although based on small numbers of exposed, risk of all the major NHL subtypes, namely diffuse large B-cell lymphoma, FL and CLL, showed increases in risk ranging 2–3.2-fold in the highest category of exposure intensity. No significant heterogeneity in risk was detected by major NHL subtypes or by study. Conclusions Our pooled analysis apparently supports the hypothesis of an increase in risk of specific NHL subtypes associated with occupational exposure to TCE.

Background We conducted a cross sectional survey of electrocardiographic changes among shift-workers. Methods We classified the electrocardiogram morphology, and measured the QTc interval in 91 male workers engaged in regular daily work-shifts, 32 in 24 hr work-shift (h24), and 93 in irregular 6 hr work-shift (h6). Results With reference to daily workers, the QTc interval was prolonged among h6 workers (P