Epidemiology of acute lymphoblastic leukaemia in Sardinia, Italy: Age, sex, and environmental correlates.

Using a database of 1974-2003 incident cases of haematological malignancies, we explored the time trend, geographic spread and socio-economic and environmental correlates of ALL incidence in Sardinia, Italy, by sex and age. The age- and sex-standardized (World population) ALL incidence rate was 2.0 per 100,000 (95% CI 1.8 - 2.1) and showed variable trend patterns by sex and age. In the total population, ALL incidence showed an annual per cent change of -1.4% (95% CI -0.59 - -3.34) over the study period, with a knot separating a downward slope in 1974-1996 from an increase in 1996-2003. ALL incidence replicated such pattern in women but not men, whose incidence did not substantially vary over the study period (APC = -2.57%, 95% CI -5.45 - 0.26). Among women, the spatial analysis suggested a clustering of ALL in the southwestern part of the region, whilst only a commune had a high posterior probability of a high ALL incidence among men. Three unrelated communes showed a high posterior probability of ALL at age ≤ 24; only the most populated urban centre showed excess cases at age ≥ 25 years. There was no correlation between the geographic spread of ALL at ages ≤ 24 and ≥ 25 years (p = 0.082). Urban residence was a risk factor for the younger age group. Residences near industrial settlements and in the most populated urban centre were risk factors for subjects aged ≥ 25 years. Our findings suggest age-related differences in ALL aetiology.

Hazardous Effects of Pesticides on Human Health.

Pesticides, a major group of biocides, are designed to control harmful and/or unwanted organisms [...].

Lifetime occupational and recreational physical activity and risk of lymphoma subtypes. Results from the European Epilymph case-control study.

Physical activity is known to convey protection against several cancers. However, results on the risk of lymphoma overall and its subtypes have been inconsistent. The aim of this study was to investigate occupational and recreational physical activity in relation to risk of lymphoma subtypes adjusting for established occupational risk factors. We applied standardized tools to assess energy expenditure at work and in recreational physical activities to the questionnaire information on lifetime work and exercise history in 1117 lymphoma cases, including Hodgkin lymphoma, and B-cell (including chronic lymphocytic leukemia, and multiple myeloma) and T-cell non-Hodgkin's lymphoma (NHL) subtypes, and 1207 controls who took part in the multicentre European EpiLymph case-control study. We calculated the risk of lymphoma (all subtypes), B-cell NHL and its most represented subtypes, and Hodgkin's lymphoma (all subtypes) associated with weekly average Metabolic Equivalent of Task (MET-hours/week) and cumulative MET-hours of lifetime recreational, occupational, and total physical activity, with unconditional logistic regression and polytomous regression analysis adjusting by age, centre, sex, education, body mass index, history of farm work and solvent use. We observed an inverse association of occupational, and total physical activity with risk of lymphoma (all subtypes), and B-cell non-Hodgkin's lymphoma among women, and an upward trend in risk of Hodgkin's lymphoma with recreational and total physical activity among men, for which we cannot exclude chance or bias. Our results suggest no effect of overall physical activity on risk of lymphoma and its subtypes.

Incidence and Bayesian Mapping of Myeloid Hematologic Malignancies in Sardinia, Italy.

BACKGROUND: The epidemiology of myeloid hematologic malignancies in Italy has been poorly investigated. METHODS: We used a validated database of 1974-2003 incident cases of hematologic malignancies among the resident population (all ages) of Sardinia, Italy, to describe the incidence of myeloid malignancies overall (N = 4389 cases) and by subtype. We investigated the time trend of acute myeloid leukemia (N = 1227 cases), chronic myeloid leukemia (N = 613 cases), and myelodysplastic syndrome (N = 1296 cases), and used Bayesian methods to explore their geographic spread, and Poisson regression analysis to estimate their association with environmental and socio-economic factors. RESULTS: The annual standardized (world population) incidence rate (IR) of myeloid malignancies over the study period was 6.5 per 100,000 (95% CI 6.2-6.7). Myelodysplastic syndromes were the most prevalent subgroup (IR = 1.7, 95% CI 1.5-1.8). Incidence of all myeloid malignancies combined increased sharply during the study period with an annual percent change (APC) of 10.06% (95% CI 9.51-10.61), 19.77% for myelodysplastic syndromes (95% CI 19.63-19.91), and 3.18% (95% CI 2.99-3.37) for acute myeloid leukemia. Chronic myeloid leukemia did not show an upward trend. Apart from sporadic excesses in small rural communities and the major urban area, there was no evidence of spatial clustering. The risk of myeloid malignancies increased with increasing prevalence of sheep breeding. CONCLUSIONS: Our results might prompt further research on the local genetic and environmental determinants of myeloid hematologic malignancies.

Is a Good Sleep on Mosquito-Free Nights Worth the Risk of Lymphoma Associated with the Use of Household Insecticides? A Case-Control Study of Lymphoma Subtypes in Adults.

BACKGROUND: The evidence linking the use of household pesticides and the risk of lymphoma is scanty. METHODS: We explored the hypothesis in a population-based case-control study on lymphoma conducted in Sardinia, Italy, in 1998-2004, including 325 cases and 465 population controls and data on lifetime frequency, seasonality, and years of use of household insecticides and potential confounders. We calculated the risk of lymphoma (all subtypes) and its major subtypes associated with using household insecticides in three time windows (up to 1978, from 1979-2001, and 2002 onwards) with unconditional logistic regression adjusting by age, sex, education, and occupational exposure to pesticides. RESULTS: Household insecticides did not increase risk of lymphoma (all subtypes), Hodgkin's lymphoma, B-cell lymphoma, and the major B-cell lymphoma subtypes. The risk of multiple myeloma (MM) but not the other subtypes showed a non-significant upward trend (p = 0.203) with increasing quartiles of days of use in the time window when propoxur was the most popular household insecticide. CONCLUSIONS: Our results suggest no association between the household use of insecticides and the risk of lymphoma. Further studies are warranted to confirm or discard an association between MM risk and the use of propoxur.

Epidemiology of Chronic Lymphocytic Leukemia in Sardinia, Italy (1974-2003).

Several reports have described a worldwide increasing incidence of chronic lymphocytic leukemia (CLL) dating back seven to eight decades. Although genetic susceptibility would be an implausible explanation, the determinants of this upward trend and its spatial coordinates are poorly understood. We explored CLL incidence in Sardinia, Italy, using a validated database including the 1700 CLL cases diagnosed during 1974-2003. We applied Bayesian methods to map the CLL probability by administrative unit and Poisson regression analysis to investigate socioeconomic and environmental determinants adjusting by possible confounders. The standardized (Standard European population) incidence rate for the Sardinian population over the study period was 5.1 per 100,000 (95% confidence interval [CI] 4.9-5.3), increased annually by 5.8% (95% CI 5.7-6.0) consistently by sex and age, and was more noticeable in urban areas. Five administrative units exceeded the 95% posterior probability of an elevated CLL incidence: these were rural areas spread over the regional territory, not suggestive of spatial clustering. The Poisson regression analysis showed that the risk was elevated in urban areas (RR = 1.11, 95% CI 1.05-1.17), among residents ≥ 30 km from the nearest hospital (RR = 1.09, 95% CI 1.06-1.12), and with the local prevalence of cork harvesting (RR = 1.62, 95% CI 1.12-2.34). Our results suggest that better access to health care facilities and improvements in diagnostic efficacy might have generated the observed upward trend in CLL incidence, along with contributing environmental factors.

Gender and Nightshift Work: A Cross Sectional Study on Sleep Quality and Daytime Somnolence.

A few studies suggested that female nightshift workers suffer more frequently from sleep deprivation and insomnia. We conducted a cross-sectional survey in two different occupational settings to address gender-related differences in nightshift work adaptation. We used the Epworth Sleepiness Scale and the Pittsburgh Sleep Quality Index questionnaires to quantify daytime sleepiness and sleep quality among 156 workers, 91 from a ceramic tile factory and 65 healthcare workers, including hospital doctors, nurses, and nurse assistants. Seventy-three percent of participants (40 women and 74 men) were engaged in nightshift work. We used logistic regression analysis to predict daytime sleepiness and poor sleep quality as a function of personal and lifestyle variables and nightshift work. The female gender showed a strong association with both daytime sleepiness and poor sleep quality. Results were also suggestive of an increase in the risk of daytime sleepiness associated with nightshift work and being married. Our results confirm that women are especially vulnerable to sleep disruption. Promoting adaptation to nightshift work requires special attention towards gender issues.

Nocturnal Heart Rate Variability Might Help in Predicting Severe Obstructive Sleep-Disordered Breathing.

Obstructive sleep apnea (OSA) can have long-term cardiovascular and metabolic effects. The identification of OSA-related impairments would provide diagnostic and prognostic value. Heart rate variability (HRV) as a measure of cardiac autonomic regulation is a promising candidate marker of OSA and OSA-related conditions. We took advantage of the Physionet Apnea-ECG database for two purposes. First, we performed time- and frequency-domain analysis of nocturnal HRV on each recording of this database to evaluate the cardiac autonomic regulation in patients with nighttime sleep breathing disorders. Second, we conducted a logistic regression analysis (backward stepwise) to identify the HRV indices able to predict the apnea-hypopnea index (AHI) categories (i.e., "Severe OSA", AHI ≥ 30; "Moderate-Mild OSA", 5 ≥ AHI < 30; and "Normal", AHI < 5). Compared to the "Normal", the "Severe OSA" group showed lower high-frequency power in normalized units (HFnu) and higher low-frequency power in normalized units (LFnu). The standard deviation of normal R-R intervals (SDNN) and the root mean square of successive R-R interval differences (RMSSD) were independently associated with sleep-disordered breathing. Our findings suggest altered cardiac autonomic regulation with a reduced parasympathetic component in OSA patients and suggest a role of nighttime HRV in the characterization and identification of sleep breathing disorders.

Next Generation Sequencing for miRNA Detection on the Exhaled Breath Condensate: A Pilot Study.

Introduction: Exhaled breath condensate (EBC) sampling has been suggested as a less-invasive and cost-effective method to detect biological macromolecules, including miRNA. To explore the feasibility of its use as a biomarker of early effects of asbestos exposure, we conducted a preliminary test on male volunteers by comparing the miRNA profile in the EBC and the plasma using 2 different sequencing platforms. Methods: Six male volunteers, all retired and unexposed to dust or fumes, participated in the test. RNA was extracted from 200 µL EBC samples and same-size plasma samples. Sample aliquots were processed in 2 laboratories using 2 different sequencing platforms: a MiSeq Illumina® platform and a more performing HiSeq Illumina® platform. Results: The HiSeq3000® sequencing platform identified twice as many unique molecular indexes (UMI)-validated miRNA as the MiSeq® platform. The Spearman's correlation coefficient between EBC counts and plasma counts was significant in 5/6 subjects with either platform (MiSeq® = 0.128-0.508, P = .026-<.001; HiSeq® = 0.156-0.412, P = .001-<.001). The intraclass correlation coefficient confirmed the consistency of the miRNA profile over the 6 participants with both biospecimens. Exploring the agreement between the EBC and plasma samples with Bland-Altman plots showed that using the HiSeq3000® platform substantially improved the EBC miRNA detection rate. Conclusion: Our preliminary study confirms that, when using the HiSeq® sequencing platform, EBC sampling is a suitable, non-invasive method to detect the miRNA profile in healthy subjects.

COVID-19 and non-Hodgkin's lymphoma: A common susceptibility pattern?

OBJECTIVE: To explore the link between COVID-19 incidence, socio-economic covariates, and NHL incidence. DESIGN: Ecological study design. SETTING: Sardinia, Italy. PARTICIPANTS: We used official reports on the total cases of COVID-19 in 2020, published data on NHL incidence, and socio-economic indicators by administrative unit, covering the whole regional population. MAIN OUTCOMES AND MEASURES: We used multivariable regression analysis to explore the association between the natural logarithm (ln) of the 2020 cumulative incidence of COVID-19 and the ln-transformed NHL incidence in 1974-2003, weighing by population size and adjusting by socioeconomic deprivation and other covariates. RESULTS: The cumulative incidence of COVID-19 increased in relation to past incidence of NHL (p < 0.001), socioeconomic deprivation (p = 0.006), and proportion of elderly residents (p < 0.001) and decreased with urban residency (p = 0.001). Several sensitivity analyses confirmed the finding of an association between COVID-19 and NHL. CONCLUSION: This ecological study found an ecological association between NHL and COVID-19. If further investigation would confirm our findings, shared susceptibility factors should be investigated among the plausible underlying mechanisms.

Herbicide use in farming and other jobs in relation to non-Hodgkin's lymphoma (NHL) risk.

OBJECTIVES: Given mixed evidence for carcinogenicity of current-use herbicides, we studied the relationship between occupational herbicide use and risk of non-Hodgkin's lymphoma (NHL) in a large, pooled study. METHODS: We pooled data from 10 case-control studies participating in the International Lymphoma Epidemiology Consortium, including 9229 cases and 9626 controls from North America, the European Union and Australia. Herbicide use was coded from self-report or by expert assessment in the individual studies, for herbicide groups (eg, phenoxy herbicides) and active ingredients (eg, 2,4-dichlorophenoxyacetic acid (2,4-D), glyphosate). The association between each herbicide and NHL risk was estimated using logistic regression to produce ORs and 95% CIs, with adjustment for sociodemographic factors, farming and other pesticides. RESULTS: We found no substantial association of all NHL risk with ever-use of any herbicide (OR=1.10, 95% CI: 0.94 to 1.29), nor with herbicide groups or active ingredients. Elevations in risk were observed for NHL subtypes with longer duration of phenoxy herbicide use, such as for any phenoxy herbicide with multiple myeloma (>25.5 years, OR=1.78, 95% CI: 0.74 to 4.27), 2,4-D with diffuse large B-cell lymphoma (>25.5 years, OR=1.47, 95% CI: 0.67 to 3.21) and other (non-2,4-D) phenoxy herbicides with T-cell lymphoma (>6 years, lagged 10 years, OR=3.24, 95% CI: 1.03 to 10.2). An association between glyphosate and follicular lymphoma (lagged 10 years: OR=1.48, 95% CI: 0.98 to 2.25) was fairly consistent across analyses. CONCLUSIONS: Most of the herbicides examined were not associated with NHL risk. However, associations of phenoxy herbicides and glyphosate with particular NHL subtypes underscore the importance of estimating subtype-specific risks.

Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes.

Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P < 5 × 10-8) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P = 3.27 × 10-9). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P < 5 × 10-8), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture.

COVID-19 incidence in a cohort of public transport workers.

BACKGROUND: Previous research has shown an excess risk of COVID-19 among several occupations, but data on public transport workers are scarce. To investigate the occupational risk posed by contact with the public, we followed up the incidence of COVID-19 in a cohort of public transport workers. METHODS: We identified the incident cases of COVID-19 between 1 September 2020 - 6 May 2021 in a cohort of 2,052 employees of a public transport agency in Sardinia, Italy. The diagnosis of COVID-19 was based on a positive molecular test. To calculate the expected events, we applied the age- and gender-specific incidence rates of the regional population in the same time period to the correspondent strata of the study cohort. We estimated the relative risk (RR) of COVID-19 as the ratio between the observed and the expected events and its 95% confidence interval (95% C.I.) among the total cohort and in two sub-cohorts: bus drivers, and the rest of the personnel (administrative staff, train and metro drivers, workers in the mechanical shop, and in the railroad maintenance, and security). RESULTS: Bus drivers run an elevated risk of COVID-19 (RR = 1.4, 95% C.I. 1.07 - 1.79). There was no excess risk among the sub-cohort including the rest of the personnel. CONCLUSIONS: Our study suggests an excess risk of COVID-19 among bus drivers even in a relatively low incidence area, which could imply inadequacy of the preventive measures in place. Further, larger size studies with detailed information on personal and lifestyle characteristics are warranted.

Time for Re-Evaluating the Human Carcinogenicity of Ethylenedithiocarbamate Fungicides? A Systematic Review.

BACKGROUND: In January 2021, the European Union ended the license of Mancozeb, the bestselling ethylenedithiocarbamate (EBDC) fungicide, because of some properties typical of human carcinogens. This decision contrasts the IARC classification of EBDC fungicides (Group 3, not classifiable as to human carcinogenicity). A systematic review of the scientific literature was conducted to explore the current evidence. METHODS: Human and experimental studies of cancer and exposure to EBDC fungicides (Mancozeb, Maneb, Zineb, and others) and ethylene thiourea (ETU), their major metabolite, published in English as of December 2021, were retrieved using PubMed, the list of references of the relevant reports, and grey literature. RESULTS: The epidemiological evidence of EBDC carcinogenicity is inadequate, with two studies each suggesting an association with melanoma and brain cancer and inconsistent findings for thyroid cancer. Experimental animal studies point at thyroid cancer in rats and liver cancer in mice, while multiple organs were affected following the long-term oral administration of Mancozeb. The mechanism of thyroid carcinogenesis in rats has also been shown to occur in humans. Genotoxic effects have been reported. CONCLUSIONS: The results of this systematic review suggest inadequate evidence for the carcinogenicity of EBDC fungicides from human studies and sufficient evidence from animal studies, with positive results on three out of ten key characteristics of carcinogens applying to humans as well. An IARC re-evaluation of the human carcinogenicity of EBDC fungicides is warranted.

B-Cell NHL Subtype Risk Associated with Autoimmune Conditions and PRS.

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.

Incidence of non-Hodgkin's lymphoma among adults in Sardinia, Italy.

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.