Cancer incidence in Swedish oil refinery workers exposed to benzene.

BACKGROUND: Oil refinery workers are exposed to benzene, which is a well-known cause of leukaemia, but results on leukaemia in oil refinery workers have been mixed, and the data on workers' exposure is limited. Oil refinery workers are also exposed to asbestos and several studies have shown increased risk of mesothelioma. AIM: The objective was to investigate cancer incidence, especially leukaemia, at low to moderate exposure to benzene in an update of a previous study of employees at three Swedish oil refineries. METHODS: Cancer incidence was followed up in 2264 men (1548 refinery operators) employed at three oil refineries in Sweden for at least one year. Job types and employment times were collected from complete company files. A retrospective assessment of the benzene exposure was performed by occupational hygienists in collaboration with the refineries using historic measurements as well as detailed information on changes in the industrial hygiene and technological developments. Cases of cancer were retrieved by a linkage with the Swedish Cancer Register through 35-47 years of follow-up and standardized incidence ratios (SIR) with 95% confidence intervals (CI) were calculated. RESULTS: In total, 258 tumors had occurred versus 240 expected (SIR 1.07; 95% CI 0.95-1.21). There were 10 cases of leukaemia, all in refinery operators (SIR 2.4; 95% CI 1.18-4.51). There were three cases of pleural mesothelioma, two of which in refinery operators. The mean estimated cumulative benzene exposure for the cases of leukaemia was 7.9 ppm-years (median 4.9, range 0.1-31.1). DISCUSSION: The study suggests that low to moderate average cumulative benzene exposure increases the risk of leukaemia. Limitations include the modest number of cases and potential misclassification of exposure. CONCLUSION: The present study indicated an increased risk of leukaemia in male oil refinery workers with low to moderate exposure to benzene.

Leukemia risk assessment of exposure to low-levels of benzene based on the linearized multistage model.

Objectives: To assess leukemia risk in occupational populations exposed to low levels of benzene. Methods: Leukemia incidence data from the Chinese Benzene Cohort Study were fitted using the Linearized multistage (LMS) model. Individual benzene exposure levels, urinary S-phenylmercapturic acid (S-PMA) and trans, trans-muconic acid (t, t-MA) were measured among 98 benzene-exposed workers from factories in China. Subjects were categorized into four groups by rounding the quartiles of cumulative benzene concentrations (< 3, 3-5, 5-12, ≥12 mg/m3·year, respectively). The risk of benzene-induced leukemia was assessed using the LMS model, and the results were validated using the EPA model and the Singapore semi-quantitative risk assessment model. Results: The leukemia risks showed a positive correlation with increasing cumulative concentration in the four exposure groups (excess leukemia risks were 4.34, 4.37, 4.44 and 5.52 × 10-4, respectively; Ptrend < 0.0001) indicated by the LMS model. We also found that the estimated leukemia risk using urinary t, t-MA in the LMS model was more similar to those estimated by airborne benzene compared to S-PMA. The leukemia risk estimated by the LMS model was consistent with both the Singapore semi-quantitative risk assessment model at all concentrations and the EPA model at high concentrations (5-12, ≥12 mg/m3·year), while exceeding the EPA model at low concentrations (< 3 and 3-5 mg/m3·year). However, in all four benzene-exposed groups, the leukemia risks estimated by these three models exceeded the lowest acceptable limit for carcinogenic risk set by the EPA at 1 × 10-6. Conclusion: This study demonstrates the utility of the LMS model derived from the Chinese benzene cohort in assessing leukemia risk associated with low-level benzene exposure, and suggests that leukemia risk may occur at cumulative concentrations below 3 mg/m3·year.

Residential exposure to air pollution and incidence of leukaemia in the industrial area of Viadana, Northern Italy.

BACKGROUND: Exposure to air pollution has been proposed as one of the potential risk factors for leukaemia. Work-related formaldehyde exposure is suspected to cause leukaemia. METHODS: We conducted a nested register-based case-control study on leukaemia incidence in the Viadana district, an industrial area for particleboard production in Northern Italy. We recruited 115 cases and 496 controls, frequency-matched by age, between 1999 and 2014. We assigned estimated exposures to particulate matter (PM10, PM2.5), nitrogen dioxide (NO2), and formaldehyde at residential addresses, averaged over the susceptibility window 3rd to 10th year prior to the index date. We considered potential confounding by sex, age, nationality, socio-economic status, occupational exposures to benzene and formaldehyde, and prior cancer diagnoses. RESULTS: There was no association of exposures to PM10, PM2.5, and NO2 with leukaemia incidence. However, an indication of increased risk emerged for formaldehyde, despite wide statistical uncertainty (OR 1.46, 95%CI 0.65-3.25 per IQR-difference of 1.2 µg/m3). Estimated associations for formaldehyde were higher for acute (OR 2.07, 95%CI 0.70-6.12) and myeloid subtypes (OR 1.79, 95%CI 0.64-5.01), and in the 4-km buffer around the industrial facilities (OR 2.78, 95%CI 0.48-16.13), although they remained uncertain. CONCLUSIONS: This was the first study investigating the link between ambient formaldehyde exposure and leukaemia incidence in the general population. The evidence presented suggests an association, although it remains inconclusive, and a potential significance of emissions related to industrial activities in the district. Further research is warranted in larger populations incorporating data on other potential risk factors.

Global burden of leukemia attributable to occupational exposure to formaldehyde from 1990 to 2019.

The objective of this study was to evaluate the worldwide burden of leukemia owing to occupational exposure to formaldehyde (OEF) from 1990 to 2019. Data on leukemia due to OEF were obtained from the Global Burden of Disease Study (GBD) 2019. By region, age, sex, and disease subtype, the numbers and age-standardized rates (ASRs) associated with deaths, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life years (DALYs) were analyzed. Annual average percentage change (AAPC) was used to estimate disease burden trends from 1990 to 2019. To measure the risk of leukemia due to OEF, the population attributable fraction (PAF) was introduced. From 1990 to 2019, the number of deaths, DALYs, YLLs, and YLDs for leukemia caused by OEF increased by 44%, 34%, 33%, and 124%, respectively. Regarding the change in ASRs, the age-standardized YLDs (ASYLDs) rate of leukemia due to OEF, which was 38.03% (AAPC = 1.17 [95% confidence interval [CI] 1.11, 1.23]), indicated an increased trend. But the age-standardized mortality rate (ASMR), age-standardized DALY (ASDALY) rate, and age-standardized YLL (ASYLL) rate showed decline trends, with - 11.90% (AAPC = - 0.41 [95% CI - 0.45, - 0.37]), - 14.19% (AAPC = - 0.5 [95% CI - 0.55, - 0.45]), and - 14.97% (AAPC = - 0.53 [95% CI - 0.58, - 0.48]), respectively. In terms of PAFs, there were increasing trends in PAFs of age-standardized deaths, ASDALYs, ASYLLs, and ASYLDs for leukemia caused by OEF, with 20.15% (95% uncertainty interval [UI] 11.76%, 30.25%), 36.28% (95% UI 21.46%, 53.42%), 51.91% (95% UI 35.05%, 72.07%), and 36.34% (95% UI 21.58%, 53.63%), respectively. Across the socio-demographic index (SDI) regions, the leukemia burden caused by OEF was concentrated in middle and high-middle SDI regions. Besides, OEF poses a more serious risk for acute leukemia among the leukemia subtype. Globally, leukemia caused by OEF remains a public health burden. Policies must be developed to avoid the burden of leukemia caused by OEF.

How Government Health Agencies Obscure the Impact of Environmental Pollution and Perpetuate Reductionist Framings of Disease: The Case of Leukemia.

Since the 1970s, environmental health researchers have documented environmental pollution's impacts on human health, which includes the bioaccumulation of industrial chemicals and how these toxicants contribute to disease. However, the relationship between disease and pollution is often difficult to discern in the disease information provided by dominant institutions. Previous scholarship has identified that print media, television news, online medical publishers, and medical associations consistently obscure the environmental causation frame. However, less has been said about disease information provided by public health agencies. To address this gap, I analyzed the leukemia information provided by Cancer Australia, the United States' National Institutes of Health, and the United Kingdom's National Health Service. My analysis shows that the disease information offered by these health agencies also obscures the environmental causation frame by failing to identify most toxicants that environmental health researchers have linked to leukemia and by emphasizing a biomedical framing of the medical condition. Beyond documenting the problem, this article also discusses the social consequences and sources of the problem.

Long-term exposure to ambient air pollution and risk of leukemia and lymphoma in a pooled European cohort.

Leukemia and lymphoma are the two most common forms of hematologic malignancy, and their etiology is largely unknown. Pathophysiological mechanisms suggest a possible association with air pollution, but little empirical evidence is available. We aimed to investigate the association between long-term residential exposure to outdoor air pollution and risk of leukemia and lymphoma. We pooled data from four cohorts from three European countries as part of the "Effects of Low-level Air Pollution: a Study in Europe" (ELAPSE) collaboration. We used Europe-wide land use regression models to assess annual mean concentrations of fine particulate matter (PM2.5), nitrogen dioxide (NO2), black carbon (BC) and ozone (O3) at residences. We also estimated concentrations of PM2.5 elemental components: copper (Cu), iron (Fe), zinc (Zn); sulfur (S); nickel (Ni), vanadium (V), silicon (Si) and potassium (K). We applied Cox proportional hazards models to investigate the associations. Among the study population of 247,436 individuals, 760 leukemia and 1122 lymphoma cases were diagnosed during 4,656,140 person-years of follow-up. The results showed a leukemia hazard ratio (HR) of 1.13 (95% confidence intervals [CI]: 1.01-1.26) per 10 µg/m3 NO2, which was robust in two-pollutant models and consistent across the four cohorts and according to smoking status. Sex-specific analyses suggested that this association was confined to the male population. Further, the results showed increased lymphoma HRs for PM2.5 (HR = 1.16; 95% CI: 1.02-1.34) and potassium content of PM2.5, which were consistent in two-pollutant models and according to sex. Our results suggest that air pollution at the residence may be associated with adult leukemia and lymphoma.

Occupational-related exposure to diesel exhaust and risk of leukemia: systematic review and meta-analysis of cohort studies.

PURPOSE: Diesel exhaust (DE) is an established lung carcinogen. The association with leukemia is not well established. We conducted a systematic review and meta-analysis of cohort studies to determine the association between occupational DE exposure and risk of leukemia. METHODS: A systematic literature review was performed to identify all cohort studies on occupational exposure to DE and associated risk of leukemia. STROBE guidelines and PECOS criteria were followed. Meta-analyses with fixed effects (and random-effects model in cases of high heterogeneity) were performed to calculate summary relative risks (RR) and 95% confidence intervals (CI), including subgroup analyses by outcome (mortality or incidence), sex, geographic region, industry type, and study quality. Study quality was assessed using the the Joanna Briggs Institute (JBI) critical appraisal checklist for cohort studies. RESULTS: Of the 30 studies retained, 20 (8 from North America, 12 from Europe) reported a total of 33 estimates of the risk of leukemia. Overall, the relative risk (RR) of leukemia was 1.01 (95% CI = 0.97-1.05, I2 = 21.2%, n = 33); corresponding results for leukemia incidence and mortality were RR = 1.02 (95% CI = 0.98-1.06, I2 = 27.9%, n = 19) and RR = 0.91 (95% CI = 0.81-1.02, I2 = 0.0%, n = 15), respectively. The main results were confirmed in analyses by sex and geographic area. A statistically significant association was detected for miners (RR = 1.58, 95% CI = 1.15-2.15, I2 = 77.0%, n = 2) but not for other occupational groups. Publication bias was not detected (p = 0.7). CONCLUSION: Our results did not indicate an association between occupational DE exposure and leukemia, with the possible exception of miners. Residual confounding cannot be excluded.

Mechanisms of Secondary Leukemia Development Caused by Treatment with DNA Topoisomerase Inhibitors.

Leukemia is a blood cancer originating in the blood and bone marrow. Therapy-related leukemia is associated with prior chemotherapy. Although cancer therapy with DNA topoisomerase II inhibitors is one of the most effective cancer treatments, its side effects include development of secondary leukemia characterized by the chromosomal rearrangements affecting AML1 or MLL genes. Recurrent chromosomal translocations in the therapy-related leukemia differ from chromosomal rearrangements associated with other neoplasias. Here, we reviewed the factors that drive chromosomal translocations induced by cancer treatment with DNA topoisomerase II inhibitors, such as mobility of ends of double-strand DNA breaks formed before the translocation and gain of function of fusion proteins generated as a result of translocation.

Leukemia Mortality among Benzene-Exposed Workers in Brazil (2006-2011).

BACKGROUND: In this study, the annual leukemia mortality rate is estimated by occupational groups potentially exposed to benzene in Brazil and compared to non-exposed workers by sex. METHODS: Data were extracted from the Mortality Information System and the National Institute of Geography and Statistics from 2006 to 2011. Occupational groups exposed to benzene were defined by using the Finnish Job-Exposure Matrix, FINJEM. RESULTS: We found 21,049 leukemia deaths in 1917 in occupational groups potentially exposed to benzene, corresponding to an annual average mortality rate of 4.5/100,000, higher than the estimate for non-exposed workers: 2.6/100,000, corresponding to a Mortality rate ratio MRR = 1.7. Each benzene-exposed occupational group had increased leukemia mortality, and printers and occupations in graphics presented the highest MRR (2.7), followed by laboratory assistants (MRR = 2.6), laundry workers, chemists, and upholsterers, each of these occupational groups presenting MRR = 2.3. CONCLUSIONS: Benzene shows the need for better enforcement of protective norms against this known carcinogen. Our results support the need for better enforcement of protective norms to reduce benzene exposure.

Association Between the Use of Topical Calcineurin Inhibitors and the Risk of Cancer Among Patients with Atopic Dermatitis: A Nationwide, Population-Based, Retrospective Cohort Study.

IMPORTANCE: The cancer risks associated with treatment with topical calcineurin inhibitors (TCIs) in patients with atopic dermatitis (AD) remain controversial, and limited evidence exists regarding the cancer risks among patients with AD treated with TCIs in Asian populations. OBJECTIVES: This study identified the association between TCI use and the risks of developing all cancers, lymphoma, skin cancers, and other cancers. DESIGN: This study was a nationwide, population-based, retrospective cohort study. SETTING: Taiwan's National Health Insurance Research Database. PARTICIPANTS: Patients diagnosed at least twice with ICD-9 code 691 or at least one time with ICD-9 codes 691 or 692.9 within 1 year between 1 January 2003 and 31 December 2010 were included and followed until 31 December 2018. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using the Cox proportional hazard ratio model. EXPOSURES: Patients using tacrolimus or pimecrolimus were identified in the National Health Insurance Research Database and compared with patients using topical corticosteroids (TCSs). MAIN OUTCOMES AND MEASURES: The main outcomes were hazard ratios (HRs) of cancer diagnoses and associated outcomes obtained from the Taiwan Cancer Registry database. RESULTS: After propensity score (PS) matching, the final cohort included 195,925 patients with AD, including 39,185 who were initial TCI users and 156,740 who were TCS users. Propensity score matching was performed according to age, sex, index year, and Charlson Comorbidity Index using a ratio of 1:4. Except for leukemia, HR and 95% CI showed no significant associations between TCI use and the risk of developing all cancer, lymphoma, skin cancers, and other cancers. Sensitivity analysis showed that the lag time HRs for every cancer subtype continued to show no significant association between TCI use and cancer risk, except for leukemia. CONCLUSIONS AND RELEVANCE: Our study found no evidence to support an association between TCI use and the risks of almost all cancers compared with TCS use in patients with AD, but physicians should be aware of potentially higher risks of leukemia with TCI use. This study represents the first population-based study focused on the cancer risk of TCI use among patients with AD in an Asian population.

Benzene and cause-specific mortality in an Italian national cohort of exposed workers through a proportions analysis.

BACKGROUND: occupational exposure to benzene represents a threat for the health of a still relevant number of workers. An increased risk of leukaemias has been demonstrated among exposed workers, while a weaker association has been found for other malignancies. OBJECTIVES: to evaluate mortality risk among workers exposed to benzene across economic sectors in Italy. DESIGN: proportionate mortality ratios (PMRs) were calculated linking exposure occupational information to national mortality statistics (2005-2018), assuming a Poisson distribution of the data. SETTING AND PARTICIPANTS: data from the Italian national registry on occupational exposure to carcinogens (SIREP) in the period 1996-2018 were selected. MAIN OUTCOMES MEASURES: PMRs by cause of death were reported. Specific analyses by cancer site and activity sector, profession, and cumulative exposure were performed. RESULTS: a total of 858 deaths (97% in men) were identified among 38,704 exposed workers (91% men). An excess of deaths from malignant neoplasm of the lung was found among exposed workers, in both genders (PMR 1.27 in men; PMR 3.00 in women). An increased proportion of deaths was also found from leukaemias (leukaemia of unspecified cell type: PMR in men 2.99; 95%CI 1.24-7.19), and multiple myeloma in the chemical industry (PMR in men 2.27; 95%CI 1.08-4.76). CONCLUSIONS: the risk of leukaemia in the petrochemical industry has been confirmed, while an excess risk of lung cancer mortality was highlighted in the retail sale of automotive fuels. Epidemiological surveillance and air and biological monitoring are recommended for workers exposed to benzene to ensure compliance with regulatory requirements and reduce exposure-related deaths.

Residential proximity to petrol stations and risk of childhood leukemia.

Petrol stations emit benzene and other contaminants that have been associated with an increased risk of childhood leukemia. We carried out a population-based case-control study in two provinces in Northern Italy. We enrolled 182 cases of childhood leukemia diagnosed during 1998-2019 and 726 age- and sex-matched population controls. We geocoded the addresses of child residences and 790 petrol stations located in the study area. We estimated leukemia risk according to distance from petrol stations within a 1000 m buffer and amount of supplied fuel within a buffer of 250 m from the child's residence. We used conditional logistic regression models to approximate risk ratios (RRs) and 95% confidence intervals (CIs) for associations of interest, adjusted for potential confounders. We also modeled non-linear associations using restricted cubic splines. In secondary analyses, we restricted to acute lymphoblastic leukemia (ALL) cases and stratifed by age (<5 and ≥5 years). Compared with children who lived≥1000 m from a petrol station, the RR was 2.2 (95% CI 0.5-9.4) for children living<50 m from nearest petrol station. Associations were stronger for the ALL subtype (RR=2.9, 95% CI 0.6-13.4) and among older children (age≥5 years: RR=4.4, 95% CI 0.6-34.1; age<5 years: RR=1.6, 95% CI 0.1-19.4). Risk of leukemia was also greater (RR=1.6, 95% CI 0.7-3.3) among the most exposed participants when assigning exposure categories based on petrol stations located within 250 m of the child's residence and total amount of gasoline delivered by the stations. Overall, residence within close proximity to a petrol station, especially one with more intense refueling activity, was associated with an increased risk of childhood leukemia, though associations were imprecise.

Benzene metabolite hydroquinone enhances self-renewal and proliferation of preleukemic cells through the Ppar-γ pathway.

Benzene is a known hematotoxic and leukemogenic chemical. Exposure to benzene cause inhibition of hematopoietic cells. However, the mechanism of how the hematopoietic cells inhibited by benzene undergo malignant proliferation is unknown. The cells carrying leukemia-associated fusion genes are present in healthy individuals and predispose the carriers to the development of leukemia. To identify the effects of benzene on hematopoietic cells, preleukemic bone marrow (PBM) cells derived from transgenic mice carrying the Mll-Af9 fusion gene were treated with benzene metabolite hydroquinone in serial replating of colony-forming unit (CFU) assay. RNA sequencing was further employed to identify the potential key genes that contributed to benzene-initiated self-renewal and proliferation. We found that hydroquinone induced a significant increase in colony formation in PBM cells. Peroxisome proliferator-activated receptor gamma (Ppar-γ) pathway, which plays a critical role in carcinogenesis in multiple tumors, was significantly activated after hydroquinone treatment. Notably, the increased numbers of the CFUs and total PBM cells induced by hydroquinone were significantly reduced by a specific Ppar-γ inhibitor (GW9662). These findings indicated that hydroquinone can enhance self-renewal and proliferation of preleukemic cells by activating the Ppar-γ pathway. Our results provide insight into the missing link between premalignant status and development of benzene-induced leukemia, which can be intervened and prevented.

Electrochemical and Optical Sensors for the Detection of Chemical Carcinogens Causing Leukemia.

The incidence and mortality due to neoplastic diseases have shown an increasing tendency over the years. Based on GLOBOCAN 2020 published by the International Agency for Research on Cancer (IARC), leukemias are the thirteenth most commonly diagnosed cancer in the world, with 78.6% of leukemia cases diagnosed in countries with a very high or high Human Development Index (HDI). Carcinogenesis is a complex process initiated by a mutation in DNA that may be caused by chemical carcinogens present in polluted environments and human diet. The IARC has identified 122 human carcinogens, e.g., benzene, formaldehyde, pentachlorophenol, and 93 probable human carcinogens, e.g., styrene, diazinone. The aim of the following review is to present the chemical carcinogens involved or likely to be involved in the pathogenesis of leukemia and to summarize the latest reports on the possibility of detecting these compounds in the environment or food with the use of electrochemical sensors.

Linking Benzene, in Utero Carcinogenicity and Fetal Hematopoietic Stem Cell Niches: A Mechanistic Review.

Previous research reported that prolonged benzene exposure during in utero fetal development causes greater fetal abnormalities than in adult-stage exposure. This phenomenon increases the risk for disease development at the fetal stage, particularly carcinogenesis, which is mainly associated with hematological malignancies. Benzene has been reported to potentially act via multiple modes of action that target the hematopoietic stem cell (HSCs) niche, a complex microenvironment in which HSCs and multilineage hematopoietic stem and progenitor cells (HSPCs) reside. Oxidative stress, chromosomal aberration and epigenetic modification are among the known mechanisms mediating benzene-induced genetic and epigenetic modification in fetal stem cells leading to in utero carcinogenesis. Hence, it is crucial to monitor exposure to carcinogenic benzene via environmental, occupational or lifestyle factors among pregnant women. Benzene is a well-known cause of adult leukemia. However, proof of benzene involvement with childhood leukemia remains scarce despite previously reported research linking incidences of hematological disorders and maternal benzene exposure. Furthermore, accumulating evidence has shown that maternal benzene exposure is able to alter the developmental and functional properties of HSPCs, leading to hematological disorders in fetus and children. Since HSPCs are parental blood cells that regulate hematopoiesis during the fetal and adult stages, benzene exposure that targets HSPCs may induce damage to the population and trigger the development of hematological diseases. Therefore, the mechanism of in utero carcinogenicity by benzene in targeting fetal HSPCs is the primary focus of this review.

Whole-exome sequencing identified recurrent and novel variants in benzene-induced leukemia.

BACKGROUND: Genome-wide sequencing may extensively identify potential pathogenic variants, which helps to understand mechanisms of tumorigenesis, but such study has not been reported in benzene-induced leukemia (BIL). METHODS: We recruited 10 BIL patients and conducted the whole-exome sequencing on their peripheral blood samples. The obtained sequencing data were screened for potential pathogenic and novel variants, then the variants-located genes were clustered to identify cancer-related pathways. Shared or recurrent variants among the BIL cases were also identified and evaluated for their potential functional impact. RESULTS: We identified 48,802 variants in exons in total, 97.3% of which were single nucleotide variants. After filtering out variants with minor allele frequency ≥ 1%, we obtained 8667 potentially pathogenic variants, of which 174 were shared by all the BIL cases. The identified variants located in genes that could be significantly enriched into certain cancer-related pathways such as PI3K-AKT signaling pathway and Ras signaling pathway. We also identified 1010 novel variants with no record in the Genome Aggregation Database and in dbSNP, and one of them was shared by 90% cases. The recurrent and novel variant caused a missense mutation in SESN3. CONCLUSIONS: We examined variations of the whole exome in BIL patients for the first time. The commonly shared variants implied a relation with BIL, and the recurrent and novel variant might be specifically related to BIL. The related variants may help unravel the carcinogenic mechanisms of BIL.

Organochlorine pesticides may induce leukemia by methylation of CDKN2B and MGMT promoters and histone modifications.

Epigenetics is the science of altering gene expression without changing nucleotide sequences and may be induced by various environmental factors, including pesticides. The aim of this study was to investigate certain epigenetic changes including the methylation of CDKN2B, CDKN2A, and MGMT gene promoters and histone modifications of H3K9ac, H4K16ac, H4K20me3, and H3K4me3, as well as their association with the levels of organochlorine pesticides (OCPs) in children with acute lymphoblastic leukemia (ALL). The evaluation of OCP levels, promoter methylation, gene expression, and expression of histone modifications was performed by gas chromatography (GC), methylation-specific polymerase chain reaction (MS-PCR), reverse transcription PCR (RT-PCR), and western blotting, respectively. The results indicated that 76.2 % of CDKN2B promoters and 85.1 % of MGMT promoters were hypermethylated in children with ALL compared to healthy children. In addition, the relative expression of CDKN2B, MGMT, H4K16ac, and H3K4me3 showed a significant decrease in children with ALL compared to healthy children. Levels of OCPs in children with ALL were significantly higher than in healthy children. Furthermore, the results revealed that the rise in the OCP levels was associated with an increase in methylation at the promoter level of CDKN2B and MGMT as well as a decrease in the relative expression of H4K16ac and H3K4me3. Therefore, it can be concluded that exposure to OCPs is associated with the induction of epigenetic changes at the level of DNA and histones, which may lead to leukemia.

Temozolomide duration and secondary hematological neoplasms: A literature review and implications for patients with neuroendocrine neoplasms.

Evidence-based recommendations for the optimal duration and sequencing of temozolomide-based treatments in advanced neuroendocrine neoplasms are lacking. Here, we conducted a systematic review of the literature for a descriptive analysis of temozolomide-associated myelodysplasias and leukemias to guide treatment planning. A database search of PubMed and Embase was conducted to identify case reports and/or case series reporting secondary myelodysplasias or leukemias in the setting of temozolomide therapy. Key data items extracted from the studies were the temozolomide dose and duration, latency to hematological disorder, type of secondary malignancy and cytogenetics. Reported cases were summarized graphically. A total of 16 studies with 27 patient cases of therapy-related hematologic neoplasms were identified, all of which were case reports or case series. The median treatment duration and cumulative dose were 19 months and 18,000 mg/m2 , respectively. Most patients (21/27) were diagnosed on, or after, 12 months, while only one patient was diagnosed before 6 months of treatment. Most of the patients were diagnosed, while still on treatment with temozolomide. Graphically, cases clustered around a cumulative dose of 10,000 to 30,000 mg/m2 and a latency period of 10 to 40 months which translates to an approximate treatment duration of 12.5 to 37.5 months. Taken together, most reported treatment-related hematological neoplasms appear to develop on or beyond the 12-month mark, while patients are still on treatment with temozolomide. For patients with neuroendocrine neoplasms, where sequencing of multiple therapies is important, we suggest an approach to optimizing treatment duration by establishing disease response at 6 months before continuing further treatment and restricting treatment to or establishing closer vigilance beyond 12 months.

Commercial outdoor plant nurseries as a confounder for electromagnetic fields and childhood leukemia risk.

BACKGROUND: Close residential proximity to powerlines and high magnetic fields exposure may be associated with elevated childhood leukemia risks as reported by prior studies and pooled analyses. Magnetic fields exposure from high-voltage powerlines is associated with proximity to these powerlines and consequently with any factor varying with distance. Areas underneath powerlines in California may be sites for commercial plant nurseries that can use pesticides, a potential childhood leukemia risk factor. OBJECTIVES: Assess if potential pesticide exposure from commercial plant nurseries is a confounder or interacts with proximity or magnetic fields exposure from high-voltage powerlines to increase childhood leukemia risk. METHODS: A comprehensive childhood leukemia record-based case-control study with 5788 cases and 5788 controls (born and diagnosed in California, 1986-2008) was conducted. Pesticide, powerline, and magnetic field exposure assessment utilized models that incorporated geographical information systems, aerial satellite images, site visits and other historical information. RESULTS: The relationship for calculated fields with childhood leukemia (odds ratio (OR) 1.51, 95% confidence interval (CI) 0.70-3.23) slightly attenuated when controlling for nursery proximity (OR 1.43, 95% CI 0.65-3.16) or restricting analysis to subjects living far (>300 m) from nurseries (OR 1.43, 95% CI 0.79-2.60). A similar association pattern was observed between distance to high-voltage powerlines and childhood leukemia. The association between nursery proximity and childhood leukemia was unchanged or only slightly attenuated when controlling for calculated fields or powerline distance; ORs remained above 2 when excluding subjects with high calculated fields or close powerline proximity (OR 2.16, 95% CI 0.82-5.67 and OR 2.15, 95% CI 0.82-5.64, respectively). The observed relationships were robust to different time periods, reference categories, and cut points. DISCUSSION: Close residential proximity to nurseries is suggested as an independent childhood leukemia risk factor. Our results do not support plant nurseries as an explanation for observed childhood leukemia risks for powerline proximity and magnetic fields exposure, although small numbers of subjects concurrently exposed to high magnetic fields, close powerline proximity and plant nurseries limited our ability to fully assess potential confounding.

Long-term treatment with clozapine and other antipsychotic drugs and the risk of haematological malignancies in people with schizophrenia: a nationwide case-control and cohort study in Finland.

BACKGROUND: Clozapine is the most efficacious treatment for schizophrenia and is associated with lower overall mortality than are other antipsychotic drugs, despite the risk of agranulocytosis. Preliminary reports over the past 10 years suggest a possible risk of haematological malignancies, but the issue has remained unsettled. We aimed to study the risk of haematological malignancies associated with use of clozapine and other antipsychotics. METHODS: We did a nationwide case-control (and cohort) study of people with schizophrenia, using prospectively gathered data from Finnish national registers. A nested case-control study was constructed by individually matching cases of lymphoid and haematopoietic tissue malignancy with up to ten controls without cancer by age, sex, and time since first schizophrenia diagnosis. For the case-control study, we restricted inclusion criteria to malignancies diagnosed on a histological basis, and excluded individuals outside of the age range 18-85 years, and any patients that had a previous malignancy. Analyses were done using conditional logistic regression adjusting for comorbid conditions. FINDINGS: For the case-control study 516 patients with a first-time diagnosis of lymphoid and haematopoietic tissue malignancy during years 2000-17 and diagnosed after their first diagnosis of schizophrenia were identified. 102 patients were excluded due to diagnosis that was without a histological basis, five patients were excluded because of their age, and 34 were excluded for a previous malignancy, resulting in 375 patients being matched to controls. We selected up to ten controls without cancer (3734 in total) for each case from the base cohort of people with schizophrenia. For the cohort study, data for 55 949 people were included for analysis. Cumulative incidence of haematological malignancies during the mean follow-up of 12·3 years (SD 6·5) was 102 (0·7%) cases among 13 712 patients who had used clozapine (corresponding to event rate of 61 cases per 100 000 person-years), and during mean follow-up of 12·9 years (SD 7·2) was 235 (0·5%) malignancies among 44 171 patients having used other antipsychotic medication than clozapine (corresponding to 41 cases per 100 000 person-years). Of the 375 individuals with haematological malignancies (305 lymphomas, 42 leukaemia, 22 myelomas, 6 unspecified) observed from 2000-17, 208 (55%) were males and 167 (45%) were female. Ethnicity data were not available. Compared with non-use of clozapine (most had used other antipsychotics and a few had used no antipsychotics), clozapine use was associated with increased odds of haematological malignancies in a dose-response manner (adjusted odds ratio 3·35, [95% CI 2·22-5·05] for ≥5000 defined daily dose cumulative exposure, p<0·0001). Exposure to other antipsychotic drugs was not associated with increased odds. A complementary analysis showed that the clozapine-related risk increase was specific for haematological malignancies, because no such finding was observed for other malignancies. Over 17 years of follow-up of the base cohort, 37 deaths occurred due to haematological malignancy among patients exposed to clozapine (26 with ongoing use at time of haematological malignancy diagnosis, and 11 in patients who did not use clozapine at the exact time of their cancer diagnosis), whereas only three deaths occurred due to agranulocytosis. INTERPRETATION: Unlike other antipsychotics, long-term clozapine use is associated with increased odds of haematological malignancies. Long-term clozapine use has a higher effect on mortality due to lymphoma and leukaemia than due to agranulocytosis. However, acknowledging that the absolute risk is small compared with the previously observed absolute risk reduction in all-cause mortality is important. Our results suggest that patients and caregivers should be informed about warning signs of haematological malignancies, and mental health clinicians should be vigilant for signs and symptoms of haematological malignancy in patients treated with clozapine. FUNDING: The Finnish Ministry of Social Affairs and Health and Academy of Finland.