Menopausal hormone therapy and central nervous system tumors: Danish nested case-control study.

BACKGROUND: Use of estrogen-containing menopausal hormone therapy has been shown to influence the risk of central nervous system (CNS) tumors. However, it is unknown how the progestin-component affects the risk and whether continuous versus cyclic treatment regimens influence the risk differently. METHODS AND FINDINGS: Nested case-control studies within a nationwide cohort of Danish women followed for 19 years from 2000 to 2018. The cohort comprised 789,901 women aged 50 to 60 years during follow-up, without prior CNS tumor diagnosis, cancer, or contraindication for treatment with menopausal hormone therapy. Information on cumulative exposure to female hormonal drugs was based on filled prescriptions. Statistical analysis included educational level, use of antihistamines, and use of anti-asthma drugs as covariates. During follow-up, 1,595 women were diagnosed with meningioma and 1,167 with glioma. The median (first-third quartile) follow-up time of individuals in the full cohort was 10.8 years (5.0 years to 17.5 years). Compared to never-use, exposure to estrogen-progestin or progestin-only were both associated with increased risk of meningioma, hazard ratio (HR) 1.21; (95% confidence interval (CI) [1.06, 1.37] p = 0.005) and HR 1.28; (95% CI [1.05, 1.54] p = 0.012), respectively. Corresponding HRs for glioma were HR 1.00; (95% CI [0.86, 1.16] p = 0.982) and HR 1.20; (95% CI [0.95, 1.51] p = 0.117). Continuous estrogen-progestin exhibited higher HR of meningioma 1.34; (95% CI [1.08, 1.66] p = 0.008) than cyclic treatment 1.13; (95% CI [0.94, 1.34] p = 0.185). Previous use of estrogen-progestin 5 to 10 years prior to diagnosis yielded the strongest association with meningioma, HR 1.26; (95% CI [1.01, 1.57] p = 0.044), whereas current/recent use of progestin-only yielded the highest HRs for both meningioma 1.64; (95% CI [0.90, 2.98] p = 0.104) and glioma 1.83; (95% CI [0.98, 3.41] p = 0.057). Being an observational study, residual confounding could occur. CONCLUSIONS: Use of continuous, but not cyclic estrogen-progestin was associated with increased meningioma risk. There was no evidence of increased glioma risk with estrogen-progestin use. Use of progestin-only was associated with increased risk of meningioma and potentially glioma. Further studies are warranted to evaluate our findings and investigate the influence of long-term progestin-only regimens on CNS tumor risk.

Pesticide exposure and risk of Central Nervous System tumors in children: a systematic review with meta-analysis. / Exposição a agrotóxicos e o risco de tumores do Sistema Nervoso Central em crianças: revisão sistemática com metanálise.

Central Nervous System (CNS) tumors represent more than half of all childhood malignant neoplasms. The aim of this study was to determine the relationship between environmental exposure to pesticides and the development of CNS tumors in children. We conducted a systematic review of the literature in the PubMed/MEDILINE, Embase, Web of Science, Scopus, and CINAHL databases. The inclusion criteria were cohort and case-control studies investigating the association between exposure to pesticides and CNS tumors (all histological types included in group III of the WHO Classification of Childhood Cancer) in children aged 0-14 years. The meta-analysis was performed using a random effects model and the Mantel-Haenszel method. Strength of association was measured using odds ratios (OR). The review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under identification number CRD42021209354. The search identified 1,158 studies, 14 of which were included in the review. There was evidence of an association between the development of astrocytomas and exposure to all classes of pesticides (OR 1.50; 95%CI 1.15-1.96; p=0.03). The synthesis of the evidence pointed to a relationship between exposure to pesticides and some histological types of CNS tumors in childhood.

Os tumores do Sistema Nervoso Central (SNC) representam mais da metade das neoplasias infantis malignas que acometem crianças. Objetivou-se analisar o risco de exposição a agrotóxicos relacionado com o desenvolvimento de tumores do SNC em crianças. Realizou-se uma revisão sistemática da literatura nas bases de dados PubMed/MEDILINE, Embase, Web of Science, Scopus e CINAHL. Foram incluídos estudos de coorte e caso-controle sobre o desenvolvimento de tumores do SNC (todos os tipos histológicos do grupo III Classificação de Câncer Infantil) decorrentes da exposição a agrotóxicos em crianças de 0-14 anos. Na metanálise utilizou-se o modelo de efeito aleatório e o método estatístico de Mantel-Haenszel. A Razão de Chances (RC) ou Odds Ratio (OR) foi a medida de associação aplicada. A revisão foi registrada no International Prospective Register of Systematic Reviews (PROSPERO) sob o número CRD42021209354. A busca identificou 1.158 estudos, dos quais 14 compuseram a revisão. Verificou-se evidência de associação entre o desenvolvimento de astrocitomas e a exposição a todas as classes de pesticidas (OR 1,50; IC95% 1,15-1,96; p=0,03). A síntese dos resultados apontou para uma relação da exposição aos agrotóxicos com o desfecho de alguns tipos histológicos de tumores do SNC na infância.

Exposure to nitrosatable drugs during pregnancy and childhood cancer: A matched case-control study in Denmark, 1996-2016.

BACKGROUND: Nitrosatable drugs can be synthesized to N-nitroso compounds in human stomach. In a pregnant woman, N-nitroso compounds can be translocated to the fetus through the placenta. Maternal exposure of nitrosatable compounds during pregnancy has been associated with childhood brain tumors and leukemia. However, few studies have investigated an association between nitrosatable drug exposure during pregnancy and childhood cancer. We examined if maternal prescriptions of nitrosatable drugs received during pregnancy are associated with childhood cancer. METHODS: A matched case-control study was conducted using Danish nationwide registry data from 1995 to 2016. Each childhood cancer case was matched with twenty-five controls. Maternal exposure of nitrosatable drugs during pregnancy was identified from the Danish National Prescription Register. A multivariable conditional logistic regression model was used to estimate adjusted odds ratios (adj.OR) with 95% confidence intervals (CI) for each childhood cancer type. RESULTS: Maternal prescriptions of nitrosatable drugs positively associate with central nervous system tumors (adj.OR = 1.25; 95% CI = 1.04-1.51) and neuroblastoma (adj.OR = 1.96; 95% CI = 1.34-2.85) in offspring. We also observed a positive association between perinatal exposure of nitrosatable drugs and acute lymphoblastic leukemia (adj.OR = 1.31; 95% CI = 1.07-1.59), however, it appeared to be due to confounding by indication, i.e., maternal infections. CONCLUSION: Nitrosatable drug use during pregnancy potentially increased risk of central nervous system tumors and neuroblastoma. While a positive association between maternal prescriptions of nitrosatable drugs and acute lymphoblastic leukemia should be interpreted cautiously because of confounding by indication.

Optimum Methotrexate Exposure in Patients With Suspected or Confirmed CNS Invasive Hematological Malignancies: A Systematic Critical Review.

BACKGROUND AND METHODS: The present review aims to evaluate the current state-of-the-art dosing regimens of high-dose (HD) and intrathecal methotrexate (MTX) using therapeutic drug monitoring (TDM) to optimize its therapeutic response and minimize associated toxicity, particularly in the central nervous system (CNS). RESULTS: MTX is administered systemically in a HD regimen (>1 g/m 2 ) for the treatment of various hematological neoplasms. HD-MTX treatment becomes complicated by marked interindividual drug elimination variability. TDM is specified to manage this high variability. Approximately 3%-7% of adults with acute lymphoblastic leukemia are diagnosed with CNS involvement, and the incidence of CNS relapse in patients, despite receiving prophylaxis, ranges from 5% to 10%. HD-MTX penetrates the blood-brain barrier and can be administered intrathecally, making this drug an important component of chemotherapy regimens for patients with hematologic malignancies involving the CNS or those at high risk of CNS relapse. CONCLUSIONS: The major evidence found was that an MTX area under the curve target between 1000 and 1100 µmol hour -1 L is associated with better clinical outcomes. However, there seems to be a clinical gap in the prospective validation of HD and IT MTX management to optimize clinical outcomes and minimize toxicity, using the relationship between exposure level (area under the curve MTX) and optimal response to MTX, at systemic and CNS exposure.

Association Between Maternal Hormonal Contraception Use and Central Nervous System Tumors in Children.

Importance: The incidence of central nervous system (CNS) tumors in children appears to be increasing, yet few risk factors are established. There is limited information regarding whether maternal hormonal contraception use increases this risk. Objective: To examine the association between maternal hormonal contraception use and CNS tumors in children (<20 years). Design, Setting, and Participants: In this nationwide cohort study based on population-based registry data, 1 185 063 children born in Denmark between January 1, 1996, and December 31, 2014, were followed up for a diagnosis of a CNS tumor (final follow-up on December 31, 2018). Exposures: Maternal hormonal contraception use was analyzed according to any use, regimen (combined/progestin only), and route of administration (oral/nonoral), categorized as recent use (≤3 months before start and during pregnancy), previous use (>3 months before start of pregnancy), and no use. For injections, implants, and intrauterine devices that are used for a different time period, the categorization was appropriately altered. Main Outcomes and Measures: Hazard ratio (HR) and incidence rate difference (IRD) of CNS tumors diagnosed at younger than 20 years. Results: After 15 335 990 person-years of follow-up (mean follow-up, 12.9 years), 725 children were diagnosed with a CNS tumor. The mean age at diagnosis was 7 years, and 342 (47.2%) of the diagnosed children were female. The adjusted incidence rate of CNS tumors per 100 000 person-years was 5.0 for children born to mothers with recent hormonal contraception use (n = 136 022), 4.5 for children born to mothers with previous use (n = 778 843), and 5.3 for children born to mothers with no use (n = 270 198). The corresponding HRs were 0.95 ([95% CI, 0.74-1.23]; 84 children with CNS tumors; IRD, -0.3 [95% CI, -1.6 to 1.0]) for recent use and 0.86 ([95% CI, 0.72-1.02]; 421 children with CNS tumors; IRD, -0.8 [95% CI, -1.7 to 0.0]) for previous use, compared with no use. No statistically significant associations were found for recent or previous use of oral combined, nonoral combined, oral progestin only, or nonoral products compared with no use of hormonal contraception. Conclusions and Relevance: Among Danish children, there was no statistically significant association between any maternal hormonal contraception use and CNS tumor risk.

Residential proximity to pesticide application as a risk factor for childhood central nervous system tumors.

BACKGROUND: Pesticide exposures have been examined previously as risk factors for childhood brain cancers, but few studies were able to assess risk from specific agents. OBJECTIVE: To evaluate risks for childhood central nervous system tumors associated with residential proximity to agricultural pesticide applications. METHODS: Using the California Cancer Registry, we identified cancer cases less than 6 years of age and frequency matched them by year of birth to 20 cancer-free controls identified from birth certificates. We restricted analyses to mothers living in rural areas and births occurring between 1998 and 2011, resulting in 667 cases of childhood central nervous system tumors and 123,158 controls. Possible carcinogens were selected per the Environmental Protection Agency's (US. EPA) classifications, and prenatal exposure was assessed according to pesticides reported by the California Department of Pesticide Regulation's (CDPR) Pesticide Use Reporting (PUR) system as being applied within 4000m of the maternal residence at birth. We computed odds ratios for individual pesticide associations using unconditional logistic and hierarchical regression models. RESULTS: We observed elevated risks in the hierarchical models for diffuse astrocytoma with exposure to bromacil (OR: 2.12, 95% CI: 1.13-3.97), thiophanate-methyl (OR: 1.64, 95% CI: 1.02-2.66), triforine (OR: 2.38, 95% CI: 1.44-3.92), and kresoxim methyl (OR: 2.09, 95% CI: 1.03-4.21); elevated risks for medulloblastoma with exposure to chlorothalonil (OR: 1.78, 95% CI: 1.15-2.76), propiconazole (OR: 1.60, 95% CI: 1.02, 2.53), dimethoate (OR: 1.60, 95% CI: 1.06, 2.43), and linuron (OR: 2.52, 95% CI: 1.25, 5.11); and elevated risk for ependymoma with exposure to thiophanate-methyl (OR: 1.72, 95% CI: 1.10-2.68). CONCLUSION: Our study suggests that exposure to certain pesticides through residential proximity to agricultural applications during pregnancy may increase the risk of childhood central nervous system tumors.

Occupational exposure to pesticides and central nervous system tumors: results from the CERENAT case-control study.

BACKGROUND: The etiology of the central nervous system (CNS) tumors remains largely unknown. The role of pesticide exposure has been suggested by several epidemiological studies, but with no definitive conclusion. OBJECTIVE: To analyze associations between occupational pesticide exposure and primary CNS tumors in adults in the CERENAT study. METHODS: CERENAT is a multicenter case-control study conducted in France in 2004-2006. Data about occupational pesticide uses-in and outside agriculture-were collected during detailed face-to-face interviews and reviewed by experts for consistency and exposure assignment. Odds ratios (ORs) and 95% confidence intervals (95% CI) were estimated with conditional logistic regression. RESULTS: A total of 596 cases (273 gliomas, 218 meningiomas, 105 others) and 1 192 age- and sex-matched controls selected in the general population were analyzed. Direct and indirect exposures to pesticides in agriculture were respectively assigned to 125 (7.0%) and 629 (35.2%) individuals and exposure outside agriculture to 146 (8.2%) individuals. For overall agricultural exposure, we observed no increase in risk for all brain tumors (OR 1.04, 0.69-1.57) and a slight increase for gliomas (OR 1.37, 0.79-2.39). Risks for gliomas were higher when considering agricultural exposure for more than 10 years (OR 2.22, 0.94-5.24) and significantly trebled in open field agriculture (OR 3.58, 1.20-10.70). Increases in risk were also observed in non-agricultural exposures, especially in green space workers who were directly exposed (OR 1.89, 0.82-4.39), and these were statistically significant for those exposed for over 10 years (OR 2.84, 1.15-6.99). DISCUSSION: These data support some previous findings regarding the potential role of occupational exposures to pesticides in CNS tumors, both inside and outside agriculture.

Parental occupational exposure to pesticides and risk of childhood cancer in Switzerland: a census-based cohort study.

BACKGROUND: Pesticide exposure is a suspected risk factor for childhood cancer. We investigated the risk of developing childhood cancer in relation to parental occupational exposure to pesticides in Switzerland for the period 1990-2015. METHODS: From a nationwide census-based cohort study in Switzerland, we included children aged < 16 years at national censuses of 1990 and 2000 and followed them until 2015. We extracted parental occupations reported at the census closest to the birth year of the child and estimated exposure to pesticides using a job exposure matrix. Cox proportional hazards models, adjusted for potential confounders, were fitted for the following outcomes: any cancer, leukaemia, central nervous system tumours (CNST), lymphoma, non-CNS solid tumours. RESULTS: Analyses of maternal (paternal) exposure were based on approximately 15.9 (15.1) million-person years at risk and included 1891 (1808) cases of cancer, of which 532 (503) were leukaemia, 348 (337) lymphomas, 423 (399) CNST, and 588 (569) non-CNS solid tumours. The prevalence of high likelihood of exposure was 2.9% for mothers and 6.7% for fathers. No evidence of an association was found with maternal or paternal exposure for any of the outcomes, except for "non-CNS solid tumours" (High versus None; Father: adjusted HR [95%CI] =1.84 [1.31-2.58]; Mother: 1.79 [1.13-2.84]). No evidence of an association was found for main subtypes of leukaemia and lymphoma. A post-hoc analysis on frequent subtypes of "non-CNS solid tumours" showed positive associations with wide CIs for some cancers. CONCLUSION: Our study suggests an increased risk for solid tumours other than in the CNS among children whose parents were occupationally exposed to pesticides; however, the small numbers of cases limited a closer investigation of cancer subtypes. Better exposure assessment and pooled studies are needed to further explore a possible link between specific childhood cancers types and parental occupational exposure to pesticides.

Residential proximity to agriculture and risk of childhood leukemia and central nervous system tumors in the Danish national birth cohort.

BACKGROUND: Living in an agricultural area or on farms has been associated with increased risk of childhood cancer but few studies have evaluated specific agricultural exposures. We prospectively examined residential proximity to crops and animals during pregnancy and risk of childhood leukemia and central nervous system (CNS) tumors in Denmark. METHODS: The Danish National Birth Cohort (DNBC) consists of 91,769 pregnant women (96,841 live-born children) enrolled in 1996-2003. For 61 childhood leukemias and 59 CNS tumors <15 years of age that were diagnosed through 2014 and a ~10% random sample of the live births (N = 9394) with geocoded addresses, we linked pregnancy addresses to crop fields and animal farm locations and estimated the crop area (hectares [ha]) and number of animals (standardized by their nitrogen emissions) by type within 250 meters (m), 500 m, 1000 m, and 2000 m of the home. We also estimated pesticide applications (grams, active ingredient) based on annual sales data for nine herbicides and one fungicide that were estimated to have been applied to >30% of the area of one or more crop. We used Cox proportional hazard models (weighted to the full cohort) to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of childhood leukemia and CNS tumors with crop area, animals, and pesticide applications adjusted for gender and maternal age. RESULTS: Sixty-three percent of mothers had crops within 500 m of their homes during pregnancy; winter and spring cereals were the major crop types. Compared to mothers with no crops <500 m, we found increasing risk of childhood leukemia among offspring of mothers with increasing crop area near their home (highest tertile >24 ha HR: 2.0, CI:1.02-3.8), which was stronger after adjustment for animals (within 1000 m) (HR: 2.6, CI:1.02-6.8). We also observed increased risk for grass/clover (highest tertile >1.1 ha HR: 3.1, CI:1.2-7.7), peas (>0 HR: 2.4, CI: 1.02-5.4), and maize (>0 HR: 2.8, CI: 1.1-6.9) in animal-adjusted models. We found no association between number of animals near homes and leukemia risk. Crops, total number of animals, and hogs within 500 m of the home were not associated with CNS tumors but we observed an increased risk with >median cattle compared with no animals in crop-adjusted models (HR = 2.2, CI: 1.02-4.9). In models adjusted for total animals, the highest tertiles of use of three herbicides and one fungicide were associated with elevated risk of leukemia but no associations were statistically significant; there were no associations with CNS tumors. CONCLUSIONS: Risk of childhood leukemia was associated with higher crop area near mothers' homes during pregnancy; CNS tumors were associated with higher cattle density. Quantitative estimates of crop pesticides and other agricultural exposures are needed to clarify possible reasons for these increased risks.

Isolated Central Nervous System Relapse Following Treatment Reduction in Low-risk Acute Lymphoblastic Leukemia at the Children's Cancer Center of Lebanon.

The aim of this trial was to decrease the incidence of life-threatening infections by decreasing the dose and the duration of dexamethasone treatment during maintenance therapy. This was a prospective, nonrandomized trial of low-risk acute lymphoblastic leukemia patients 1 to 18 years of age who were treated at the Children's Cancer Center of Lebanon (CCCL). Patients consecutively diagnosed between 2002 and 2013 were divided into groups 1 and 2 receiving total dexamethasone doses of 1144 and 618 mg/m, respectively. A total of 84 patients were assigned to group 1 and 33 patients to group 2. The 5-year cumulative incidence of isolated central nervous system relapse increased from (n=0% [95% confidence interval: 0%-4.4%]) in group 1 to 9.1% [95% confidence interval: 3%-23%]; P=0.021) in group 2. Decreasing cumulative dose of dexamethasone for low-risk childhood acute lymphoblastic leukemia patients aiming to avoid serious viral infections led to a significant increase in isolated central nervous system relapse.

Case-control study of brain and other central nervous system cancer among workers at semiconductor and storage device manufacturing facilities.

OBJECTIVE: This study evaluated the relationship between brain and other central nervous system cancer ('CNS cancer') and exposures at two semiconductor and electronic module manufacturing facilities and at a storage device manufacturing facility. METHODS: The case-control study, nested in a cohort of 126 836 employees, compared 120 CNS cancer cases and 1028 matched controls with respect to employment in 10 process groups and estimated cumulative exposure to 31 known or possible carcinogens. RESULTS: CNS cancer was associated with module manufacturing operations at two facilities. Module manufacturing is a process that begins with production of ceramic substrates followed by attachment of completed semiconductor chips and metal-containing circuitry resulting in a high performing electronic device. Positive associations with the highest tertile of estimated cumulative exposure were found for several chemicals, including 2-butoxyethanol, cyclohexanone, ortho-dichlorobenzene, cadmium, molybdenum, trichloroethylene and vinyl chloride. CONCLUSIONS: Results suggested positive associations between CNS cancer and specific operations and chemicals experienced in the semiconductor and electronic module manufacturing industry. However, lack of external support for these findings precludes a causal interpretation, and the observed associations may have been due to chance.

Central nervous system tumors in 2-year rat carcinogenicity studies: perspectives on human risk assessment.

Rodent in vivo carcinogenicity bioassays are required for human risk assessment and have been utilized in this capacity for decades. Accordingly, there is an abundance of data that could be accessed and analyzed to better understand the translatability of xenobiotic-induced rodent tumors to human risk assessment. In the past decade, various groups have published assessments of the value garnered by these life-time rodent studies. Results and recommendations from the International Council for Harmonization Expert Working Group (ICH-S1 EWG) on the predictability of the current testing paradigm and proposal for an integrated approach to human carcinogenicity risk assessment are pending. Central nervous system (CNS) tumors in rats are rare and translatability to human remains unknown. This review focuses on microglial cell tumors (MCT) of the CNS in rats including its classification, nomenclature, incidence and translatability to human risk assessment. Based on emerging immunohistochemistry (IHC) characterization, glial tumors previously thought of astrocytic origin are more likely MCTs. These may be considered rodent specific and glucose dysregulation may be one component contributing to their formation. Based on review of the literature, MCTs are rarely diagnosed in humans, thus this tumor type may be rat-specific. We propose to include MCTs as a tumor type in revised International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) classification and all glial tumors to be classified as MCTs unless proven otherwise by IHC.

Increased risk of central nervous system tumours with carbamate insecticide use in the prospective cohort AGRICAN.

BACKGROUND: Pesticide exposures are suspected to be implicated in the excess of central nervous system (CNS) tumours observed in farmers, but evidence concerning individual pesticides remains limited. Carbamate insecticides, used on a wide range of crops, have shown evidence of carcinogenicity in some experimental studies. In the cohort AGRICAN (AGRIculture & CANcer), we assessed the associations between potential exposures to carbamate insecticides and the incidence of CNS tumours, overall and by histological subtype. METHODS: AGRICAN enrolled 181 842 participants involved in agriculture. Incident CNS tumours were identified by linkage with cancer registries from enrolment (2005-07) until 2013. Carbamate exposure was assessed by combining information on lifetime periods of pesticide use on crop or livestock and the French crop-exposure matrix PESTIMAT, individually for each of the 19 carbamate insecticides registered in France since 1950. Associations were estimated using proportional hazards models with age as the underlying time scale, adjusting for gender, educational level and smoking. RESULTS: During a 6.9-year average follow-up, 381 incident cases of CNS tumours occurred, including 164 gliomas and 134 meningiomas. Analyses showed increased risks of CNS tumours with overall exposure to carbamate insecticides and linear trends with duration of use of each carbamate. Considering tumour subtypes, hazard ratios for gliomas ranged from 1.18 for thiofanox to 4.60 for formetanate, and for meningiomas from 1.51 for carbaryl to 3.67 for thiofanox. CONCLUSIONS: Findings reinforce carcinogenicity evidence for already suspected active ingredients and draw attention to additional active ingredients, notably used on fruit trees, vineyards, potatoes and beets.

Is ibrutinib associated with disseminated cryptococcosis with CNS involvement?

Chronic lymphocytic leukemia (CLL) is a disorder of B cells that affects humoral as well as cell-mediated immunity. Protection against cryptococcal infections is mounted by an intricate and synchronized interplay of both integral arms of immunity. Whether CLL or small molecule tyrosine kinase inhibitors are independently predisposing hosts to cryptococcal infections remain to be explored. Herein, we present a report of a patient who developed disseminated cryptococcosis while receiving ibrutinib therapy for CLL in the salvage setting. We further present relevant literature available thus far on the topic and discuss immunologic mechanisms that may be involved in the fungal pathogenesis in such patients.

Natalizumab-Associated Primary Central Nervous System Lymphoma.

OBJECTIVE: Natalizumab, a selective adhesion molecule inhibitor binding to an α-4 subunit of integrin, has emerged to be an effective immunomodulator, especially in the treatment of relapsing-remitting multiple sclerosis and Crohn disease. Recent reports documenting the development of primary central nervous system lymphoma (PCNSL) as a result of its administration have been concerning, and they trigger a debate about a possible causal association. In our report, we provide a comprehensive review of the literature on lymphoma development after natalizumab use, and we report an additional case of PCNSL development in a young woman who received natalizumab for her Crohn disease. METHODS: A systematic (qualitative) review of literature on lymphoma development after natalizumab therapy was performed by use of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data on patient characteristics, indication for drug therapy, dosages, radiologic findings, potential risk factors for PCNSL, and tumor markers were synthesized. Additionally, we present the findings from the case of a young woman who received natalizumab therapy (4 doses, 300 mg each) for Crohn disease and in whom PCNSL developed. RESULTS: Overall, 8 reports including our index case document lymphoma development after natalizumab use. Our case finding revisits the debate suggesting a remote possibility of association that warrants further evaluation and validation. CONCLUSIONS: Evidence documenting a causal association of natalizumab and PCNSL is weak. Considering the potential benefits of using natalizumab for current indications, we recommend vigilant monitoring of patients receiving the drug for PCNSL outlook.

Central nervous system tumors and agricultural exposures in the prospective cohort AGRICAN.

Studies in farmers suggest a possible role of pesticides in the occurrence of Central Nervous System (CNS) tumors but scientific evidence is still insufficient. Using data from the French prospective agricultural cohort AGRICAN (Agriculture & Cancer), we investigated the associations between exposure of farmers and pesticide users to various kinds of crops and animal farming and the incidence of CNS tumors, overall and by subtypes. Over the 2005-2007, 181,842 participants completed the enrollment questionnaire that collected a complete job calendar with lifetime history of farming types. Associations were estimated using proportional hazards models with age as underlying timescale. During a 5.2 years average follow-up, 273 incident cases of CNS tumors occurred, including 126 gliomas and 87 meningiomas. Analyses showed several increased risks of CNS tumors in farmers, especially in pesticide users (hazard ratio = 1.96; 95% confidence interval: 1.11-3.47). Associations varied with tumor subtypes and kinds of crop and animal farming. The main increases in risk were observed for meningiomas in pig farmers and in farmers growing sunflowers, beets and potatoes and for gliomas in farmers growing grasslands. In most cases, more pronounced risk excesses were observed among pesticide applicators. Even if we cannot completely rule out the contribution of other factors, pesticide exposures could be of primary concern to explain these findings.

Risk factors for central nervous system tumors in children: New findings from a case-control study.

BACKGROUND: Central nervous system tumors (CNS) are the most frequent solid tumor in children. Causes of CNS tumors are mainly unknown and only 5% of the cases can be explained by genetic predisposition. We studied the effects of environmental exposure on the incidence of CNS tumors in children by subtype, according to exposure to industrial and/or urban environment, exposure to crops and according to socio-economic status of the child. METHODS: We carried out a population-based case-control study of CNS tumors in Spain, covering 714 incident cases collected from the Spanish Registry of Childhood Tumors (period 1996-2011) and 4284 controls, individually matched by year of birth, sex, and autonomous region of residence. We built a covariate to approximate the exposure to industrial and/or urban environment and a covariate for the exposure to crops (GCI) using the coordinates of the home addresses of the children. We used the 2001 Census to obtain information about socio-economic status (SES). We fitted logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (95%CIs). RESULTS: The results for all CNS tumors showed an excess risk (OR = 1.37; 95%CI = 1.09-1.73) for SES, i.e., children living in the least deprived areas had 37% more risk of CNS tumor than children living in the most deprived areas. For GCI, an increase of 10% in crop surface in the 1-km buffer around the residence implied an increase of 22% in the OR (OR = 1.22; 95%CI = 1.15-1.29). Children living in the intersection of industrial and urban areas could have a greater risk of CNS tumors than children who live outside these areas (OR = 1.20; 95%CI = 0.82-1.77). Living in urban areas (OR = 0.90; 95%CI = 0.65-1.24) or industrial areas (OR = 0.96; 95%CI = 0.81-1.77) did not seem to increase the risk for all CNS tumors together. By subtype, Astrocytomas, Intracranial and intraspinal embryonal tumors, and other gliomas showed similar results. CONCLUSION: Our results suggest that higher socioeconomic status and exposure to crops could increase the risk of CNS tumors in children.

Development of primary central nervous system lymphoma in a systemic lupus erythematosus patient after treatment with mycophenolate mofetil and review of the literature.

Primary central nervous system lymphoma (PCNSL) is a rare form of extranodal non-Hodgkin lymphoma and four cases of PCNSL have previously been described in association with mycophenolate mofetil. We report the fifth case of PCNSL in a patient with lupus nephropathy while on mycophenolate mofetil treatment.

Differences in environmental exposure assignment due to residential mobility among children with a central nervous system tumor: Texas, 1995-2009.

In epidemiologic studies of childhood cancer, environmental exposures are often assigned based on either residence at birth or diagnosis without considering the impact of residential mobility. Therefore, we evaluated residential mobility and exposure assignment differences to hazardous air pollutants between birth and diagnosis in children with a central nervous system (CNS) tumor. Children diagnosed with CNS tumors during 1995-2009 (N=1,196) were identified from the Texas Cancer Registry. Census tract-level estimates of 1,3-butadiene and benzene were used to assign quartiles of exposure based on the maternal residence at birth and the child's residence at diagnosis. Overall, 64% of younger (0-4 years) children and 79% of older (5-14 years) children moved between birth and diagnosis. Using mixed-effects ordinal logistic regression, residence at diagnosis compared to birth did not result in a significant change in exposure assignment for younger children; however, older children were more likely to be placed in a lower 1,3-butadiene or benzene exposure quartile based on residence at diagnosis compared to birth (odds ratio (OR)=0.58, 95% confidence interval (CI)=0.45-0.76; OR=0.57, 95% CI=0.44-0.75, respectively). In conclusion, while the majority of children moved between birth and CNS tumor diagnosis, mobility did not significantly impact 1,3-butadiene and benzene exposure assessment in younger children.