Effectiveness and safety of everolimus treatment in patients with tuberous sclerosis complex in real-world clinical practice.

BACKGROUND: The randomised double-blinded placebo-controlled EXIST-1-3 studies have showed everolimus effective with adverse effects reported as acceptable in treatment of symptoms in patients with tuberous sclerosis complex (TSC), although evidence of outcomes in clinical practice remains limited. This study aimed to investigate, in clinical practice, the effectiveness and safety of everolimus for epilepsy, renal angiomyolipoma (rAML), and subependymal giant cell astrocytoma (SEGA) in patients with TSC. RESULTS: The study included 64 patients with TSC (median age: 19, range 0.9-54 years) receiving everolimus treatment (Norway: n = 35; Denmark: n = 29). Among 45 patients with epilepsy, 14 (31%) were responders experiencing ≥ 50% reduction in seizure frequency in the last 3 months of treatment compared with the last 3 months before treatment. Nineteen (42%) patients changed their anti-seizure medications (ASMs). Responders were more common among patients < 18 years (46%) than among patients ≥ 18 years (14%, p = 0.03). In 29 patients with rAML, everolimus reduced (≥ 30% decrease) and stabilized (< 20% increase, ≤ 30% decrease) longest diameter of rAML in 38% and 59%, respectively, after a mean treatment duration of 37 months. SEGA volume was reduced in three patients by 71%, 43%, and 48% after 39, 34, and 82 months. Adverse effects were reported in 61 of 64 patients (95%) after a median treatment duration of 31 months (range 0-106), with oral ulceration/stomatitis (63%) and upper respiratory tract infections (38%) being the most common. The most common laboratory abnormalities were increased cholesterol (41%), anaemia (30%), and leucopoenia (25%). Grade 3-4 adverse effects were reported in 36% of cases, and life-threatening conditions were reported in two patients. Nine patients discontinued everolimus treatment. CONCLUSIONS: Seizure reduction in this study sample was consistent with results from EXIST, but might be lower than expected, given that changes in concomitant ASMs are part of clinical practice. Seizure reduction was associated with younger age. As with EXIST, everolimus reduced or stabilised rAML size in most patients. SEGA volume was reduced in all three patients. Close follow-up is needed for this group, especially for children and patients who may not be able to report adverse effects.

Feasibility of preirradiation temozolomide in cases of high-grade gliomas: Our experience and review of literature.

Aim: The purpose of this study was to evaluate the efficacy and safety of preradiation temozolomide (TMZ) in high-grade gliomas. Study and Design: It is a single-center, single arm, prospective study. The study included postoperative, histopatholgically proven cases of high-grade gliomas. Materials and Methods: Nine patients of anaplastic astrocytoma (AA) and twenty patients of glioblastoma multiforme (GBM) were enrolled in the study. All patients had undergone partial or complete resection. Three weeks after surgery, patients were started on chemotherapy, consisting of two cycles of TMZ, 150 mg/m2/day for 5 days, repeated at an interval of 4 weeks. Patients were subsequently treated with concomitant chemoradiotherapy. A dose of 60 Gy was given over thirty fractions along with TMZ, 75 mg/m2/day. Four cycles of TMZ were given after completion of radiotherapy, in a dose and manner similar to preradiotherapy. Statistical Analysis and Result: Treatment-related toxicity was assessed using common terminology for toxicity criteria (CTCAE v4). Progression-free survival and overall survival (OS) analysis was done. Nearly 79% of patients completed the two cycles of preradiation chemotherapy. Chemotherapy was tolerated well. Median time to progression was 11 months and 8.2 months in AA and GBM patients, respectively. Median OS was 17.4 months in AA patients and 11.4 months in GBM patients. Conclusions: Most patients of postoperative high-grade gliomas tolerated two cycles of TMZ. A good safety profile of TMZ allows it to be used in frontline settings, especially in high volume centers where a delay in starting radiotherapy frequently occurs. The use of TMZ before radiotherapy is a safe and feasible approach, and further studies are required to validate this approach.

Acrylamide-induced mitochondria collapse and apoptosis in human astrocytoma cells.

Acrylamide (ACR) can be produced during food processing and has neurotoxic effects in humans. This study aims to determine ACR induced apoptotic responses in human astrocytoma U-1240 MG cells to realize the incurred toxic mechanisms. Under 1 and 2mM ACR exposure, cell viability decreased as time increased. The increments in sub-G(1) phase were 87.5-fold, and pro-caspase 3 and PARP protein expressions decreased 35% and 54.5% respectively relative to the control after 2mM ACR treatment. Molecular evidence of Bax/bcl-2 ratio and cytochrome c expression increased 8.86-fold and 6.81-fold as well as pro-caspase 9 decreased 67.8% relative to the control respectively under 2mM ACR exposure. Trolox, an ROS scavenging agent, attenuated cell death and induced ROS production by 2mM ACR. The ultrastructure alterations of mitochondria showed marked vesicular matrix compartmentalization and cytoplasmic vacuole formation after 2mM ACR was treated for 48h, whereas those treated for 72h showed chromatin condensation, pyknosis, and swelling. These results indicate long-term exposure to ACR induced mitochondria collapse and finally led to apoptosis. Although 2mM ACR is higher than average daily intake dosage, workers in chemical industries may be exposed to sufficient doses to entail health risks.

[Tumour induction by ethylnitrosourea in the central nervous system]. / Inducción de tumores en el sistema nervioso central mediante etilnitrosourea.

INTRODUCTION: Experimental central nervous system (CNS) tumours have been proposed as a useful model for the study of oncogenesis, epiphenomena related to cancer and for the design of new therapeutic strategies. DEVELOPMENT: The administration of chemical substances is one of the most commonly-used methods to induce CNS neoplasms. N-ethyl-N-nitrosourea (ENU) belongs to the nitrosourea family, a wide group of alkylating agents that are able to induce brain tumours in litters after transplacentary administration at the 15th day of pregnancy. This nitrogenous urea compound has a high mutation inducibility affecting the expression of oncogenes such as p53, neu/erbB-2 and Ras. Prenatal exposition of Sprague Dawley rats to ENU induces intra-axial tumours of glial lineage and extra-axial malignant schwannomas. Although the precise mechanism of tumour induction is unclear, it is known to affect cell differentiation of primitive neuroepithelium from the subventricular plate generating oligodendrogliomas, astrocytomas, mixed gliomas or ependimomas. CONCLUSION: The transplacentary administration of ENU induces the development of gliomas and schwannomas that are similar to those found in humans. Animal models are necessary and useful for further studies to get an early diagnosis and to establish correct therapeutic indications.

Inducción de tumores en el sistema nervioso central mediante etilnitrosourea / Tumour induction by ethylnitrosourea in the central nervous system

Introducción. La utilización de modelos experimentalesin vivo de tumores en el sistema nerviosos central (SNC) ha traídoimportantes avances a la neurooncología. Estos modelos animaleshan permitido el estudio de procesos de oncogénesis, de sus epifenómenosy del diseño de nuevas estrategias terapéuticas. Desarrollo.Existen varios métodos de inducción de neoplasias en el SNC,de los cuales la administración de sustancias químicas es una delas modalidades más utilizadas. La N-etil-N-nitrosourea (ENU) esun agente alquilante capaz de inducir tumores cerebrales en la descendenciade ratas gestantes tras su administración transplacentaria.Se tata de un compuesto nitrogenado de la urea con alto podermutagénico que afecta a la expresión de ciertos oncogenes comop53, neu/erbB-2 y Ras. Mediante la exposición prenatal a ratasSprague Dawley del carcinógeno ENU se inducen tumores intraaxialesde estirpe glial y tumores extraaxiales como los schwannomasmalignos. Aunque se desconoce el mecanismo preciso de inducciónde los tumores gliales, se sabe que afecta a la diferenciaciónde las células neuroepiteliales primitivas de la placa subventricular,lo que genera oligodendrogliomas, astrocitomas, gliomasmixtos o ependimomas. Conclusión. La administración transplacentariade ENU permite obtener gliomas y schwannomas malignossimilares a los encontrados en los humanos. Esto puede ayudaral estudio en profundidad de dichos tumores para llegar a realizarun diagnóstico precoz y asentar unas indicaciones terapéuticasprecisas

Introduction. Experimental central nervous system (CNS) tumours have been proposed as a useful model for thestudy of oncogenesis, epiphenomena related to cancer and for the design of new therapeutic strategies. Development. Theadministration of chemical substances is one of the most commonly-used methods to induce CNS neoplasms. N-ethyl-Nnitrosourea(ENU) belongs to the nitrosourea family, a wide group of alkylating agents that are able to induce brain tumoursin litters after transplacentary administration at the 15th day of pregnancy. This nitrogenous urea compound has a highmutation inducibility affecting the expression of oncogenes such as p53, neu/erbB-2 and Ras. Prenatal exposition of SpragueDawley rats to ENU induces intra-axial tumours of glial lineage and extra-axial malignant schwannomas. Although theprecise mechanism of tumour induction is unclear, it is known to affect cell differentiation of primitive neuroepithelium fromthe subventricular plate generating oligodendrogliomas, astrocytomas, mixed gliomas or ependimomas. Conclusion. The transplacentaryadministration of ENU induces the development of gliomas and schwannomas that are similar to those found inhumans. Animal models are necessary and useful for further studies to get an early diagnosis and to establish correcttherapeutic indications

Effects of lipid association on lomustine (CCNU) administered intracerebrally to syngeneic 36B-10 rat brain tumors.

A syngeneic, intracerebral rat brain tumor model was developed and characterized and then used to evaluate the therapeutic enhancement of lipid-associated 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). The Fisher rat glioma cell 36B-10 (100,000-500,000 cells) was implanted intracranially to Fisher F-344 rats into the caudate nucleus. Animals treated with lipid-associated CCNU showed a 2- to 10-fold decrease in tumor size compared with animals treated with free CCNU, indicating that lipid association increases the therapeutic index of intracerebral CCNU treatment. Moreover, the syngeneic rat brain tumor model may be useful for evaluation of other therapeutic modalities.

Abnormal cortical cells and astrocytomas in the Eker rat model of tuberous sclerosis complex.

PURPOSE: In patients with tuberous sclerosis complex (TSC), a wide range of neurologic abnormalities develop, including mental retardation and seizures. Brains from TSC patients are characterized by the presence of cortical tubers, large dysmorphic neurons, and abnormal cytomegalic cells. Although analysis of human TSC brain samples led to the identification of these abnormal cell types, very little is known about how these cells function. In an effort to model TSC-associated CNS abnormalities (and ultimately to analyze the electrophysiologic properties of abnormal cells), we examined Eker rats carrying a Tsc2 mutation. Anatomic studies, including standard histologic stains and immunocytochemistry, were performed on young Eker rats exposed to a carcinogen in utero or aged untreated Eker rats (18-24 months old). METHODS: Pregnant TSC2+/- females were injected once a day with hydroquinone (HQ), and offspring were killed at postnatal day P14 or P28. Coronal tissue sections throughout the CNS were prepared and stained for cresyl violet. In separate studies, brains of old untreated Eker rats were sectioned for anatomic analysis by using standard immunohistochemical techniques. RESULTS: Tissue sections stained with cresyl violet did not reveal any gross differences between HQ-treated Eker (Tsc2Ek/+) rats and siblings (Tsc2+/+). However, two classes of abnormal giant cells were observed in brain sections from untreated aged Eker rats: (a) large dysmorphic pyramid-like cells immunoreactive for NeuN, tuberin, and EAAC-1 in layers IV-VI; and (b) abnormal cytomegalic cells immunoreactive for glial fibrillary acidic protein (GFAP), vimentin, and nestin in deep cortical layers or along the white matter. In addition, large subependymal astrocytomas were observed in four animals. CONCLUSIONS: Our data suggest that cortical tuber formation in Eker rats is a rare event and that prenatal exposure to a nongenotoxic carcinogen such as HQ is not sufficient to induce tuber formation. However, with advanced age, an increased likelihood of astrocytoma formation and the emergence of dysmorphic neurons and cytomegalic cells in the Eker rat brain might exist; each of these abnormalities mimics those seen clinically and could contribute to neurologic problems associated with TSC. Further analysis of this rodent model may be warranted.

Household water source and the risk of childhood brain tumours: results of the SEARCH International Brain Tumor Study.

BACKGROUND: The period in utero is a time of increased vulnerability. Offspring of pregnant women exposed to carcinogenic substances in drinking water may be more likely to develop cancer. We examined whether household water source and the presence of nitrates or nitrites in residential water were associated with increased risks of childhood brain tumours (CBT). METHODS: We used data from a multicentre, case-control study with maternal information on residential water source, and nitrate/nitrite levels of tap water measured by dipstick. Subjects included 836 CBT cases and 1485 controls from five countries. RESULTS: The risks of CBT associated with reliance on well water (versus public water) during pregnancy varied widely, with significantly increased risks noted in two (of seven) regions and a decreased risk observed in one region. CBT risk did not increase with increasing nitrate levels. However, our results based on tap water tested in the pregnancy residences suggest the risk of astrocytoma may be associated with increasing levels of nitrite (odds ratio [OR] = 4.3, 95% CI: 1.4, 12.6 for nitrite levels of 1-<5 mg/l nitrite ion; OR = 5.7, 95% CI: 1.2, 27.2 of nitrite > or =5 mg/l). CONCLUSIONS: These results should be interpreted with caution because women's recollection of water sources may have contained inaccuracies, and nitrate and nitrite measurements, available for only a portion of subjects, were often obtained years after the pregnancies occurred. However, our results suggest a need for closer evaluation of well water content in some regions and the possibility that a nitrite-related water exposure may be associated with CBT.

Parental occupational exposure to pesticides and childhood brain cancer.

The authors examined the risk of childhood brain cancer in relation to parental exposure to classes of pesticides among 154 children diagnosed with astrocytoma and 158 children diagnosed with primitive neuroectodermal tumors (PNET) in the United States and Canada between 1986 and 1989. Controls were selected by random digit dialing and were individually matched to cases by race, age, and geographic area. Each job in the fathers' work history and the usual occupation of mothers were assigned a probability, intensity, and frequency of exposure to insecticides, herbicides, and agricultural and nonagricultural fungicides. Elevated risks of astrocytoma were found for paternal exposure (ever vs. never) to all four classes of pesticides (odds ratio (OR) = 1.4-1.6). An increased risk of PNET was observed for only herbicides (OR = 1.5). For mothers, odds ratios for astrocytoma were elevated for insecticides, herbicides, and nonagricultural fungicides (OR = 1.3-1.6) but not agricultural fungicides (OR = 1.0). No indication was found of an increased risk for PNET. There was little indication for an association with cumulative and average parental exposure. Most risk estimates were around unity, and exposure-response patterns were absent. Overall, it seems unlikely that parental exposure to pesticides plays an important role in the etiology of childhood brain cancer.

Never forget the risks of immunosuppression.

It has been widely reported in the literature that malignant neoplasms are a recognised complication of immunosuppression following organ transplantation. These days, immunosuppressive drugs are being used for many conditions outside the transplant setting. A case of a de novo astrocytoma in a patient on long-term immunosuppression for psoriatic arthritis is described.

Dietary restriction reduces angiogenesis and growth in an orthotopic mouse brain tumour model.

Diet and lifestyle produce major effects on tumour incidence, prevalence, and natural history. Moderate dietary restriction has long been recognised as a natural therapy that improves health, promotes longevity, and reduces both the incidence and growth of many tumour types. Dietary restriction differs from fasting or starvation by reducing total food and caloric intake without causing nutritional deficiencies. No prior studies have evaluated the responsiveness of malignant brain cancer to dietary restriction. We found that a moderate dietary restriction of 30-40% significantly inhibited the intracerebral growth of the CT-2A syngeneic malignant mouse astrocytoma by almost 80%. The total dietary intake for the ad libitum control group (n=9) and the dietary restriction experimental group (n=10) was about 20 and 13 Kcal x day(-1), respectively. Overall health and vitality was better in the dietary restriction-fed mice than in the ad libitum-fed mice. Tumour microvessel density (Factor VIII immunostaining) was two-fold less in the dietary restriction mice than in the ad libitum mice, whereas the tumour apoptotic index (TUNEL assay) was three-fold greater in the dietary restriction mice than in the ad libitum mice. CT-2A tumour cell-induced vascularity was also less in the dietary restriction mice than in the ad libitum mice in the in vivo Matrigel plug assay. These findings indicate that dietary restriction inhibited CT-2A growth by reducing angiogenesis and by enhancing apoptosis. Dietary restriction may shift the tumour microenvironment from a proangiogenic to an antiangiogenic state through multiple effects on the tumour cells and the tumour-associated host cells. Our data suggest that moderate dietary restriction may be an effective antiangiogenic therapy for recurrent malignant brain cancers.

Three-generation reproduction study of rats receiving acrylonitrile in drinking water.

Acrylonitrile, a high volume organic chemical, was tested for reproductive effects in a three generation drinking water study with two matings per generation. Sprague-Dawley rats were exposed to acrylonitrile in drinking water at 0, 100, or 500 ppm. This corresponds to 0, 11+/-5 and 37+/-10 mg/kg, respectively, for males and 0, 20+/-3 and 40+/-8 mg/kg per day for the females, respectively. Water consumption was reduced in F0 rats in the 100 and 500 ppm groups. At 500 ppm, acrylonitrile reduced body weight gain and food intake of the first generation parental rats (F0). These parameters were not investigated at subsequent generations. The pup survival (both viability and lactation indices) was reduced at the 500 ppm treatment level in both matings of all three generations. Fostering the 500 ppm pups onto untreated mothers following the second mating lessened mortality, suggesting a maternal effect consistent with decreased water consumption. There was no remarkable change in the reproductive capacity in any of matings in rats at the 100 ppm concentration. In contrast, in all three generations, the body weights of the pups of the 500 ppm treatment level were reduced on Day 21 at both matings. No adverse findings were observed in the tissues of a limited number of third generation weanlings (F3b) upon gross and microscopic evaluation. No effect on the sciatic nerve was evident among the adult female rats held for 20 weeks after weaning of the second litter. There was a dose-related effect of acrylonitrile on gross masses in female rats at each parental generation held 20 weeks after the weaning of the second litter. Histopathological evaluation of these dams showed an increase in astrocytomas and zymbal gland tumors.

Evaluation of ENU-induced gliomas in rats: nomenclature, immunochemistry, and malignancy.

Rats developed mixed gliomas, oligodendrogliomas, and a few astrocytomas in response to transplacental ethylnitrosourea. The neoplastic cell composition of mixed gliomas must be defined; this study required a 20-80% admixture of neoplastic astrocytes and oligodendroglia for the diagnosis of mixed glioma. A battery of immunoantibodies, including Leu-7, S-100, and vimentin, were helpful in classifying rat gliomas, and the histologic features of each tumor type are described. Other brain tumor characteristics that may decide the outcome of carcinogenicity studies include incidence, multiplicity, latency, fatality, size, and malignancy. The size of tumors was determined by measuring their 3-dimensional volumes. Brain tumor volume was found to be highly correlated with malignancy and fatality. Systematic evaluation of the malignancy of brain tumors is an important but often overlooked adjunct method of measuring the effectiveness of a carcinogen. A system to estimate malignancy, one that grades 9 tumor characteristics and weights, each according to clinical outcome, was developed. It was found that mixed gliomas grew larger, had a shorter latency, and were significantly more malignant than were other gliomas.

Examination of low-incidence brain tumor responses in F344 rats following chemical exposures in National Toxicology Program carcinogenicity studies.

Neoplasms in the brain are uncommon in control Fischer 344 (F344) rats; they occur at a rate of less than 1% in 2-yr toxicity/carcinogenicity studies. Furthermore, only 10 of nearly 500 studies conducted by the National Toxicology Program (NTP) showed any evidence of chemically related neoplastic effects in the brain. Generally, the brain tumor responses were considered equivocal, because the characteristics of potential neurocarcinogenic agents (such as statistically significant increased incidences, decreased latency and/or survival, and demonstration of dose-response relationships) were not observed. A thorough examination, including comparisons with a well-established historical database, is often critical in evaluating rare brain tumors. Chemicals that gave equivocal evidence of brain tumor responses were generally associated with carcinogenicity at other sites, and many chemicals were mutagenic when incubated with metabolic activating enzymes. Other factors that were supportive of the theory that marginal increases in brain tumor incidence were related to chemical exposure were that (a) some of the tumors were malignant, (b) no brain neoplasms were observed in concurrent controls from some studies, and/or (c) brain tumors were also seen following exposure to structurally related chemicals. In 2-yr studies in F344 rats (studies conducted by the NTP), equivocal evidence of carcinogenicity was observed for the following 9 chemicals: isoprene, bromoethane, chloroethane, 3,3'-dimethylbenzidine dihydrochloride, 3,3'-dimethoxybenzidine dihydrochloride, furosemide, C.I. direct blue 15, diphenhydramine hydrochloride, and 1-H-benzotriazole. Glycidol was the only chemical evaluated by the NTP with which there was clear evidence of brain tumor induction in F344 rats. Clarification of the potential neurocarcinogenic risks of chemicals that produce equivocal evidence of a brain tumor response in conventional 2-yr rodent studies may be aided by the use of transgenic mouse models that exhibit genetic alterations that reflect those present in human brain tumors as well as by the use of in utero exposures.

CNS tumors and exposure to acrylonitrile: inconsistency between experimental and epidemiology studies.

Acrylonitrile is a potent CNS tumorigen in rats leading to concern that it may be a tumorigen in humans. There have been 12 epidemiology studies of 37,352 workers exposed to acrylonitrile which evaluate CNS cancers. We summarize and evaluate these epidemiology studies for CNS cancers using the methods of meta-analysis. Our analyses indicate that workers with acrylonitrile exposure have null findings for CNS cancer (relative risk = 1.1, 95% confidence interval 0.8-1.5), which are in stark contrast to the projected risk to humans using the rat findings (relative risk = 3.5, 95% confidence interval 3.0-4.0). We discuss several explanations for the inconsistency between animal and human findings, including the possibility that the acrylonitrile-induced rat CNS tumors may not be relevant to humans. Given the rarity of CNS tumors in humans and a lack of understanding of the causal mechanisms of these tumors in rats, however, a more definitive conclusion will have to await additional experimental and observational data. Nevertheless, the epidemiology evidence indicates that acrylonitrile is not a potent CNS tumorigen.

Changes in VEGF expression and in the vasculature during the growth of early-stage ethylnitrosourea-induced malignant astrocytomas in rats.

Vascular endothelial growth factor (VEGF), a potent angiogenic and vascular permeability factor, may be important as a mediator of brain tumour progression. However, it is still not clear whether VEGF plays a causative role in the early stage of glioma development. We investigated the relationship between VEGF protein expression (as assayed by immunohistochemistry) and different morphological parameters reflecting tumour progression (tumour diameter, vascular density and vascular diameter) in tumours at various stages. As a tumour model, ethylnitrosourea (ENU)-induced rat malignant astrocytoma was used. Tumours were classified by size and level of vascularity estimated by the von Willebrand factor (vWF) staining. Tumours less than 10 mm in diameter were designated early stage neoplastic lesions. All 34 early astroglial tumours were found to be VEGF positive. Increase in the VEGF immunopositive rate of tumour cells correlated significantly with increase in vascular density and vascular diameter. We suggest that VEGF induces angiogenesis and growth of microvessels, promoting growth of the early stage malignant astrocytoma.

Increased telomerase activity and absence of p53 mutation in oligoastrocytomas induced by N-ethyl-N-nitrosourea in rats.

The question of whether the changes in telomerase activity and/or the alteration of the p53 gene are involved in the development of oligo-astrocytomas induced by N-ethyl-N-nitrosourea (ENU) in rats was addressed. Telomerase activity levels of oligo-astrocytomas, including early neoplastic lesions, were significantly increased as compared to the normal controls, correlating with the degree of malignancy. In contrast, no mutations of p53 exons 5-7 were found in early neoplastic lesions or oligo-astrocytomas. These results indicate that the activation of telomerase occurs during astrocytoma carcinogenesis and contributes to the development of brain tumors, but the alterations of p53, at least on exons 5-7, may not be involved in this process.

Cancer risk and residential proximity to cranberry cultivation in Massachusetts.

OBJECTIVES: This study evaluated the relationship between cancer risk and residential proximity to cranberry cultivation. METHODS: A population-based case-control study was conducted. Cases, diagnosed during 1983 through 1986 among residents of the Upper Cape Cod area of Massachusetts, involved incident cancers of the lung (n = 252), breast (n = 265), colon-rectum (n = 326), bladder (n = 63), kidney (n = 35), pancreas (n = 37), and brain (n = 37), along with leukemia (n = 35). Control subjects were randomly selected from among telephone subscribers (n = 184), Medicare beneficiaries (n = 464), and deceased individuals (n = 723). RESULTS: No meaningful increases in risk were seen for any of the cancer sites except for the brain. When latency was considered, subjects who had ever lived within 2600 ft (780 m) of a cranberry bog had a twofold increased risk of brain cancer overall (95% confidence interval [CI] = 0.8, 4.9) and a 6.7-fold increased risk of astrocytoma (95% CI = 1.6, 27.8). CONCLUSIONS: Residential proximity to cranberry bog cultivation was not associated with seven of the eight cancers investigated; however, an association was observed with brain cancer, particularly astrocytoma. Larger, more detailed studies are necessary to elucidate this relationship.

Maternal exposure to N-nitrosatable drugs as a risk factor for childhood brain tumours.

BACKGROUND: Animal models suggest that compounds containing a nitrosyl group (N-nitroso compounds (NNO)) can act as potent transplacental carcinogens. Many common drug formulations have the potential to undergo nitrosation in vivo. The association between maternal use of nitrosatable drugs during pregnancy and development of brain tumours in the offspring was examined in a SEER-based case-control study. METHODS: Maternal exposure to nitrosatable drugs during pregnancy was compared among 361 childhood brain tumour cases and 1083 matched controls recruited through random-digit dialing. RESULTS: There was no increase in risk observed for childhood brain tumours overall (OR = 1.15; 95% CI: 0.69-1.94) or for astrocytomas individually (OR = 1.16; 95% CI: 0.50-2.69). A slight elevation in risk was noted for medulloblastomas (OR = 1.47; 95% CI: 0.28-7.62) and 'other' tumours (OR = 1.27; 95% CI: 0.56-2.86), however, both estimates were based on small numbers. CONCLUSIONS: Our findings suggest that no increased risk of childhood brain tumours was associated with maternal exposure to nitrosatable drugs. The study results should be viewed with caution given the imprecision of the point estimates as well as the lack of data on specific timing and dosage of exposure and degree of nitrosatability of drugs taken.