R. Peris-Bonet

Spatial clustering of childhood leukaemia: summary results from the EUROCLUS project.

The interpretation of reports of clusters of childhood leukaemia is difficult, first because little is known about the causes of the disease, and second because there is insufficient information on whether cases show a generalized tendency to cluster geographically. The EUROCLUS project is a European collaborative study whose primary objective is to determine whether the residence locations of cases at diagnosis show a general tendency towards spatial clustering. The second objective is to interpret any patterns observed and, in particular, to see if clustering can be explained in terms of either infectious agents or environmental hazards as aetiological agents. The spatial distribution of 13351 cases of childhood leukaemia diagnosed in 17 countries between 1980 and 1989 has been analysed using the Potthoff-Whittinghill method. The overall results show statistically significant evidence of clustering of total childhood leukaemia within small census areas (P=0.03) but the magnitude of the clustering is small (extra-Poisson component of variance (%) = 1.7 with 90% confidence interval 0.2-3.1). The clustering is most marked in areas that have intermediate population density (150-499 persons km[-2]). It cannot be attributed to any specific age group at diagnosis or cell type and involves spatial aggregation of cases of different ages and cell types. The results indicate that intense clusters are a rare phenomenon that merit careful investigation, although aetiological insights are more likely to come from investigation of large numbers of cases. We present a method for detecting clustering that is simple and readily available to cancer registries and similar groups.

Spatial temporal patterns in childhood leukaemia: Further evidence for an infectious origin

The EUROCLUS project included information on residence at diagnosis for 13351 cases of childhood leukaemia diagnosed in the period 1980-89 in defined geographical regions in 17 countries. A formal algorithm permits identification of small census areas as containing case excesses. The present analysis examines spatial-temporal patterns of the cases (n = 970) within these clustered areas. The objectives were, first, to compare these results with those from an analysis conducted for UK data for the period 1966-83, and, second, to extend them to consider infant leukaemias. A modification of the Knox test investigates, within the small areas, temporal overlap between cases in a subgroup of interest at a putative critical time and all other cases at any time between birth and diagnosis. Critical times were specified in advance as follows: for cases of acute lymphoblastic leukaemia aged 2-4 years, the 18-month period preceding diagnosis; for cases of total leukaemia aged 5-14 years, 1 year before to 1 year after birth; and for infant cases (diagnosed < 1 year), 1 year before to 6 months after birth. Each of the analyses found evidence of excess space-time overlap compared with that expected; these were 10% (P = 0.005), 15% (P= 0.0002) and 26% (P= 0.03) respectively. The results are interpreted in terms of an infectious origin of childhood leukaemia.

Prenatal vitamin supplementation and risk of childhood brain tumors.

An international case‐control study of primary pediatric brain tumors included interviews with mothers of cases diagnosed from 1976 to 1994 and mothers of population controls. Data are available on maternal vitamin use during pregnancy for 1,051 cases and for 1,919 controls from 8 geographic areas in North America, Europe and Israel. While risk estimates varied by study center, combined results suggest that maternal supplementation for 2 trimesters decreased risk of brain tumor [odds ratio (OR) = 0.7; 95% confidence interval (CI) = 0.5, 0.9], with a trend of less risk with longer duration of use (p trend = 0.0007). The greatest risk reduction was among children diagnosed under 5 years of age whose mothers used supplements during all 3 trimesters (OR = 0.5; CI = 0.3, 0.8). This effect did not vary by histology and was seen for supplementation during pregnancy rather than during the month before pregnancy or while breast‐feeding. Our findings are largely driven by data from the United States, where most mothers took vitamins. The proportion of control mothers who took vitamins during pregnancy varied markedly from 3% in Israel and in France, 21% in Italy, 33% in Canada and 52% in Spain to 86–92% at the 3 U.S. centers. The composition of the various multivitamin compounds taken also varied: daily dose of vitamin C ranged from 0 to 600 mg; vitamin E from 0 to 70 mg; vitamin A from 0 to 30,000 IU; and folate from 0 to 2,000 μg. Mothers also took individual micronutrient supplements (e.g., vitamin C tablets), but most mothers who took these also took multivitamins, making it impossible to determine the potential independent effects of these micronutrients. Int. J. Cancer Supplement 11:17–22, 1998.

Population density and childhood leukaemia: results of the EUROCLUS study

The EUROCLUS study assembled incidence data for 13,551 cases of childhood leukaemia (CL) diagnosed between 1980 and 1989 in 17 countries (or regions of countries). These were referenced by location at diagnosis to small census areas of which there were 25,723 in the study area. Population counts, surface area and, hence, population density were available for all these small areas. Previous analyses have shown limited extra-Poisson variation (EPV) of case counts within small areas; this is most pronounced in areas of intermediate population density (150-499 persons/km2). In this study, the data set was examined in more detail for evidence that variations in incidence and EPV of CL are associated with population density. Incidence showed a curvilinear association with population density and was highest in areas which were somewhat more densely populated (500-750 persons/km2), where the incidence rate ratio relative to areas having > or = 1000 persons/km2 was 1.16 (95% confidence interval 1.07-1.26) and the P value for quadratic trend across eight strata of population density was 0.02. Incidence in these areas is uniformly elevated and showed no evidence of heterogeneity (i.e. EPV). Statistically significant evidence of EPV was evident amongst some of the areas previously classified as intermediate density areas (specifically, those with a density of 250-499 persons/km2, P < 0.001 for CL). These results were interpreted in terms of the current aetiological hypotheses for CL which propose that exposure to localised epidemics of one or more common infectious agent may contribute to the development of leukaemia. They suggest that such epidemics arise regularly in moderately densely populated areas and also sporadically in areas which are somewhat less densely populated. Although other interpretations are possible, these results may assist in the identification of characteristics which infectious agents must possess if direct or indirect causes of CL.

An International Case-Control Study of Maternal Diet During Pregnancy and Childhood Brain Tumor Risk : A Histology-Specific Analysis by Food Group

PURPOSE Maternal dietary data from an international collaborative case-control study on childhood brain tumors were used to evaluate associations between histology-specific risk and consumption of specific food groups during pregnancy. METHODS Nine study centers from seven countries contributed 1218 cases and 2223 controls. Most cases were diagnosed between 1982 and 1992 and ranged in age from 0 to 19 years. Dietary consumption was measured as average grams per day. RESULTS Foods generally associated with increased risk were cured meats, eggs/dairy, and oil products; foods generally associated with decreased risk were yellow-orange vegetables, fresh fish, and grains. The cured meat association was specific to astrocytomas (odds ratio [OR] range=1.8-2.5 across astrocytoma subtypes for 4th vs. 1st quartile of consumption, p trends <or= 0.03) and ependymomas (OR, 2.0; 95% confidence interval (CI), 0.4-2.9 for 4th vs. 1(st) quartile; p trend=0.03) and was similar in magnitude to previously reported ORs relating maternal cured meat consumption to increased astroglial risk. Other histology-specific associations were decreased risk of anaplastic astrocytomas from cruciferous vegetables (OR, 0.4; 95% CI, 0.3-0.7 for 4th vs. 1st quartile; p trend<0.0001), decreased risk of astroglial tumors from fresh fish (OR, 0.6; 95% CI, 0.5-0.9 for 4th vs. 1st quartile; p trend=0.008), and increased risk of medulloblastoma from oil products (OR, 1.5; 95% CI, 1.0-2.2 for 4th vs. 1(st) quartile; p trend=0.005). CONCLUSIONS These results suggest the need for dietary analysis not only by brain tumor histology, but also by specific foods within a broad food group.

Prenatal vitamin supplementation and pediatric brain tumors: huge international variation in use and possible reduction in risk

Abstract An international case-control study of primary pediatric brain tumors included interviews with mothers of cases diagnosed from 1976–1994 and mothers of population controls. Data are available on maternal vitamin use during pregnancy for 1051 cases and for 1919 controls in eight geographic areas of North America, Europe and Israel. While risk estimates varied by study center, combined results suggest that maternal supplementation for two trimesters may decrease risk of brain tumor [odds ratio (OR)=0.7; 95% confidence interval (CI)=0.5– 0.9], with a trend toward less risk with longer duration of use (P trend= 0.0007). The greatest risk reduction was among children diagnosed under 5 years of age whose mothers used supplements during all three trimesters (OR=0.5; CI=0.3– 0.8). This effect did not vary by histology and was seen for supplementation during pregnancy rather than during the month before pregnancy or while breast feeding. These findings are largely driven by data from the US, where most mothers took vitamins. The proportion of control mothers who took vitamins during pregnancy varied tremendously, from 3% in Israel and in France through 21% in Italy, 33% in Canada, 52% in Spain to 86–92% at the three US centers. The composition of the various multivitamin compounds taken also varied: daily dose of vitamin C ranged from 0 up to 600 mg; vitamin E from 0 to 70 mg; vitamin A from 0 to 30,000 IU and folate from 0 to 2000 mg. Mothers also took individual micronutrient supplements (e.g., vitamin C tablets), but most mothers who took these also took multivitamins, making it impossible to determine potential independent effects of these micronutrients.

Maternal medication use and the risk of brain tumors in the offspring: The SEARCH international case-control study

N‐nitroso compounds (NOC) have been associated with carcinogenesis in a wide range of species, including humans. There is strong experimental data showing that nitrosamides (R1NNO·COR2), a type of NOC, are potent neuro‐carcinogens when administered transplacentally. Some medications are a concentrated source of amides or amines, which in the presence of nitrites under normal acidic conditions of the stomach can form NOC. Therefore, these compounds, when ingested by women during pregnancy, may be important risk factors for tumors of the central nervous system in the offspring. The aim of the present study was to test the association between maternal use of medications that contain nitrosatable amines or amides and risk of primary childhood brain tumors (CBT). A case‐control study was conducted, which included 1,218 cases and 2,223 population controls, recruited from 9 centers across North America, Europe and Australia. Analysis was conducted for all participants combined, by tumor type (astroglial, primitive neuroectodermal tumors and other glioma), and by age at diagnosis (≤5 years; >5 years). There were no significant associations between maternal intake of medication containing nitrosatable amines or amides and CBT, for all participants combined and after stratification by age at diagnosis and histological subtype. This is the largest case‐control study of CBT and maternal medications to date. Our data provide little support for an association between maternal use of medications that may form NOC and subsequent development of CBT in the offspring.