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F E Alexander

Publications and source records attributed to F E Alexander.

At least 37 records · Page 2Linked to original sources
PubMed2000

Space-time clustering patterns in childhood leukaemia support a role for infection.

Previous studies of space-time clustering in childhood leukaemia have produced equivocal and inconsistent results. To address this issue we have used Manchester Children's Tumour Registry leukaemia data in space-time clustering analyses. Knox tests for space-time interactions between cases were applied with fixed thresholds of close in space, <5 km and close in time <1 year apart. Addresses at birth as well as diagnosis were utilized. Tests were repeated replacing geographical distance with distance to the Nth nearest neighbour. N was chosen such that the mean distance was 5 km. Data were also examined by a second order procedure based on K-functions. All methods showed highly significant evidence of space-time clustering based on place of birth and time of diagnosis, particularly for all leukaemias aged 0-14 and 0-4 years, and acute lymphoblastic leukaemia (ALL) 0-4 years. Some results based on location at diagnosis were significant but mainly gave larger P-values. The results are consistent with an infectious hypothesis. Furthermore, we found an excess of male cases over females involved in space-time pairs. We suggest this may be related to genetic differences in susceptibility to infection between males and females. These findings provide the basis for future studies to identify possible infectious agents.

Adolescent↗
PubMed2000

Pathology characteristics that optimize outcome prediction of a breast screening trial.

The ability of pathology characteristics to predict outcome was tested with the 1029 cancers accumulated in the Edinburgh Randomized Trial of breast screening after 14 years follow-up. The majority (55.7%) were in the screening arm, which also had more operable cases (81.3% vs 62.2%); the reduction in the proportion of inoperable breast cancers in a UK female population invited to mammographic screening is a notable effect of the trial. In the 691 operable invasive cases the size, histological type, grade, node status and node number group individually showed highly significant (P<0.001) association with survival. In multivariate analysis the Nottingham Prognostic Index (NPI) derived from these features showed highly significant association with survival (P<0.001). However, when first adjusted for NPI, combined addition of pathological size in 6 categories and histological type as special or not had an independent association with survival that was statistically firmly based (P<0.001). For operable breast cancer the gains are in smaller sizes, better histological features, and higher proportion node negative. The weighting factors applied to pathology indicators of survival in the NPI are not optimal for a population included in a trial of screening. In particular, a linear trend of the index with pathological size is not appropriate. Inclusion of histological type as special or not improves the index further.

Analysis of Variance↗
PubMed1999

A lack of a functional NAD(P)H:quinone oxidoreductase allele is selectively associated with pediatric leukemias that have MLL fusions. United Kingdom Childhood Cancer Study Investigators.

Rearrangements and fusion of the MLL gene with various alternative partner genes occur in approximately 80% of infant leukemias and are acquired during fetal hemopoiesis in utero. Similar MLL gene recombinants also occur in topoisomerase II-inhibiting drug-induced leukemias. These data have led to the suggestion that some infant leukemia may arise via transplacental fetal exposures during pregnancy to substances that form cleavable complexes with topoisomerase II and induce illegitimate recombination of the MLL gene. A structural feature shared by many topoisomerase II-inhibiting drugs and other chemicals is the quinone moiety. We assayed, by PCR-RFLP, for a polymorphism in an enzyme that detoxifies quinones, NAD(P)H:quinone oxidoreductase (NQO1), in a series (n = 36) of infant leukemias with MLL rearrangements versus unselected cord blood controls (n = 100). MLL-rearranged leukemias were more likely to have genotypes with low NQO1 function (heterozygous CT or homozygous TT at nucleotide 609) than controls (odds ratio, 2.5; P = 0.015). In contrast, no significant allele bias was seen in other groups of pediatric leukemias with TEL-AML1 fusions (n = 50) or hyperdiploidy (n = 29). In the subset of infant leukemias that had MLL-AF4 fusion genes (n = 21), the bias increase in low or null function NQO1 genotypes was more pronounced (odds ratio, 8.12; P = 0.00013). These data support the idea of a novel causal mechanism in infant leukemia involving genotoxic exposure in utero and modulation of impact on a selective target gene by an inherited allele encoding a rate-limiting step in a carcinogen detoxification pathway.

Acute Disease↗
PubMed1999

A comparison of some simple methods to identify geographical areas with excess incidence of a rare disease such as childhood leukaemia.

Six statistics are compared in a simulation study for their ability to identify geographical areas with a known excess incidence of a rare disease. The statistics are the standardized incidence ratio, the empirical Bayes method of Clayton and Kaldor, Poisson probability, a statistic based on the 'Breslow T' test (BT) and two statistics based on the 'Potthoff-Whittinghill' test (PW) for extra-Poisson variance. Two alternative processes of clustering are simulated in which high-risk locations could be caused by environmental sources or could be sites of microepidemics of an infectious agent contributing to a rare disease such as childhood leukaemia. The simulation processes use two parameters (proportion of cases found in clusters and mean cluster size) which are varied to embrace a variety of situations. Real and artificial data sets of small area populations are considered. The most extreme of the artificial sets has all areas of equal population size. The other data sets use the small census areas (municipalities) in Finland since these have extremely heterogeneous population size distribution. Subset selection allows examination of this variability. Receiver operator curve methodology is used to compare the efficacy of the statistics in identifying the cluster areas; statistics are compared for the proportion of true high-risk areas identified in the top 1 per cent and 10 per cent of ranked areas. One of the PW statistics performed consistently well under all circumstances, although the results for the BT statistic were marginally better when only the top 1 per cent of ranked areas was considered. The standardized incidence ratio performed consistently worst.

Bayes Theorem↗
PubMed1999

14 years of follow-up from the Edinburgh randomised trial of breast-cancer screening.

BACKGROUND: The Edinburgh randomised trial of breast-cancer screening recruited women aged 45-64 years from 1978 to 1981 (cohort 1), and those aged 45-49 years during 1982-85 (cohorts 2 and 3). Results based on 14 years of follow-up and 270,000 woman-years of observation are reported. METHODS: Breast-cancer mortality rates in the intervention group (28,628 women offered screening) were compared with those in the control group (26,026) with adjustment for socioeconomic status (SES) of general medical practices. Rate ratios were derived by means of logistic regression for the total trial population and for women first offered screening while younger than 50 years. Analyses were by intention to treat. FINDINGS: Initial unadjusted results showed a difference of just 13% in breast-cancer mortality rates between the intervention and control groups (156 deaths [5.18 per 10,000] vs 167 [6.04 per 10,000]; rate ratio 0.87 [95% CI 0.70-1.06]), but the results were influenced by differences in SES by trial group. After adjustment for SES, the rate ratio was 0.79 (95% CI 0.60-1.02). When deaths after diagnosis more than 3 years after the end of the study were censored the rate ratio became 0.71 (0.53-0.95). There was no evidence of heterogeneity by age at entry and no evidence that younger entrants had smaller or delayed benefit (rate ratio 0.70 [0.41-1.20]). No breast-cancer mortality benefit was observed for women whose breast cancers were diagnosed when they were younger than 50 years. Other-cause mortality rates did not differ by trial group when adjusted for SES. INTERPRETATION: Our findings confirm results from randomised trials in Sweden and the USA that screening for breast cancer lowers breast-cancer mortality. Similar results are reported by the UK geographical comparison, UK Trial of Early Detection of Breast Cancer. The results for younger women suggest benefit from introduction of screening before 50 years of age.

Age Factors↗
PubMed1999

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.

Child↗
PubMed1999

Clusters and clustering of childhood cancer: a review.

Methodological considerations in the study of clusters and clustering of childhood cancer are reviewed briefly. A selection of 11 studies of individual clusters of childhood leukaemia which are either particularly notable or recent and have been reported in peer review journals is then considered. Focus is placed on sources of alerts, descriptive studies, field-work studies, conclusions and communication management. Some of these studies are probably essential but they are unlikely to yield firm conclusions; studies of large data sets are recommended. No causal factor has been identified which can explain a single cluster of childhood leukaemia.

Adolescent↗
PubMed1998

Spatial temporal patterns in childhood leukaemia: further evidence for an infectious origin. EUROCLUS project.

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.

Adolescent↗
PubMed1998

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.

Adolescent↗
PubMed1998

Epstein-Barr virus and Hodgkin's disease: further evidence for the three disease hypothesis.

The epidemiology of Hodgkin's disease suggests that it is a heterogeneous condition comprising more than one disease entity. The Epstein-Barr virus (EBV) is present in the Reed-Sternberg cells of a proportion of cases and is likely to play a role in the pathogenesis of these cases. In this study we show that EBV association rates vary with age at diagnosis. We suggest that Hodgkin's disease can be divided into three disease entities on the basis of EBV association and age, thereby providing biological support for the multiple aetiology hypothesis proposed by MacMahon (Cancer Res 1966; 26: 1189-1290).

Adolescent↗
PubMed1998

Ionising radiation and leukaemia potential risks: review based on the workshop held during the 10th Symposium on Molecular Biology of Hematopoiesis and Treatment of Leukemia and Lymphomas at Hamburg, Germany on 5 July 1997.

Unexplained clusters of childhood leukaemia have generated concern that they may be causally related to environmental exposure to ionising radiation. The workshop provides in-depth examination of the aetiology of childhood leukaemia, patterns of clustering exhibited by cases and the influence of exposure to ionising radiation. Special attention has been focussed on the EUROCLUS study of clustering of childhood leukaemia and monitoring of populations exposed to contamination following the Chernobyl accident. There is insufficient evidence to conclude that environmental ionising radiation exposure is a causative agent for small clusters such as that reported in the vicinity of the Krümmel nuclear facility

Child↗
PubMed1997

Determination of HLA-A*02 antigen status in Hodgkin's disease and analysis of an HLA-A*02-restricted epitope of the Epstein-Barr virus LMP-2 protein.

There is good evidence for an association between Epstein-Barr virus (EBV) and Hodgkin's disease (HD). In approximately one-third of cases, the EBV genome is detectable in Reed-Sternberg (RS) cells and there is expression of the viral nuclear antigen EBNA-1 and the latent membrane protein LMP-1. Expression of LMP-2 has been demonstrated at the mRNA level, and it is presumed that the protein is expressed alongside LMP-1. The LMP-2 protein is known to contain an epitope presented to cytotoxic T-cells which is restricted through the HLA class I antigen A*0201 in healthy seropositive individuals. Since most HLA-A*02-positive Caucasians are HLA-A*0201-positive, it was hypothesized that HLA-A*02-positive individuals would be under-represented among Caucasians with EBV-associated HD. HLA-A*02 status was determined, using flow cytometry and/or the polymerase chain reaction, for 276 individuals including 176 cases of HD. There was no significant difference between the frequency of HLA-A*02 positivity in HD cases and controls, and between EBV-associated and non-associated cases of HD. The A*02 alleles of 14 cases of EBV-associated HD were further subtyped using nested PCR; all except one case were found to be A*0201-positive. We therefore investigated whether there was any evidence for mutation of the epitope representing amino acids 426-434 of LMP-2a which is restricted through HLA-A*0201. In 10/11 cases the nucleotide sequence encoding this epitope was identical to the published sequence; in the remaining case there was a mutation which would not be expected to alter the conformation of the epitope. Overall, our data suggest that other mechanisms of immune escape must be operative in EBV-associated HD.

Adolescent↗
PubMed1997

Aggregation of childhood leukemia in geographic areas of Greece.

A total of 872 children aged up to 14 years, who were diagnosed with leukemia in Greece during the decade 1980-89, were allocated by place of residence to the 601 administrative districts of the country. Evaluation of spatial clustering was done using the Potthoff-Whittinghill method, which validly assesses heterogeneity of leukemia risk among districts with variable expected numbers of cases. There was highly significant evidence for spatial clustering occurring particularly among children living in urban and, to a lesser extent, semi-urban areas. The evidence was stronger for children younger than 10 years old, applied also to children in different five-year age groups, and persisted when cases of acute lymphoblastic leukemia were analyzed separately. These findings provide support to the hypothesis that localized environmental exposures could contribute to the etiology of childhood leukemia, but they cannot distinguish between exposures of physical or chemical nature, nor can they exclude socially conditioned patterns of exposure to infectious agents.

Adolescent↗
PubMed1997

Is Mycoplasma Pneumonia associated with childhood acute lymphoblastic leukemia?

Acute lymphoblastic leukemia (ALL) in the childhood peak may be a rare response to delayed first exposure to one or more common infectious agent(s). Mycoplasma Pneumonia has the appropriate socioeconomic correlates and clinical symptoms and the hypothesis that delayed first exposure to it may contribute to ALL is considered. Counts of positive reports of M Pneumonia from disease surveillance data for England and Wales (United Kindom) for 1975-92 have been taken as proxies for community burden of infection. Variation by months of birth (cohort) and diagnosis (period) of incidence of ALL in children born and diagnosed 1975-92 are compared with predictions. When periods were classified by mean M Pneumonia count rate in the nine preceding months, standardized morbidity ratios (SMR) for the highest and lowest 20 percent were 108 and 89 (rate ratio [RR] = 1.2, 95 percent confidence interval [CI] = 1.1-1.4). SMRs for cohorts with highest and lowest predicted risk (i.e., lowest and highest M Pneumonia count rate around birth and during infancy) were 110 and 97 (RR = 1.1, CI = 1.0-1.3). The trend for period was most marked in the cohorts with low opportunity for exposure when young. This ecologic analysis provides preliminary support for the hypothesis.

Analysis of Variance↗
PubMed1997

Clustering of childhood leukaemia in Hong Kong: association with the childhood peak and common acute lymphoblastic leukaemia and with population mixing.

Incidence data of childhood leukaemia (CL) in Hong Kong (1984-90) have been analysed for evidence of variation between small areas. All cases (n=261) were classified by morphological cell type, with the majority (n=205) being acute lymphoblastic leukaemia (ALL), and haematological review has permitted immunophenotypic classification for 73% of these. The data have been examined for evidence of spatial clustering within small census areas (TPUs) and for association with population mixing, with attention focused on those subgroups (especially the childhood peak of ALL--taken here to be diagnoses in children from 24 months up to the seventh birthday--and common ALL) which, it has been hypothesized, may be caused by unusual patterns of exposure and response to common infections. For the whole of Hong Kong, there was evidence of spatial clustering of ALL at ages 0-4 years (P = 0.09) and in the childhood peak (P<0.05). When these analyses were restricted to TPUs where extreme population mixing may have occurred, overall incidence was elevated and significant evidence of clustering was found for ALL (P<0.007) at these ages and for the common ALL in the childhood peak (P = 0.032). Replication of the analyses for subsets of leukaemia that were not dominated by the childhood peak of ALL found no evidence of clustering. This is the first investigation of an association between population mixing and childhood leukaemia in Asia and the first to include clustering and to consider particular subsets. The results are supportive of the 'infectious' aetiology hypothesis for subsets of childhood leukaemia, specifically common ALL in the childhood peak.

Adolescent↗