Viruses, clusters and clustering of childhood leukaemia: a new perspective?

Alexander, Freda E.

doi:10.1016/0959-8049(93)90016-9

Cited by 64 publications

(46 citation statements)

References 137 publications

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“…The method, although based on that of Knox, addresses more specific aetiological hypotheses and is also more complex than tests of space-time clustering using time and place of diagnosis. The last tests have been applied widely to CL with somewhat equivocal conclusions (for example van Steensel-Moll et al, 1983) and positive results most frequent for young children (0-4 years) (Alexander, 1993). The Knox test has not been applied to the present data, with the exception of Greece where marked space-time interaction was observed for this youngest age group .…”

Section: Discussionmentioning

confidence: 89%

“…The justification for this and the selection of series A2 in the original analysis (Alexander, 1992) were considerably weaker; they came directly from the analysis of residential histories in two case-control studies (Smith et al, 1976;Alexander et al, 1992) with indirect support coming from comparisons of the ages of the persons most likely to have been involved in mixing with the ages of the subsequent leukaemia excess in Kinlen's studies in which, in general, mixing of adults is associated with excess CL outside the childhood peak ages (reviewed in Alexander, 1993). Mixing of adults will most obviously influence children in utero or during early life.…”

Section: Discussionmentioning

confidence: 99%

“…Reports of clusters of leukaemia, usually involving children, have been frequent throughout this century (Alexander, 1993), but their aetiological significance remains obscure. The EUROCLUS project was established to investigate the geographical pattern of the disease using specialist registry data from a wide spectrum of European countries, and also from Queensland, Australia.…”

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confidence: 99%

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

Alexander

Boyle²,

Carli³

et al. 1998

Br J Cancer

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Summary The EUROCLUS project included information on residence at diagnosis for 13 351 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.Keywords: infection; childhood leukaemia; acute lymphoblastic leukaemia; delayed exposure; infant leukaemia; in utero exposure; cluster Leukaemia is the most frequent childhood malignancy (Parkin et al, 1988), but the cause of the majority of cases remains unknown (Doll, 1989). Reports of clusters of leukaemia, usually involving children, have been frequent throughout this century (Alexander, 1993), but their aetiological significance remains obscure. The EUROCLUS project was established to investigate the geographical pattern of the disease using specialist registry data from a wide spectrum of European countries, and also from Queensland, Australia. The primary objective was to determine whether the disease showed a general tendency to cluster within small areas. The results (Alexander et al, 1998) show statistically significant evidence of clustering, although the magnitude is small. The only previous investigation of spatial clustering of childhood leukaemia (CL) in a large dataset was conducted in the UK (Draper, 1990 (1993) and Kinlen (1995). A second objective of EUROCLUS was to test these hypotheses and make comparisons with the results of the UK analysis (Alexander, 1992). Specific subgroups of interest are (a) cases of acute lymphoblastic leukaemia (ALL) in the childhood peak, and (b) cases of CL aged 5-14 years. Critical times, specified in advance are for (a) the 18-month period preceding diagnosis, and for (b), 1 year before to 1 year after birth.A third subgroup of interest that had not been included in the UK analysis is infant leukaemia (diagnosed < 1 year or < 18 months), which has recently emerged as an interesting biological entity as a large...

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Alexander

Boyle²,

Carli³

et al. 1998

Br J Cancer

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“…We have chosen respectively 5 km and 1 year since these are the round numbers closely representing the limits that were used by several investigators who reported space-time clustering in earlier publications (Meighan and Knox, 1965;Mainwaring, 1966;Smith et al, 1976;Morris, 1990), as summarised by Alexander (1993). Moreover, these limits are compatible with the presumed variability of the latency of childhood leukaemia among survivors of the atomic bombs (Finch, 1984) and the mobility of healthy children in the study population.…”

mentioning

confidence: 94%

“…Thus, childhood leukaemia has been reported to be more common among first-born children, who tend to be exposed to infectious agents at an older age than children of higher birth order (MacMahon, 1992); in situations of population mixing that tend to increase the level of contacts between infected and susceptible individuals (Kinlen et al, 1990 Kinlen and Petridou, 1995); and among children who do not attend day care centres and thus lose the opportunity of an early protective exposure (Van Steensal-Moll et al, 1986;Petridou et al, 1993). More direct evidence for involvement of infectious agents in the aetiology of childhood leukaemia has come from reports indicating space -time clustering and spatial clustering (reviewed by Alexander, 1993). Infectious agents in general tend to affect individuals that are close in both space and time, if latent periods are relatively short; this can occur even when there is no evidence of spatial clustering which can be created by both infectious agents and fixed environmental sources.…”

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confidence: 99%

Space-time clustering of childhood leukaemia in Greece: evidence supporting a viral aetiology

Petridou

Revinthi²,

Alexander³

et al. 1996

Br J Cancer

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SummaryThe method introduced by Knox for evaluation of space-time clustering has been applied to 872 cases of childhood (0-14 year old) leukaemia diagnosed in Greece over the 10 year period 1980-89. Greek towns are characterised by substantial population mixing due to internal migration, whereas there is relative isolation in mountainous rural areas. Predetermined space (5 km) and time (1 year) limits were used on the basis of previous reports in order to define the clustering cell. There is highly significant evidence for clustering of childhood leukaemia in Greece as a whole, the observed number of pairs that are close in both space and time exceeding the expected number by 5.2% (P= 0.004). The excess is particularly evident for leukaemia cases in 0 to 4-year-old children, among whom the observed number of pairs that are close in both space and time exceeded the expected number by 9.4% (P= 0.004). There is no evidence of space-time clustering for leukaemia cases older than 5 years. The overall pattern is descriptively similar in urban and semiurban areas and is especially marked for acute lymphoblastic leukaemia at the childhood peak ages (2-4 years) with an excess of 19% (P=0.0006). In the rural population there is evidence for clustering of cases belonging to older and broader age groups, a phenomenon compatible with a delay in the development of herd immunity against putative infectious aetiological agents. The findings of the present study provide support for the hypothesis that a substantial proportion of cases of childhood leukaemia may arise as a rare sequel to exposure to an agent or agents, most probably viral in nature.

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Investigation of leukemia cells from children with common acute lymphoblastic leukemia for genomic sequences of the primate polyomaviruses JC virus, BK virus, and Simian virus 40

Smith

Strickler

Granovsky

et al. 1999

Med. Pediatr. Oncol.

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Background An infectious etiology for childhood acute lymphoblastic leukemia (ALL) has long been suspected, although the characteristics of the putative childhood ALL‐inducing agent(s) remain a mystery. We describe the testing of ALL leukemia cells for the presence of DNA sequences of the polyomavirus family: JC virus, BK virus, and simian virus 40 (SV40). Procedure Cryopreserved leukemia cells from 25 children between 2 and 5 years of age at the time of diagnosis and classified as having “common” ALL (B‐precursor ALL expressing the CD19 and CD10 surface antigens) were tested for the presence of polyomavirus sequences using standard PCR methods. Results Human β‐globin gene sequences were detected in 22 of 25 leukemia specimens. However, polyomavirus sequences were not detected in any of the 22 specimens with amplifiable DNA. Conclusions The inability to detect JC virus, BK virus, and SV40 virus DNA sequences in any of the 22 specimens with amplifiable DNA suggests that that these members of the polyomavirus family are unlikely to be causally associated with most childhood ALL. Med. Pediatr. Oncol. 33:441–443, 1999. Published 1999 Wiley‐Liss, Inc.

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Viruses, clusters and clustering of childhood leukaemia: a new perspective?

Cited by 64 publications

References 137 publications

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

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

Space-time clustering of childhood leukaemia in Greece: evidence supporting a viral aetiology

Investigation of leukemia cells from children with common acute lymphoblastic leukemia for genomic sequences of the primate polyomaviruses JC virus, BK virus, and Simian virus 40

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