Epidemiology of Hodgkin's disease: a review.

The descriptive and aetiological epidemiology of Hodgkin's Disease (HD) are reviewed. Key issues which are highlighted include the evidence suggesting that HD is a complex of related conditions that are part mediated by infectious diseases, immune deficits and genetic susceptibilities. There is little convincing evidence to suggest any other environmental factors are involved in the aetiology. The apparent changing pattern of disease by time and from country to country, needs careful future study.

Bladder cancer in patients with spinal cord injuries.

OBJECTIVE: To evaluate the age-standardized incidence rate of bladder cancer in patients with spinal cord injury (SCI) and the overall risk for this population. PATIENTS AND METHODS: We reviewed 1334 patients with SCI whose dates of SCI, or first attendance at our centre, were between 1940 and 1998. The length of follow-up was calculated for each patient and age-specific incidence rates of bladder cancer calculated using 5-year age bands. This was used to calculate the overall incidence rate, using direct standardization with the European standard population. The cancers were analysed histochemically to characterize the phenotype. RESULTS: The 1324 patients contributed a total of 12 444 person-years of follow-up. There were four cases of bladder cancer, giving an age-standardized incidence rate of 30.7 per 100 000 person-years. Histochemistry showed areas were positive for cytokeratin 14, which was also positive in the undifferentiated areas. Immunohistochemical staining was positive for cytokeratin 14 and consistently negative for cytokeratin 20, suggesting a pure squamous phenotype. CONCLUSIONS: The age-standardized incidence of invasive bladder cancer in patients in our SCI unit is not statistically different from that of the general population. However, the incidence of invasive bladder cancer in the present study appears to be lower than that reported in other series. Histochemical analysis confirmed a squamous cell phenotype in these tumours.

Occupational exposure to electromagnetic fields and acute leukaemia: analysis of a case-control study.

AIMS: To investigate whether the risk of acute leukaemia among adults is associated with occupational exposure to electromagnetic fields. METHODS: Probable occupational exposure to electromagnetic fields at higher than typical residential levels was investigated among 764 patients diagnosed with acute leukaemia during 1991-96 and 1510 sex and age matched controls. A job exposure matrix was applied to the self reported employment histories to determine whether or not a subject was exposed to electromagnetic fields. Risks were assessed using conditional logistic regression for a matched analysis. RESULTS: Study subjects considered probably ever exposed to electromagnetic fields at work were not at increased risk of acute leukaemia compared to those considered never exposed. Generally, no associations were observed on stratification by sex, leukaemia subtype, number of years since exposure stopped, or occupation; there was no evidence of a dose-response effect using increasing number of years exposed. However, relative to women considered never exposed, a significant excess of acute lymphoblastic leukaemia was observed among women probably exposed to electromagnetic fields at work that remained increased irrespective of time prior to diagnosis or job ever held. CONCLUSION: This large population based case-control study found little evidence to support an association between occupational exposure to electromagnetic fields and acute leukaemia. While an excess of acute lymphoblastic leukaemia among women was observed, it is unlikely that occupational exposure to electromagnetic fields was responsible, given that increased risks remained during periods when exposure above background levels was improbable.

Age-specific incidence rates for cytogenetically-defined subtypes of acute myeloid leukaemia.

It is generally considered that most cancers arise following the accumulation of several genetic events and that as a consequence its incidence increases with age. We report a cytogenetic subgroup of acute myeloid leukaemia whose incidence is independent of age. This observation indicates that acute myeloid leukaemia can develop via multiple pathways, and underlines the importance of cytogenetics in understanding this disease.

Smoking and the risk of acute myeloid leukaemia in cytogenetic subgroups.

Cytogenetically-defined subgroups of acute myeloid leukaemia have distinct biologies, clinical features and outcomes. Evidence from therapy-related leukaemia suggests that chromosomal abnormalities are also markers of exposure. Our results suggest that the smoking-associated risk for acute myeloid leukaemia is restricted to the t(8;21)(q22;q22) subgroup. This supports the hypothesis that distinct cytogenetic subgroups of acute myeloid leukaemia have separate aetiologies.

Leukaemia incidence near coastal features.

BACKGROUND: The aim of the study was to independently test the hypothesis that leukaemia incidence is higher in proximity to estuaries. METHODS: Electoral wards were classified as to whether they included estuarine, coastal or only inland features. Rates of different adult and childhood leukaemias were computed for each ward category; that is, acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML) aged 0-79 and for all childhood leukaemias combined (aged 0-14). RESULTS: Poisson regression analysis controlling for the effects of sex, age, and socioeconomic and urban-rural status, showed no statistically significant differences in incidence between wards with different levels of estuarine classification. CONCLUSION: The hypothesis created from an earlier dataset that a link exists between leukaemia and residence near estuaries is not upheld.

Polymorphism in glutathione S-transferase P1 is associated with susceptibility to chemotherapy-induced leukemia.

Glutathione S-transferases (GSTs) detoxify potentially mutagenic and toxic DNA-reactive electrophiles, including metabolites of several chemotherapeutic agents, some of which are suspected human carcinogens. Functional polymorphisms exist in at least three genes that encode GSTs, including GSTM1, GSTT1, and GSTP1. We hypothesize, therefore, that polymorphisms in genes that encode GSTs alter susceptibility to chemotherapy-induced carcinogenesis, specifically to therapy-related acute myeloid leukemia (t-AML), a devastating complication of long-term cancer survival. Elucidation of genetic determinants may help to identify individuals at increased risk of developing t-AML. To this end, we have examined 89 cases of t-AML, 420 cases of de novo AML, and 1,022 controls for polymorphisms in GSTM1, GSTT1, and GSTP1. Gene deletion of GSTM1 or GSTT1 was not specifically associated with susceptibility to t-AML. Individuals with at least one GSTP1 codon 105 Val allele were significantly over-represented in t-AML cases compared with de novo AML cases [odds ratio (OR), 1.81; 95% confidence interval (CI), 1.11-2.94]. Moreover, relative to de novo AML, the GSTP1 codon 105 Val allele occurred more often among t-AML patients with prior exposure to chemotherapy (OR, 2.66; 95% CI, 1.39-5.09), particularly among those with prior exposure to known GSTP1 substrates (OR, 4.34; 95% CI, 1.43-13.20), and not among those t-AML patients with prior exposure to radiotherapy alone (OR,1.01; 95% CI, 0.50-2.07). These data suggest that inheritance of at least one Val allele at GSTP1 codon 105 confers a significantly increased risk of developing t-AML after cytotoxic chemotherapy, but not after radiotherapy.

Epstein-Barr Virus and HLA-DPB1-*0301 in young adult Hodgkin's disease: evidence for inherited susceptibility to Epstein-Barr Virus in cases that are EBV(+ve).

Cases of Hodgkin's disease (HD) may be distinguished by whether they do [EBV-positive ((+ve)) cases] or do not [EBV-negative ((-ve)) cases] have evidence of EBV DNA in the Reed-Sternberg cells. Only one study has attempted to distinguish epidemiological risk factors for EBV(+ve) and EBV(-ve) HD, and none have compared inherited susceptibility. The present study involves a population-based case series of HD, diagnosed in patients between 16-24 years of age in the United Kingdom (n = 118), of whom 87% were classified by EBV status (EBV(+ve), 19, EBV(-ve), 84). History of infectious illness, EBV antibody titers, and HLA-DPB1 type have been compared in EBV(+ve) and EBV(-ve) cases. Reported infectious mononucleosis was more frequent in EBV(+ve) cases (odds ratio (OR), 5.10; 95% confidence interval (CI), 1.12-24.4). EBV antibody titers to viral capsid antigen were significantly higher in EBV(+ve) cases (P for trend = 0.02). Higher proportions of EBV(+ve) (43%) than EBV(-ve) (31%) cases typed positive for HLA-DPB1*0301, but this was not statistically significant; the association of infectious mononucleosis with EBV(+ve) cases was stronger in this HLA subgroup (OR, 17.1; 95%CI, 1.06-1177) than in other cases (OR, 1.24; 95% CI, 0.02-15.4). Although these results are based on small numbers of HD cases, they provide suggestive evidence that the etiology of EBV(+ve) HD may involve inherited susceptibility to EBV.

Karyotype and age in acute myeloid leukemia. Are they linked?

A novel hierarchical cytogenetic classification for acute myeloid leukemia (AML) has been developed. Patients with successful cytogenetics and a diagnosis of AML were categorized into four mutually exclusive karyotype groups: normal, translocation, deletion and trisomy. Patients with more than one chromosomal abnormality were classified using the hierarchy: established translocation>established deletion>established trisomy>non-established translocation>non-established deletion>non-established trisomy. A total of 593 AML patients from a large population-based case-control study of acute leukemia were classified according to their diagnostic karyotype. The four karyotype groups showed different age distributions. Overall the frequency of patients increased with age as did the frequency of patients with a deletion, trisomy or normal karyotype. Although the increase of patients with age was much sharper for patients with a deletion. In contrast, the distribution of patients with a translocation was roughly constant with age. We concluded that there was a link between karyotype and the age of the patient at diagnosis. Furthermore, two karyotype groups, translocations and deletions, may define disease entities with different etiologies. This novel cytogenetic classification will allow other studies to examine whether AML cases with very different types of chromosomal abnormality have the same etiology.

Childhood cancer and parental use of tobacco: findings from the inter-regional epidemiological study of childhood cancer (IRESCC).

Parental smoking data have been re-abstracted from the interview records of the Inter-Regional Epidemiological Study of Childhood Cancer (IRESCC) to test further the hypothesis that paternal cigarette smoking is a risk factor for the generality of childhood cancer. Reported cigarette smoking habits for the parents of 555 children diagnosed with cancer in the period 1980-1983 were compared, in two separate matched pairs analyses, with similar information for the parents of 555 children selected from GP lists (GP controls) and for the parents of 555 hospitalized children (hospital controls). When cases were compared with GP controls there was a statistically significant positive trend (P = 0.02) between the risk of childhood cancer and paternal daily consumption of cigarettes before the pregnancy; there was no significant trend for maternal smoking habit. When cases were compared with hospital controls there was a statistically significant negative trend (P< 0.001) between the risk of childhood cancer and maternal daily consumption of cigarettes before the pregnancy; there was no significant trend for paternal smoking habit. Neither of the significant trends could be explained by adjustment for socioeconomic grouping, ethnic origin or parental age at the birth of the child, or by simultaneous analysis of parental smoking habits. Relations between maternal consumption of cigarettes and birth weights suggested that (maternal) smoking data were equally reliable for case and control subjects, although comparisons with national data suggested that the hospital control parents were unusually heavy smokers. These findings give some support for the hypothesis that paternal cigarette smoking is a potential risk factor for the generality of childhood cancers.

The onset of the excess of childhood cancer in Seascale, Cumbria.

BACKGROUND: The objective of this study was to formally investigate the onset of the Seascale cluster of childhood and young person's cancer. This has not previously been attempted. METHODS: A mortality study within the Whitehaven registration district was set up and death records were abstracted for 1906-1970. They were categorized as death from leukaemias, lymphomas, other cancers and all other causes in persons aged 0-14, 0-24 and 25-84. The number of deaths, death rates and standardized mortality ratios were calculated. RESULTS: The mortality of persons aged 25-84 in Seascale civil parish, Gosforth civil parish and the rest of the Whitehaven district was unremarkable compared with national data 1906-1970. There were no cancer deaths aged 0-24 in Gosforth civil parish during 1906-1970. In Seascale civil parish a hitherto unrecorded childhood cancer case was revealed, dying in 1954. No cancer deaths aged 0-24 were found before that date. In the period 1946-1955 three cancer deaths gave a statistically significant excess owing to non-leukaemia cases, whereas in the period 1956-1965 a statistical excess of all types of leukaemia occurred as a result of two deaths. There was no case excess (based on one leukaemia death) in the period 1966-1970. CONCLUSION: We found no clear temporal associations of the case excesses either with the periods of significant nuclear activity on the Sellafield site or with the main periods of population growth in the area.

Risk factors for Hodgkin's disease by Epstein-Barr virus (EBV) status: prior infection by EBV and other agents.

A UK population-based case-control study of Hodgkin's disease (HD) in young adults (16-24 years) included 118 cases and 237 controls matched on year of birth, gender and county of residence. The majority (103) of the cases were classified by Epstein-Barr virus (EBV) status (EBV present in Reed-Stenberg cells), with 19 being EBV-positive. Analyses using conditional logistic regression are presented of subject reports of prior infectious disease (infectious mononucleosis (IM), chicken pox, measles, mumps, pertussis and rubella). In these analyses HD cases are compared with matched controls, EBV-positive cases and EBV-negative cases are compared separately with their controls and formal tests of differences of association by EBV status are applied. A prior history of IM was positively associated with HD (odds ratio (OR) = 2.43, 95% confidence interval (CI) = 1.10-5.33) and with EBV-positive HD (OR = 9.16, 95% CI = 1.07-78.31) and the difference between EBV-positive and EBV-negative HD was statistically significant (P = 0.013). The remaining infectious illnesses (combined) were negatively associated with HD, EBV-positive HD and EBV-negative HD (in the total series, for > or =2 episodes compared with < or =1, OR = 0.45, 95% CI = 0.25-0.83). These results support previous evidence that early exposure to infection protects against HD and that IM increases subsequent risk; the comparisons of EBV-positive and EBV-negative HD are new and generate hypotheses for further study.

Haematologists' approaches to the management of adolescents and young adults with acute leukaemia.

Approaches to the management of adolescents and young adults with acute leukaemia were investigated by sending a questionnaire to hospitals identified as having diagnosed or treated patients aged 15-29 years. The responses demonstrated the types of hospital treating these patients, the haematologists' perceived practice for entry of patients to Medical Research Council (MRC) leukaemia trials and reasons for non-entry. Data were linked to MRC trials data to determine the proportion of patients aged 15-29 years at diagnosis in responding hospitals actually treated in MRC leukaemia trials in the 5 years preceding the questionnaire. Eighty-two per cent of haematologists stated that they entered patients 'always' or 'whenever possible' for acute myeloid leukaemia (AML) and 76% for acute lymphoblastic leukaemia (ALL), but actual entry rates from the study hospitals were 46% of 239 AML patients and 36% of 182 ALL patients. The reasons most commonly reported for not entering eligible patients to national leukaemia trials were clinician preference for one arm of an MRC trial, a regional study or non-trial protocol, and concern about workload and ethical approval.

Topical chloramphenicol and the risk of acute leukaemia in adults.

PURPOSE: To investigate the possible role of topical chloramphenicol in the development of adult acute leukaemia. METHODS: The design of the study was a population-based age- and sex-matched case-control study, which collected cases of adult acute leukaemia between 1991 and 1996. Caucasian cases (807) and 1593 Caucasian controls were interviewed in person using a highly structured questionnaire. General practitioner medical records were abstracted for previous topical chloramphenicol use. RESULTS: 797 cases and 1570 controls were included in the analysis. No association was observed for topical chloramphenicol use and acute leukaemia (adjusted odds ratio, 1-year lag period (OR) 0.91 95% confidence interval (CI) 0.70-1.17). Similar results were observed when the analysis was repeated by diagnostic subgroup and sex. For all the data, a small, non-significant increased risk was observed (OR=1.21, 95% CI 0.65-2.25) if chloramphenicol had been prescribed three, or more times, but there was no statistically significant dose-response relationship (chi(2)=1.40, two-sided p=0.24). CONCLUSIONS: The results, based on a robust study design, show no evidence of an increased risk of developing adult acute leukaemia after topical chloramphenicol use. Copyright (c) 2000 John Wiley & Sons, Ltd.

Space-time clustering of Hodgkin's Disease in parts of the UK, 1984-1993.

The object of this study was to examine cases of Hodgkin's Disease (HD) for evidence of space-time clustering of onsets by age group, sex and disease subtype. Data comprised 2024 cases of HD aged 0-79 years arising throughout the period 1984 to 1993 in the areas covered by a specialist population based register of leukaemias and lymphomas. Knox space-time analysis was used separately for 3 different age groups: childhood (0-14 years), young adult (15-34 years) and older adults (35-79 years); for adult cases separate analysis was carried out by sex and for the nodular and non-nodular sclerosing subtypes. Results showed that space-time clustering of onsets was limited to the nodular sclerosing cases. It was more prominent in young adult nodular sclerosing cases aged 15-34 years (particularly females) diagnosed in the period 1984-88, than in those diagnosed in 1989-93. We conclude that clustering may provide further evidence that an infectious process is involved in the aetiology of young adult nodular sclerosing cases of HD.

Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults.

Reduction of 5,10-methylenetetrahydrofolate (methyleneTHF), a donor for methylating dUMP to dTMP in DNA synthesis, to 5-methyltetrahydrofolate (methylTHF), the primary methyl donor for methionine synthesis, is catalyzed by 5,10-methylenetetrahydrofolate reductase (MTHFR). A common 677 C --> T polymorphism in the MTHFR gene results in thermolability and reduced MTHFR activity that decreases the pool of methylTHF and increases the pool of methyleneTHF. Recently, another polymorphism in MTHFR (1298 A --> C) has been identified that also results in diminished enzyme activity. We tested whether carriers of these variant alleles are protected from adult acute leukemia. We analyzed DNA from a case-control study in the United Kingdom of 308 adult acute leukemia patients and 491 age- and sex-matched controls. MTHFR variant alleles were determined by a PCR-restriction fragment length polymorphism assay. The MTHFR 677TT genotype was lower among 71 acute lymphocytic leukemia (ALL) cases compared with 114 controls, conferring a 4.3-fold decrease in risk of ALL [odds ratio (OR = 0.23; 95% CI = 0.06-0.81]. We observed a 3-fold reduction in risk of ALL in individuals with the MTHFR 1298AC polymorphism (OR = 0.33; 95% CI = 0.15-0.73) and a 14-fold decreased risk of ALL in those with the MTHFR 1298CC variant allele (OR = 0.07; 95% CI = 0.00-1.77). In acute myeloid leukemia, no significant difference in MTHFR 677 and 1298 genotype frequencies was observed between 237 cases and 377 controls. Individuals with the MTHFR 677TT, 1298AC, and 1298CC genotypes have a decreased risk of adult ALL, but not acute myeloid leukemia, which suggests that folate inadequacy may play a key role in the development of ALL.

Epidemiology of multiple myeloma in parts of England, 1984-1993.

This paper presents a new analysis of aspects of the descriptive epidemiology of multiple myeloma (MM) for parts of the U.K., 1984-1993. It provides no indication for geographical heterogeneity, nor is there evidence of a decline in rates over the decade. There is, however, evidence that cancer registration inflates MM rates in the elderly.