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Background Melanoma is a significant health problem in Caucasian populations. The most recently available data from cancer registries often have a delay of several months up to a few years and they are generally not easily accessible. Objectives To assess recent age- and sex-specific trends in melanoma incidence and make predictions for 2010 and 2015. Methods A retrospective registry-based analysis was performed with data from 29 European cancer registries. Most of them had data available from 1990 up to 2006/7. World-standardized incidence rates ( WSR) and the estimated annual percentage change ( EAPC) were computed. Predictions were based on linear projection models. Results Overall the incidence of melanoma is rapidly rising and will continue to do so. The incidence among women in Europe was generally higher than in men. The highest incidence rates were seen for Northern and north-western countries like the UK, Ireland and the Netherlands. The lowest incidence rates were observed in Portugal and Spain. The incidence overall remained stable in Norway, where, amongst young (25-49 years) Norwegian males rates significantly decreased ( EAPC −2.8, 95% CI −3.6; −2.0). Despite a low melanoma incidence among persons above the age of 70, this age group experienced the greatest increase in risk during the study period. Conclusions Incidence rates of melanoma are expected to continue rising. These trends are worrying in terms of disease burden, particularly in eastern European countries. [ABSTRACT FROM AUTHOR]

Objectives: Trichloroethylene (TCE) and Perchloroethylene (PER) are two chlorinated solvents that are applied widely as degreasers of metal parts, and in dry cleaning and other applications. In 2012, the International Agency for Research on Cancer classified TCE as carcinogenic to humans and PER as probably carcinogenic to humans. We explored exposure-response relations for TCE and PER and non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), and cancers of the kidney and liver in the Nordic Occupational Cancer cohort., Methods: The cohort was set up by linking occupational information from censuses to national cancer registry data using personal identity codes in use in all Nordic countries. Country, time period, and job-specific exposure estimates were generated for TCE, PER and potentially confounding occupational exposures with a job-exposure matrix. A conditional logistic regression was conducted for exposure groups as well as for continuous cumulative exposure., Results: HRs for liver cancer, NHL and MM but not kidney cancer were slightly elevated in groups with high exposure to PER (compared to occupationally unexposed subjects). HRs for liver cancer and NHL also increased with increasing continuous exposure to PER. We did not observe evidence for an association between exposure to TCE and NHL, MM or liver and kidney cancer., Conclusions: Although this study was subject to limitations related to the low prevalence of exposure to PER and TCE in the Nordic population and a limited exposure assessment strategy, we observed some evidence indicative of an excess risk of cancer of the liver and NHL in subjects exposed to PER.

Some large ecological studies have noted a significant association of testicular cancer (TC) with maternal smoking during pregnancy, while several more controlled studies have been negative. It has been difficult to obtain reliable data on exposure because of the long lag time to cancer diagnosis. We performed a case-control study nested within Finnish, Swedish and Icelandic maternity cohorts exploiting early pregnancy serum samples to evaluate the role of maternal smoking in the risk of TC in the offspring. After reviewing the literature, we also performed a meta-analysis of published studies. For each index mother of the TC patient, three to nine matched control mothers with a cancer-free son born at the same time as the TC case were identified within each cohort. First trimester sera were retrieved from the 70 index mothers and 519 control mothers and were tested for cotinine level by a novel HPLC-MS-MS method developed. No statistically significant association between maternal cotinine level and risk of TC in the offspring was found (OR 0.68; 95% CI 0.35, 1.34). This is the first study based on individual exposure measurements. Its results agree with our meta-analysis of seven previous epidemiological studies (total number of 2149 cases, 2762 controls) using indirect exposure assessment (OR 1.0; 95% CI 0.88, 1.12).

During recent decades the incidence of testicular cancer (TC) has increased rapidly around the world. Associated exogenous etiological factors might therefore be identifiable. We performed a case-control study nested within Finnish, Swedish and Icelandic maternity cohorts exploiting early pregnancy serum samples to evaluate the role of congenital or neonatal infections with Epstein-Barr virus (EBV) and cytomegalovirus (CMV) as risk factors of TC in the offspring. For each case-index mother pair, three or four matched control-control mother pairs were identified using national population registries. First trimester sera were retrieved from the index mothers of 66 TC cases and 258 matched control mothers, and were tested for antibodies to EBV and CMV. High level of maternal EBV IgG antibodies was associated with significantly increased risk of TC in the offspring (odds ratio (OR), 2.50; 95% confidence interval (CI), 1.15, 5.40), especially with risk of non-seminoma TC (OR, 2.73; 950% CI, 1.25, 5.99) and non-seminoma TC diagnosed under 8 years of age (OR, 2.72; 95% CI, 1.05, 7.04). In contrast, offspring of CMV IgG-seropositive mothers had a decreased risk of TC diagnosed under 8 years of age (OR, 0.35; 95% CI, 0.14, 0.89). Our results suggest that EBV and CMV infections may be associated with TC.

Purpose: The aim of this study is to quantify excess absolute risk (EAR) and excess relative risk (ERR) of secondary leukemia among a large population-based group of testicular cancer survivors., Methods: We identified 42,722 1-year survivors of testicular cancer within 14 population-based cancer registries in Europe and North America (1943-2002). Poisson regression analysis was used to model EAR (per 100,000 person-years [PY]) and ERR of secondary leukemia. Cumulative risks were calculated using a competing risk model., Results: Secondary leukemia developed in 89 patients (EAR = 10.8 per 100,000 PY, 95% confidence interval [CI] = 7.6-14.6; ERR = 1.6, 95%CI = 1.0-2.2). Statistically significantly elevated risks were observed for acute myeloid leukemia (AML) (EAR = 7.2, 95%CI = 4.7-10.2) and acute lymphoblastic leukemia (EAR = 1.3, 95%CI = 0.4-2.8). In multivariate analyses, AML risk was higher among patients whose initial management included chemotherapy compared to those receiving radiotherapy alone (p = 0.1). Excess cumulative leukemia risk was approximately 0.23% by 30 years after testicular cancer diagnosis., Conclusions: Although ERR of leukemia following testicular cancer is large, EAR and cumulative risk, which are better gauges of the population burden, are small.

Objective: To study the risk of second primary cancers in nasopharyngeal carcinoma (NPC) patients and the risk of NPC as second primary cancer., Methods: We used data from the cancer registries from Singapore and from 12 low-incidence areas, including a total of 8,947 first occurring NPC cases, and 167 second occurring cases. We calculated standardized incidence ratios (SIRs) by comparing the second cancer incidence in NPC patients to the first primary cancer incidence in non-cancer population. We also calculated SIRs of second NPC after other primaries., Results: In Singapore, the risk of cancers of the lung (SIR=0.42), stomach (SIR=0.41), and colon (SIR=0.23) was significantly decreased after NPC, whereas that of cancer of the tongue (SIR=11.1) was significantly increased. In Australia, Canada, and Europe, the risk of non-Hodgkin's lymphoma (NHL) (SIR=3.06), tongue cancer (SIR=5.29), brain cancer (SIR=3.89), myeloid leukemia (SIR=3.85), and non-melanoma skin cancer (NMSC) (SIR=3.47) was significantly increased after NPC. Incidences of second occurring NPCs following various primary cancers were not significantly altered compared to the incidence of first occurring NPCs., Conclusions: Immune suppression (NHL, NMSC), shared genetic factors (lung cancer, NHL, myeloid leukemia), and shared environmental risk factors (tongue and brain cancers) might explain the associations. Except for NHL, there was no evidence of association with other Epstein-Barr virus-related cancers.

Worldwide an estimated 11 million cancer cases were diagnosed in 2002, one quarter being in Europe. We estimated the potential in avoidable numbers and proportions of 11 cancers amenable to prevention (cancers of the oral cavity, oesophagus, stomach, colorectal, pancreas, laryngeal, lung, female breast, endometrium, kidney and bladder) in 28 European countries. We assumed that the aggregated rate of 3 countries with lowest incidence to be attainable throughout Europe. The difference between the age- and gender-specific national cancer incidence rates and the lowest rate observed in 2002 was determined and defined as "avoidable." Of the 1.4 million adult cases of selected cancers and countries within our study, 363,000 (59%) cancers in males and 326,000 (45%) cancers in females were hypothetically avoidable. Among men, the proportion was largest in Hungary (77%) and among women, in Belgium (54%). Assuming that differences in cancer incidence are not attributable to genetic susceptibility or diagnostic activity, about 50% of all cases of these 11 cancers could be potentially avoided, especially by decreased smoking among men. Interventions directed at reducing smoking, obesity and alcohol use as well as increasing physical activity and fruit and vegetable intake are necessary to attain lower incidence rates. It is important to recognize that the actual preventable cancer by eliminating currently known risk factors is somewhat less than we have estimated., ((c) 2006 Wiley-Liss, Inc.)

We investigated the risk of second malignancies among 29,511 survivors of germ-cell testicular cancer recorded in 13 cancer registries. Standardized incidence ratios (SIRs) were estimated comparing the observed numbers of second malignancies with the expected numbers obtained from sex-, age-, period- and population-specific incidence rates. Seminomas and nonseminomas, the 2 main histological groups of testicular cancer, were analyzed separately. During a median follow-up period of 8.3 years (0-35 years), we observed 1,811 second tumors, with a corresponding SIR of 1.65 (95% confidence interval (CI): 1.57-1.73). Statistically significant increased risks were found for fifteen cancer types, including SIRs of 2.0 or higher for cancers of the stomach, gallbladder and bile ducts, pancreas, bladder, kidney, thyroid, and for soft-tissue sarcoma, nonmelanoma skin cancer and myeloid leukemia. The SIR for myeloid leukemia was 2.39 (95% CI: 1.41-3.77) after seminomas, and 6.77 (95% CI: 4.14-10.5) after nonseminomas. It increased to 37.9 (95% CI: 18.9-67.8; based on 11 observed cases of leukemia) among nonseminoma patients diagnosed since 1990. SIRs for most solid cancers increased with follow-up duration, whereas they did not change with year of testicular cancer diagnosis. Among subjects diagnosed before 1980, 20 year survivors of seminoma had a cumulative risk of solid cancer of 9.6% (95% CI: 8.7-10.5%) vs. 6.5% expected, whereas 20 years survivors of nonseminoma had a risk of 5.0% (95% CI: 4.2-6.0%) vs. 3.1% expected. In conclusion, survivors of testicular cancers have an increased risk of several second primaries, where the effect of the treatment seems to play a major role.

Data on 1690 childhood and adolescent cases of thyroid cancer registered in 61 European cancer registries were extracted from the database of the Automated Childhood Cancer Information System (ACCIS) and included in analyses of incidence and survival. In 1988-1997, the age-standardised incidence rates (ASR) for children aged 0-14 years varied in European regions from 0.5 to 1.2 per million and the age-specific incidence in adolescents aged 15-19 years ranged from 4.4 to 11.0 per million. Over the age-span 0-19 years, the female to male ratio increased from 1 to around 3. Papillary thyroid cancer accounted for almost 65% of cases in children and 77% in adolescents. In the childhood population of Belarus, the ASR for 1989-1997 was 23.6 per million and the proportion of papillary tumours was 87%. No association was found between thyroid cancer risk and national dietary iodine status across 16 countries. Incidence of thyroid carcinoma among children and adolescents in Europe (excluding Belarus) increased during 1978-1997 by 3% per year, largely due to papillary carcinoma. Survival of children and adolescents was high over the entire study period and in all regions of Europe. Children with medullary carcinoma had slightly lower 5-year survival (95%, 95% CI 81-99), than those with papillary carcinoma (99%, 95% CI 95-100). More than 90% of patients survived 20 years after diagnosis. Further standardisation of diagnostic, classification and registration criteria will be fundamental for future studies of thyroid carcinomas in young people.

This study profiles testicular cancer incidence and mortality across Europe, and the effects of age, period and generational influences, using age-period-cohort modeling. Despite a 5-fold variation in incidence rates, there were consistent mean increases in incidence in each of the 12 European countries studied, ranging from around 6% per annum (Spain and Slovenia) to 1-2% (Norway). In contrast, declines in testicular cancer mortality of 3-6% per annum were observed in the 1980s and 1990s for the majority of the 22 countries studied, particularly in Northern and Western Europe. The mortality trends in several European countries were rather stable (Romania and Bulgaria) or increasing (Portugal and Croatia). Short-term attenuations in increasing cohort-specific risk of incidence were indicated among men born between 1940 and 1945 in 7 European countries. In Switzerland, successive generations born from the mid 1960s may have experienced a steadily declining risk of disease occurrence. While the underlying risk factors responsible remain elusive, the temporal and geographical variability in incidence may point to an epidemic in different phases in different countries-the result of country-specific differences in the prevalence of one or several ubiquitous and highly prevalent environmental determinants of the disease. Advances in treatment have led to major declines in mortality in many European countries from the mid 1970s, which has translated to cohorts of men at successively lower risk of death from the disease. Slower progress in the delivery of optimal care is however evident from the mortality trends in several lower-resource countries in Southern and Eastern Europe. The first beneficiaries of therapy in these populations may be those men born--rather than diagnosed--in the era of major breakthrough in testicular cancer care., (Copyright 2006 Wiley-Liss, Inc.)

The incidence of the two main clinical subentities of testicular germ cell cancer (seminoma and nonseminoma) is increasing throughout Europe. Most studies have revealed little variation in risk factors between the two subtypes. This study compared generation-specific trends in eight European countries, hypothesizing that similar temporal pattern by birth cohort implied that seminoma and nonseminoma had a largely comparable etiology. The results are presented using the age-period-cohort model and the nonidentifiability problem highlighted by partitioning the age, period, and cohort effects in terms of their linear and curvature component parts, assuming a priori that cohort effects predominated. Despite uniform overall increases by calendar period, declining rates of nonseminoma but not pure seminoma were observed in the majority of countries during the 1990s. The subtype trends were, however, largely analogous on a birth cohort scale. Notable observations were a decline in rates of both subtypes among recent birth cohorts in Switzerland and a short-term wartime effect in several countries, involving an attenuation of increasing risk of both subtypes in men born in 1940 to 1945. Departures from the steady increases in testicular cancer over time were likely to occur for nonseminomas some years ahead of seminoma on a period scale. The importance of birth cohort coincided with the view that given a short time interval of susceptibility to exposures earlier in life and a biologically constant time to diagnosis, all temporal changes in rate-limiting exposures should appear as generational effects. Trends in seminoma and nonseminoma conform to largely the same temporal patterns on this scale, implying that they share important etiologic factors.

Background: Although second primary cancers are a leading cause of death among men with testicular cancer, few studies have quantified risks among long-term survivors., Methods: Within 14 population-based tumor registries in Europe and North America (1943-2001), we identified 40,576 1-year survivors of testicular cancer and ascertained data on any new incident solid tumors among these patients. We used Poisson regression analysis to model relative risks (RRs) and excess absolute risks (EARs) of second solid cancers. All statistical tests were two-sided., Results: A total of 2,285 second solid cancers were reported in the cohort. The relative risk and EAR decreased with increasing age at testicular cancer diagnosis (P < .001); the EAR increased with attained age (P < .001) but the excess RR decreased. Among 10-year survivors diagnosed with testicular cancer at age 35 years, the risk of developing a second solid tumor was increased (RR = 1.9, 95% confidence interval [CI] = 1.8 to 2.1). Risk remained statistically significantly elevated for 35 years (RR = 1.7, 95% CI = 1.5 to 2.0; P < .001). We observed statistically significantly elevated risks, for the first time, for cancers of the pleura (malignant mesothelioma; RR = 3.4, 95% CI = 1.7 to 5.9) and esophagus (RR = 1.7, 95% CI = 1.0 to 2.6). Cancers of the lung (RR = 1.5, 95% CI = 1.2 to 1.7), colon (RR = 2.0, 95% CI = 1.7 to 2.5), bladder (RR = 2.7, 95% CI = 2.2 to 3.1), pancreas (RR = 3.6, 95% CI = 2.8 to 4.6), and stomach (RR = 4.0, 95% CI = 3.2 to 4.8) accounted for almost 60% of the total excess. Overall patterns were similar for seminoma and nonseminoma patients, with lower risks observed for nonseminoma patients treated after 1975. Statistically significantly increased risks of solid cancers were observed among patients treated with radiotherapy alone (RR = 2.0, 95% CI = 1.9 to 2.2), chemotherapy alone (RR = 1.8, 95% CI = 1.3 to 2.5), and both (RR = 2.9, 95% CI = 1.9 to 4.2). For patients diagnosed with seminomas or nonseminomatous tumors at age 35 years, cumulative risks of solid cancer 40 years later (i.e., to age 75 years) were 36% and 31%, respectively, compared with 23% for the general population., Conclusions: Testicular cancer survivors are at statistically significantly increased risk of solid tumors for at least 35 years after treatment. Young patients may experience high levels of risk as they reach older ages. The statistically significantly increased risk of malignant mesothelioma in testicular cancer survivors has, to our knowledge, not been observed previously in a cohort of patients treated with radiotherapy.

Objectives: To assess the risk of lung cancer mortality related to occupational exposure to titanium dioxide (TiO2)., Methods: A mortality follow-up study of 15,017 workers (14,331 men) employed in 11 factories producing TiO2 in Europe. Exposure to TiO2 dust was reconstructed for each occupational title; exposure estimates were linked with the occupational history. Observed mortality was compared with national rates, and internal comparisons were based on multivariate Cox regression analysis., Results: The cohort contributed 371,067 person-years of observation (3.3% were lost to follow-up and 0.7% emigrated). 2652 cohort members died during the follow-up, yielding standardized mortality ratios (SMRs) of 0.87 (95% confidence interval [CI] 0.83-0.90) among men and 0.58 (95% CI 0.40-0.82) among women. Among men, the SMR of lung cancer was significantly increased (1.23, 95% CI 1.10-1.38); however, mortality from lung cancer did not increase with duration of employment or estimated cumulative exposure to TiO2 dust. Data on smoking were available for over one third of cohort members. In three countries, the prevalence of smokers was higher among cohort members compared to the national populations., Conclusions: The results of the study do not suggest a carcinogenic effect of TiO2 dust on the human lung.

Cosmic radiation is an occupational risk factor for commercial aircrews. In this large European cohort study (ESCAPE) its association with cancer mortality was investigated on the basis of individual effective dose estimates for 19,184 male pilots. Mean annual doses were in the range of 2-5 mSv and cumulative lifetime doses did not exceed 80 mSv. All-cause and all-cancer mortality was low for all exposure categories. A significant negative risk trend for all-cause mortality was seen with increasing dose. Neither external and internal comparisons nor nested case-control analyses showed any substantially increased risks for cancer mortality due to ionizing radiation. However, the number of deaths for specific types of cancer was low and the confidence intervals of the risk estimates were rather wide. Difficulties in interpreting mortality risk estimates for time-dependent exposures are discussed.

Airline pilots and flight engineers are exposed to ionizing radiation of cosmic origin and other occupational and life-style factors that may influence their health status and mortality. In a cohort study in 9 European countries we studied the mortality of this occupational group. Cockpit crew cohorts were identified and followed-up in Denmark, Finland, Germany, Great Britain, Greece, Iceland, Italy, Norway and Sweden, including a total of 28,000 persons. Observed and expected deaths for the period 1960-97 were compared based on national mortality rates. The influence of period and duration of employment was analyzed in stratified and Poisson regression analyses. The study comprised 547,564 person-years at risk, and 2,244 deaths were recorded in male cockpit crew (standardized mortality ratio [SMR] = 0.64, 95% confidence interval [CI] = 0.61-0.67). Overall cancer mortality was decreased (SMR = 0.68; 95% CI = 0.63-0.74). We found an increased mortality from malignant melanoma (SMR = 1.78, 95% CI = 1.15-2.67) and a reduced mortality from lung cancer (SMR = 0.53, 95% CI = 0.44-0.62). No consistent association between employment period or duration and cancer mortality was observed. A low cardiovascular mortality and an increased mortality caused by aviation accidents were noted. Our study shows that cockpit crew have a low overall mortality. The results are consistent with previous reports of an increased risk of malignant melanoma in airline pilots. Occupational risk factors apart from aircraft accidents seem to be of limited influence with regard to the mortality of cockpit crew in Europe., (Copyright 2003 Wiley-Liss, Inc.)

There is concern about the health effects of exposure to cosmic radiation during air travel. To study the potential health effects of this and occupational exposures, the authors investigated mortality patterns among more than 44,000 airline cabin crew members in Europe. A cohort study was performed in eight European countries, yielding approximately 655,000 person-years of follow-up. Observed numbers of deaths were compared with expected numbers based on national mortality rates. Among female cabin crew, overall mortality (standardized mortality ratio (SMR) = 0.80, 95% confidence interval (CI): 0.73, 0.88) and all-cancer mortality (SMR = 0.78, 95% CI: 0.66, 0.95) were slightly reduced, while breast cancer mortality was slightly but nonsignificantly increased (SMR = 1.11, 95% CI: 0.82, 1.48). In contrast, overall mortality (SMR = 1.09, 95% CI: 1.00, 1.18) and mortality from skin cancer (for malignant melanoma, SMR = 1.93, 95% CI: 0.70, 4.44) among male cabin crew were somewhat increased. The authors noted excess mortality from aircraft accidents and from acquired immunodeficiency syndrome in males. Among airline cabin crew in Europe, there was no increase in mortality that could be attributed to cosmic radiation or other occupational exposures to any substantial extent. The risk of skin cancer among male crew members requires further attention.

Purpose: To quantify the relative and absolute excess risks (AER) of site-specific second cancers, in particular solid tumors, among long-term survivors of Hodgkin's disease (HD) and to assess risks according to age at HD diagnosis, attained age, and time since initial treatment., Patients and Methods: Data from 32,591 HD patients (1,111 25-year survivors) reported to 16 population-based cancer registries in North America and Europe (1935 to 1994) were analyzed., Results: Two thousand one hundred fifty-three second cancers (observed-to-expected ratio [O/E] = 2.3; 95% confidence interval [CI] = 2.2 to 2.4), including 1,726 solid tumors (O/E = 2.0; 95% CI, 1.9 to 2.0) were reported. Cancers of the lung (observed [Obs] = 377; O/E = 2.9), digestive tract (Obs = 376; O/E = 1.7), and female breast (Obs = 234; O/E = 2.0) accounted for the largest number of subsequent malignancies. Twenty-five years after HD diagnosis, the actuarial risk of developing a solid tumor was 21.9%. The relative risk of solid neoplasms decreased with increasing age at HD diagnosis, however, patients aged 51 to 60 years at HD diagnosis sustained the highest cancer burden (AER = 79.2/10,000 patients/year). After a progressive rise in relative risk and AER of all solid tumors over time, there was an apparent downturn in risk at 25 years. Temporal trends and treatment group distribution for cancers of the esophagus, stomach, rectum, female breast, bladder, thyroid, and bone/connective tissue were suggestive of a radiogenic effect., Conclusion: Significantly increased risks of second cancers were observed in all HD age groups. Although significantly elevated risks of stomach, female breast, and uterine cervix cancers persisted for 25 years, an apparent decrease in relative risk and AER of solid tumors at other sites is suggested.

Background: Men with testicular cancer are at an increased risk of leukemia, but the relationship to prior treatments is not well characterized. The purpose of our study was to describe the risk of leukemia following radiotherapy and chemotherapy for testicular cancer., Methods: Within a population-based cohort of 18 567 patients diagnosed with testicular cancer (from 1970 through 1993), a case-control study of leukemia was undertaken. Radiation dose to active bone marrow and type and cumulative amount of cytotoxic drugs were compared between 36 men who developed leukemia and 106 matched control patients without leukemia. Conditional logistic regression was used to estimate the relative risk of leukemia associated with specific treatments. All P values are two-sided., Results: Radiotherapy (mean dose to active bone marrow, 12.6 Gy) without chemotherapy was associated with a threefold elevated risk of leukemia. Risk increased with increasing dose of radiation to active bone marrow (P for trend =.02), with patients receiving radiotherapy to the chest as well as to the abdominal/pelvic fields accounting for much of the risk at higher doses. Radiation dose to active bone marrow and the cumulative dose of cisplatin (P for trend =.001) were both predictive of excess leukemia risk in a model adjusted for all treatment variables. The estimated relative risk of leukemia at a cumulative dose of 650 mg cisplatin, which is commonly administered in current testicular cancer treatment regimens, was 3.2 (95% confidence interval = 1.5-8.4); larger doses (1000 mg) were linked with statistically significant sixfold increased risks., Conclusions: Past treatments for testicular cancer are associated with an increased risk of leukemia, with evidence for dose-response relationships for both radiotherapy and cisplatin-based chemotherapy. Statistically nonsignificant excesses are estimated for current radiotherapy regimens limited to the abdomen and pelvis: Among 10 000 patients given a treatment dose of 25 Gy and followed for 15 years, an excess of nine leukemias is predicted; cisplatin-based chemotherapy (dose, 650 mg) might result in 16 cases of leukemia. The survival advantage provided by current radiotherapy and chemotherapy regimens for testicular cancer far exceeds the small absolute risk of leukemia.

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.

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.

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.

The European Childhood Leukaemia - Lymphoma Incidence Study (ECLIS) is designed to address concerns about a possible increase in the risk of cancer in Europe following the nuclear accident in Chernobyle in 1986. This paper reports results of surveillance of childhood leukaemia in cancer registry populations from 1980 up to the end of 1991. There was a slight increase in the incidence of childhood leukaemia in Europe during this period, but the overall geographical pattern of change bears no relation to estimated exposure to radiation resulting from the accident. We conclude that at this stage of follow-up any changes in incidence consequent upon the Chernobyl accident remain undetectable against the usual background rates. Our results are consistent with current estimates of the leukaemogenic risk of radiation exposure, which, outside the immediate vicinity of the accident, was small.

Background: The pattern of second cancers after treatment for cervical cancer provides important information on the risk of radiation-induced malignancies. Large numbers of women survive many years and can be studied for late effects., Methods: Incident second cancers in 86,193 patients with cervical cancer reported to 13 population-based cancer registries in 5 countries were evaluated to estimate the risk of second cancer among very long term survivors., Results: Overall, 7543 second cancers were observed versus 6015 cancers expected based on population rates (observed/expected = 1.2). Lung cancer accounted for nearly half of the excess cancers. Among the 49,828 women treated with radiation, 3750 survived 30 or more years and a two-fold risk of cancers of heavily irradiated organs was seen. Most of the excess cancers were of the rectum, vagina, vulva, ovary, and bladder. Patterns of risk over time since treatment were consistent with a radiation etiology. Significant increases of nonchronic lymphocytic leukemia and cancers of the bone and kidney were also linked to radiotherapy. Women treated surgically were also at significant risk of second cancers, in all likelihood related to cigarette smoking and risk factors similar to those of cervical cancer., Conclusions: Curative therapy for cervical cancer results in large numbers of long term survivors who develop second cancers very late in life. Radiation is an important cause of this increase and there is no evidence that risk returns to normal levels.