Circulating concentrations of insulin-like growth factor-I, insulin-like growth factor-binding protein-3, genetic polymorphisms and mammographic density in premenopausal Mexican women: results from the ESMaestras cohort.

The insulin-like growth factor (IGF) axis plays an essential role in the development of the mammary gland. High circulating levels of IGF-I and of its major binding protein IGFBP3 have been related with increased mammographic density in Caucasian premenopausal women. Some common single nucleotide polymorphisms (SNPs) in genes of the IGF pathway have also been suggested to play a role in mammographic density. We conducted a cross-sectional study nested within the large Mexican ESMaestras cohort to investigate the relation between circulating levels of IGF-I, IGFBP-3, the IGF-I/IGFBP-3 ratio, five common SNPs in the IGF-1, IGFBP-3 and IGF-1R genes and mammographic density in 593 premenopausal Mexican women. Mean age at mammogram was 43.1 (standard deviation, SD = 3.7) years, and average body mass index (BMI) at recruitment was 28.5 kg/m(2). Mean percent mammographic density was 36.5% (SD: 17.1), with mean dense tissue area of 48.3 (SD: 33.3) cm(2) . Mean IGF-I and IGFBP-3 concentrations were 15.33 (SD: 5.52) nmol/l and 114.96 (SD: 21.34) nmol/l, respectively. No significant associations were seen between percent density and biomarker concentrations, but women with higher IGF-I and IGF-I/IGFBP-3 concentrations had lower absolute dense (p(trend) = 0.03 and 0.09, respectively) and nondense tissue areas (p(trend) < 0.001 for both parameters). However, these associations were null after adjustment by BMI. SNPs in specific genes were associated with circulating levels of growth factors, but not with mammographic density features. These results do not support the hypothesis of a strong association between circulating levels of growth hormones and mammographic density in Mexican premenopausal women.

Comparison of fully and semi-automated area-based methods for measuring mammographic density and predicting breast cancer risk.

BACKGROUND: Mammographic density is a strong risk factor for breast cancer but the lack of valid fully automated methods for quantifying it has precluded its use in clinical and screening settings. We compared the performance of a recently developed automated approach, based on the public domain ImageJ programme, to the well-established semi-automated Cumulus method. METHODS: We undertook a case-control study within the intervention arm of the Age Trial, in which ∼54,000 British women were offered annual mammography at ages 40-49 years. A total of 299 breast cancer cases diagnosed during follow-up and 422 matched (on screening centre, date of birth and dates of screenings) controls were included. Medio-lateral oblique (MLO) images taken closest to age 41 and at least one year before the index case's diagnosis were digitised for each participant. Cumulus readings were performed in the left MLO and ImageJ-based readings in both left and right MLOs. Conditional logistic regression was used to examine density-breast cancer associations. RESULTS: The association between density readings taken from one single MLO and breast cancer risk was weaker for the ImageJ-based method than for Cumulus (age-body mass index-adjusted odds ratio (OR) per one s.d. increase in percent density (95% CI): 1.52 (1.24-1.86) and 1.61 (1.33-1.94), respectively). The ImageJ-based density-cancer association strengthened when the mean of left-right MLO readings was used: OR=1.61 (1.31-1.98). CONCLUSIONS: The mean of left-right MLO readings yielded by the ImageJ-based method was as strong a predictor of risk as Cumulus readings from a single MLO image. The ImageJ-based method, using the mean of two measurements, is a valid automated alternative to Cumulus for measuring density in analogue films.

Fertility treatment, twin births, and unplanned pregnancies in women with eating disorders: findings from a population-based birth cohort.

OBJECTIVE: To investigate fertility treatment, twin births, and unplanned pregnancies in pregnant women with eating disorders in a population-based sample. DESIGN: A longitudinal population-based birth cohort (Generation R). SETTING: Rotterdam, the Netherlands. SAMPLE: Women from the Generation R study who reported a history of (recent or past) anorexia nervosa (n = 160), bulimia nervosa (n = 265), or both (n = 130), and a history of psychiatric disorders other than eating disorders (n = 1396) were compared with women without psychiatric disorders (n = 4367). METHODS: Women were compared on the studied outcomes using logistic regression. We performed crude and adjusted analyses (adjusting for relevant confounding factors). MAIN OUTCOME MEASURES: Fertility treatment, twin births, unplanned pregnancies, and women's feelings towards unplanned pregnancies. RESULTS: Relative to women without psychiatric disorders, women with bulimia nervosa had increased odds (odds ratio, OR, 2.3; 95% confidence interval, 95% CI, 1.1-5.2) of having undergone fertility treatment. Women with all eating disorders had increased odds of twin births (anorexia nervosa, OR 2.7, 95% CI 1.0-7.7; bulimia nervosa, OR 2.7, 95% CI 1.1-6.6; anorexia and bulimia nervosa, OR 3.795% CI 1.3-10.7). Anorexia nervosa was associated with increased odds of unplanned pregnancies (OR 1.8, 95% CI 1.2-2.6) and mixed feelings about these pregnancies (adjusted OR 5.0, 95% CI 1.7-14.4). Pre-pregnancy body mass index did not explain the observed associations. CONCLUSIONS: Eating disorders are associated with increased odds of receiving fertility treatment and twin births. Women with anorexia nervosa were more likely to have an unplanned pregnancy and have mixed feelings about the unplanned pregnancy. Fertility treatment specialists should be aware that both active and past eating disorders (both anorexia nervosa and bulimia nervosa) might underlie fertility problems.

Mammographic density and molecular subtypes of breast cancer.

BACKGROUND: Gene expression profiling has led to a subclassification of breast cancers independent of established clinical parameters, such as the Sorlie-Perou subtypes. Mammographic density (MD) is one of the strongest risk factors for breast cancer, but it is unknown if MD is associated with molecular subtypes of this carcinoma. METHODS: We investigated whether MD was associated with breast cancer subtypes in 110 women with breast cancer, operated in Stockholm, Sweden, during 1994 to 1996. Subtypes were defined using expression data from HGU133A+B chips. The MD of the unaffected breast was measured using the Cumulus software. We used multinomial logistic models to investigate the relationship between MD and Sorlie-Perou subtypes. RESULTS: Although the distribution of molecular subtypes differed in women with high vs low MD, this was statistically non-significant (P=0.249), and further analyses revealed no association between the MD and Sorlie-Perou subtypes as a whole, nor with individual subtypes. CONCLUSION: These findings suggest that although MD is one of the strongest risk factors for breast cancer, it does not seem to be differentially associated with breast cancer molecular subtypes. However, larger studies with more comprehensive covariate information are needed to confirm these results.

Perinatal outcomes and gestational weight gain in women with eating disorders: a population-based cohort study.

OBJECTIVE: To investigate adverse perinatal outcomes and gestational weight gain trajectories in women with lifetime (current/past) eating disorders (ED: anorexia nervosa [AN] and bulimia nervosa [BN]). DESIGN: A longitudinal population-based birth cohort. SETTING: Rotterdam, the Netherlands. SAMPLE: Women who enrolled prenatally, had complete information on exposure (lifetime ED), and gave birth to a live singleton (n = 5256). Four groups of exposed women: lifetime AN (n = 129), lifetime BN (n = 209), lifetime AN + BN (n = 100), other lifetime psychiatric disorder (n = 1002) were compared with unexposed women (n = 3816). METHODS: Perinatal outcomes and gestational weight gain were obtained from obstetric and midwifery records, self-report and objective measurements. Exposed women were compared with unexposed women within the cohort using linear, logistic regression and mixed models. MAIN OUTCOME MEASURES: Any pregnancy, delivery and postnatal complications. Birthweight adjusted for gestational age, prematurity (born <37 weeks), small-for-gestational age; maternal weight gain during pregnancy. RESULTS: Maternal AN was positively associated with suspected fetal distress. No differences were found in mean birthweight, prevalence of a small-for-gestational-age, or premature birth. Relative to unexposed women, women with AN had, on average, a lower body weight but a higher rate of weight gain subsequently; whereas women with BN had a higher body weight but a lower rate of weight gain. CONCLUSIONS: Maternal lifetime ED is associated with few adverse perinatal outcomes in this sample. Differential gestational weight gain patterns in women with AN and BN are consistent with possible biological compensatory mechanisms aimed at protecting the fetus.

Evaluation of variation in the phosphoinositide-3-kinase catalytic subunit alpha oncogene and breast cancer risk.

BACKGROUND: Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer. METHODS: A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC). RESULTS: Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR)=0.97, 95% confidence interval (CI) 0.95-0.99, P=4.6 × 10(-3)), but did not reach significance in the BCAC replication study alone (OR=0.98, 95% CI 0.96-1.01, P=0.139). CONCLUSION: Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer.

Cancer mortality in ethnic South Asian migrants in England and Wales (1993-2003): patterns in the overall population and in first and subsequent generations.

BACKGROUND: Cancer mortality has been examined among ethnic South Asian migrants in England and Wales, but not by generation of migration. METHODS: Using South Asian mortality records, identified by a name-recognition algorithm, and census information, age-standardised rates among South Asians, and South Asian vs non-South Asian rate ratios, were calculated. RESULTS AND CONCLUSIONS: All-cancer rates in ethnic South Asians were half of those in non-South Asians in first-generation (all-cancer-standardised mortality ratio (SMR) in males 0.51 and in females 0.56) and subsequent-generation South Asians (SMR in males 0.43 and in females 0.36). The higher mortality in first-generation South Asians for liver (both sexes), oral cavity and gallbladder cancer (females), particularly marked among Bangladeshis, was reduced in subsequent generations.

Dietary calcium and vitamin D intakes in childhood and throughout adulthood and mammographic density in a British birth cohort.

We examined the role of dietary calcium and vitamin D intakes in childhood and throughout adulthood in relation to mammographic density using data from a nationally representative cohort of 1161 women followed up since their birth in 1946. Dietary intakes at the age of 4 years were determined by 24-h recalls and at the ages of 36, 43 and 53 years by 5-day food records. After adjusting for known risk factors and confounders, no evidence of a relationship between dietary calcium or vitamin D intakes and mammographic density approximately at the age of 50 years was found, except for a cross-sectional relationship between dietary calcium intake at the age of 53 years and breast density in women who were post-menopausal at the time of mammography, with those in the top fifth of the distribution of calcium intake having a 0.53 s.d. lower percent breast density than those in the lowest fifth (P-value <0.01 for linear trend).

Urinary estrogen metabolites and mammographic parenchymal patterns in postmenopausal women.

It has been hypothesized that women who metabolize their endogenous estrogens predominantly via 16(alpha)-hydroxylation rather than via 2-hydroxylation and, as a result, have a low ratio of 2-hydroxyestrone (2-OHE1):16(alpha)-hydroxyestrone (16(alpha)-OHE1) are at an increased risk of breast cancer. Epidemiological evidence in support of this hypothesis is scarce and mostly based on measurements made after the onset of the disease. To gain insight into the role of these metabolites in the etiology of breast cancer, we assessed their relationship with high-density Wolfe mammographic parenchymal patterns (P2/DY), a recognized indicator of risk of this tumor. The study was nested within a large cross-sectional survey on determinants of mammographic patterns carried out in a population-based breast screening program in Northern Greece. Urinary levels of 2-OHE1 and 16(alpha)-OHE1 were measured in a random sample of 70 postmenopausal women with P2/DY mammographic patterns and in a random sample of 70 women with N1 mammographic patterns, individually matched to the P2/DY women on year of birth, years since menopause and date of urine collection. Women with a P2/DY pattern had, on average, 58% higher levels of 2-OHE1 (P = 0.002) and 15% higher levels of 16(alpha)-OHE1 (P = 0.37) than those with an N1 pattern. The ratio of 2-OHE1:16(alpha)-OHE1 was 35% higher (P = 0.005) in women with a P2/DY pattern. Women in the highest one-third of this ratio were six times more likely to have a P2/DY pattern than those in the lowest one-third after adjusting for potential confounders (prevalence odds ratio, 6.2; 95% CI, 1.7-22.9; test for linear trend, P = 0.002). These findings seem to suggest that a high, rather than a low, 2-OHE1:16(alpha)-OHE1 ratio may be associated with an increase in breast cancer risk at postmenopausal ages, unless the pathway through which estrogen metabolites may affect breast cancer risk is unrelated to mammographic parenchymal patterns.

Mortality in the Portuguese thorotrast study.

The Portuguese Thorotrast study cohort consists of a group of patients who received Thorotrast for diagnostic reasons between 1929 and 1956, and a group of similar patients who were given nonradioactive contrast agents. The cohort members were identified from medical records that contained information on reasons for the radiological investigation, type of procedure employed, and name and dose of the contrast medium used. This cohort was assembled in 1961, but its follow-up was interrupted in 1976. We have now reactivated this cohort and extended its follow-up through the end of 1996. Similar methods were used to follow up and ascertain cause of death for the Thorotrast-exposed and unexposed subjects. A total of 1931 patients who received Thorotrast systemically and 2258 unexposed subjects were initially identified from medical records. We were able to successfully follow up 58.6% (1131) of the Thorotrast patients and 45.7% (1032) of the unexposed patients. By the end of 1996, 92.2% of the Thorotrast patients and 75.2% of the unexposed patients were dead. Mortality from all causes was increased in the Thorotrast patients compared to those who were not exposed. This excess in mortality increased with time since exposure, peaking 30 years after administration of Thorotrast. The rise in overall mortality was essentially due to neoplasms [relative risk (RR) adjusted for sex, age and period = 6.04, 95% CI = 4.42-8.26], nonmalignant liver disorders (RR = 5.67, 95% CI 3.13-10.3) and nonmalignant hematological conditions (RR = 14.2, 95% CI = 2.54-79.3). The increase in mortality from neoplasms was explained mainly by increases in the risk of liver cancer (RR = 70.8, 95% CI = 19.9-251.3) and, to a much lesser extent, leukemia (RR = 15.2, 95% CI = 1. 28-181.7).

Validation and utility of a computerized South Asian names and group recognition algorithm in ascertaining South Asian ethnicity in the national renal registry.

BACKGROUND: The UK Renal Registry (UKRR) reports on equity and quality of renal replacement therapy (RRT). Ethnic origin is a key variable, but it is only recorded for 76% patients overall in the UKRR and there is wide variation in the degree of its completeness between renal centres. Most South Asians have distinctive names. AIM: To test the relative performance of a computerized name recognition algorithm (SANGRA) in identifying South Asian names using the UKRR database. DESIGN: Cross-sectional study of patients (n = 27 832) starting RRT in 50 renal centres in England and Wales from 1997 to 2005. METHODS: Kappa statistics were used to assess the degree of agreement of SANGRA coding with existing ethnicity information in UKRR centres. RESULTS: In 12 centres outside London (number of patients = 7555) with 11% (n = 747) self-ascribed South Asian ethnicity, the level of agreement between SANGRA and self-ascribed ethnicity was high (kappa=0.91, 95% CI 0.90-0.93). In two London centres (n = 779) with 21% (n = 165) self-ascribed South Asian ethnicity, SANGRA's agreement with self-ascribed ethnicity was lower (kappa=0.60, 95% CI 0.54-0.67), primarily due to difficulties in distinguishing between South Asian ethnicity and other non-White ethnic minorities. Use of SANGRA increased numbers defined as South Asian from 1650 to 2076 with no overall change in percentage of South Asians. Kappa values showed no obvious association with degree of missing data returns to the UKRR. CONCLUSION: SANGRA's use, taking into account its lower validity in London, allows increased power and generalizability for both ethnic specific analyses and for analyses where adjustment for ethnic origin is important.

Oral and pharyngeal cancer in South Asians and non-South Asians in relation to socioeconomic deprivation in South East England.

From UK Thames Cancer Registry data, after controlling for socioeconomic deprivation of area of residence, South Asian males showed a higher relative risk of oral (1.36; 95% CI: 1.11, 1.67), but not of pharyngeal cancer than non-South Asian males, whereas South Asian females had much higher risks of these cancers (3.67; 95% CI: 2.97, 4.53 and 2.06; 95% CI: 1.44, 2.93), respectively, than non-South Asians.

A prospective study of serum insulin-like growth factor-I (IGF-I), IGF-II, IGF-binding protein-3 and breast cancer risk.

The associations between serum concentrations of insulin-like growth factor-I (IGF-I), IGF-II and IGF-binding proteins (IGFBP)-3 and risk of breast cancer were investigated in a nested case-control study involving 117 cases (70 premenopausal and 47 postmenopausal at blood collection) and 350 matched controls within a cohort of women from the island of Guernsey, UK. Women using exogenous hormones at the time of blood collection were excluded. Premenopausal women in the top vs bottom third of serum IGF-I concentration had a nonsignificantly increased risk for breast cancer after adjustment for IGFBP-3 (odds ratio (OR) 1.71; 95% confidence interval (CI): 0.74-3.95; test for linear trend, P=0.21). Serum IGFBP-3 was associated with a reduction in risk in premenopausal women after adjustment for IGF-I (top third vs the bottom third: OR 0.49; 95% CI: 0.21-1.12, P for trend=0.07). Neither IGF-I nor IGFBP-3 was associated with risk in postmenopausal women and serum IGF-II concentration was not associated with risk in pre- or postmenopausal women. These data are compatible with the hypothesis that premenopausal women with a relatively high circulating concentration of IGF-I and low IGFBP-3 are at an increased risk of developing breast cancer.

Socioeconomic differences in reproductive behaviour.

There are marked socioeconomic variations in the risk of female reproductive cancers. We examine here data from the World Fertility Surveys, the Demographic and Health Surveys, and other national surveys, to assess whether these variations in cancer risk might be explained, at least in part, by socioeconomic variations in reproductive behaviour. There were marked socioeconomic differentials in achieved parity, age at first birth, final childlessness, duration of breastfeeding, and possibly also age at menopause. These differentials were present in almost all settings: countries with low and high levels of modernization, and countries with low and high levels of fertility. In general, women of higher socioeconomic status and with more education had lower fertility and later age at first birth, but a greater prevalence of childlessness, shorter duration of breastfeeding and later age at menopause. However, the size and even the direction of these differentials varied markedly from country to country according to its level of economic development and, within each country, from generation to generation of women. It is possible that some of these socioeconomic differences may be narrowing in recent generations in Western countries. There was little evidence of socioeconomic variations in age at menarche. The observed socioeconomic differentials in most aspects of reproductive behaviour could potentially account for some of the socioeconomic variation in the risk of female reproductive cancers. However, this relationship could not be assessed directly because such analysis would require birth-cohort-specific data on socioeconomic variations in reproductive behaviour and in cancer risks. Unfortunately, these data are not available.

Recent trends in incidence of and mortality from breast, ovarian and endometrial cancers in England and Wales and their relation to changing fertility and oral contraceptive use.

Reproductive-related factors play a major role in the aetiology of cancers of the breast, ovary and endometrium. Pregnancy history influences the risk of each of these cancers, and oral contraceptive use modifies the risks of ovarian and endometrial cancers, although its effect on breast cancer risk is less certain. We analysed recent time trends in the incidence and mortality of these cancers in England and Wales and assessed whether they can be explained by changes in fertility and oral contraceptive use. During 1962-87, there were significant increases in the overall incidence of breast cancer (0.95% increase per annum) and ovarian cancer (0.76% per annum) but little increase in endometrial cancer (0.13% per annum). At young ages incidence of each of the cancers has declined in recent years, whereas at older ages there have been substantial increases. Mortality data show similar time trends. In analyses by birth cohort, incidence of each of the cancers increased steeply for successive cohorts born before the turn of the century, and more slowly for cohorts thereafter, reaching a maximum for those born in the 1920s, and decreased for those born subsequently. The increases in incidence for women born before the turn of the century paralleled marked declines in their fertility. The fall in risk for women born after the 1920s was not accompanied by significant increases in their fertility, but coincided with the introduction and increase in use of oral contraceptives. For ovarian and endometrial cancers this accords with strong evidence from person-based studies of the protective effect of oral contraceptives. For breast cancer, the reasons for the recent decline are not clear. It would accord with recent suggestions of a long-term protective effect of oral contraceptives, on which further studies are needed. It is also possible, however, that changes in other risk factors such as dietary fat intake and menarcheal age might have contributed to the recent declines in the risk of these cancers.

Thymus cancer epidemiology in England and Wales.

Thymus cancer epidemiology has been little investigated, but recent clinical studies have suggested an association with the Epstein-Barr virus. We studied thymus cancer incidence 1963-83 and mortality 1959-86 in England and Wales, using data from the National Cancer Register and national mortality files. Mean age-standardised incidence rates of the tumour were 0.72 per million per annum for males and 0.64 for females; mortality rates were about half of this: 0.43 for males and 0.29 for females. There was no significant change in rates over time, nor any consistent pattern of risk by region of residence. Birth cohort analysis of mortality showed in each sex, lowest risk for persons born during the Second World War. The age distribution of the tumour was unusual: a progressive rise in both incidence and mortality rates occurred in each sex at ages up to 60-69, at which there was a striking peak, more marked for males and for incidence data, with a sharp decline thereafter. Immigrants from China and Cyprus had significantly high proportional registration ratios, but based on small numbers.

Ovarian germ cell malignancies in England: epidemiological parallels with testicular cancer.

The epidemiology of germ cell cancer of the ovary has been little investigated. We studied ovarian germ cell cancers incident 1971-84 in England, using data from the England and Wales national cancer register. The age distribution showed a sharp peak at ages 15-19, to which both teratomas and dysgerminomas contributed equally, and a secondary, much wider peak, at ages 65-69, mainly due to teratomas. For teratomas there were diverging secular trends by age: incidence has been increasing at ages 0-44 (P around 0.05) and decreasing at ages over 44 (P less than 0.01). Birth cohort analysis showed an increase in risk at ages 0-44 for more recent generations of women. There were no changes over time for dysgerminomas. There was no clear geographic pattern of distribution across the regions of England. The early age peak, and the increase in incidence of ovarian germ cell cancers at young ages but decrease at older ages, resembles testicular cancer epidemiology. Interestingly, discrepancies and similarities in the age distribution of these tumours between the sexes parallel lifetime profiles of gonadotropin levels in each sex.

Geographic distribution of lung and stomach cancers in England and Wales over 50 years: changing and unchanging patterns.

The distribution of cancers of the lung and stomach in the counties of England and Wales in 1968-81 was mapped, and compared to the distribution in the country in 1921-30 described by Stocks. The high risk of stomach cancer in North Wales noted by Stocks was found still to exist in each sex, although its disparity from the rest of the country has diminished. In general the geographic distribution of stomach cancer in both periods has paralleled that of post-neonatal mortality, at the same time and earlier, as an index of general poverty, but postneonatal mortality in North Wales has not been exceptionally high. In 1921-30 the highest risk of lung cancer was in and around London. In the modern data this was still true for older women, but for men and women under 45 years of age, and to a lesser extent for older men, the pattern has changed greatly; the epidemic has moved north, and highest risk is now in Northumberland and Durham. This spread appears to have occurred earlier for men than for women, and for urban than for rural areas, occurring latest of all for women in rural areas. Regional disparity has also increased, especially in males: risks in the northern regions are now over twice those in much of Wales and the South.

Sex differences in the risks of hormone-dependent cancers.

There are marked variations in the risk of hormone-dependent cancers between males and females, and these are likely to reflect sex differences in endogenous hormone profiles. The authors examined sex differences in the risk of hormone-dependent cancers of sex-shared sites by using data from the England and Wales national cancer registry for 1962-1984. Both breast and thyroid cancers showed marked excesses in risk for women, but the female: male ratio peaked around menopause for breast cancer and a puberty for thyroid cancer, suggesting that although female sex hormones may influence the risk of these two cancers, the mechanisms involved are probably different. In the descending colon, the risk of cancer was greater in females than in males at ages under 60 years, but greatest in males at ages above this, whereas in the ascending colon there were no age-specific differences in risk between the sexes. This is consistent with the hypothesis that female reproductive events may decrease a woman's risk of cancer in the descending but not in the ascending colon. Sex differences in bone cancer risk at puberty, particularly for osteosarcomas and Ewing's sarcomas, paralleled known sex differences in skeletal growth; there was a peak in age-specific rates earlier and lower in girls than in boys. Rhabdomyosarcoma, a soft tissue cancer, also showed a rise in risk at puberty with age differences between boys and girls that correlated with sex differences in muscle growth patterns; this suggests that its etiology may be hormonally related as well.

Thyroid cancer epidemiology in England and Wales: time trends and geographical distribution.

Thyroid cancer incidence has been increasing in many countries, whereas mortality has been falling due to better survival. Radiation is the best-established risk factor and there has been concern that recent rises in incidence might be related to fallout radiation from atmospheric nuclear weapon tests. We examined thyroid cancer time trends and geographical distribution in England and Wales and possible interpretations of these. During 1962-84, there were significant increases in incidence (P < 0.001) in each sex at ages under 45. Cohort analysis by single year of birth showed an overall increase in incidence risks in women aged 0-44 born since 1920, with a sudden rise in risk for the birth years 1952-55 followed by a lower risk for the more recent cohorts. In men, there was an overall increase in risk at ages 0-44 in successive birth cohorts, but the pattern was irregular. In each sex, the risk in persons aged 45 and over decreased slightly in successive generations. Geographically, highest incidence risks were in countries in North and Mid Wales, in which the risk was almost twice that in the rest of the country. This pattern was present only at ages 45 and over and was most clear in rural areas. The peak of thyroid cancer risk in women born in 1952-55 is consistent with a carcinogenic effect of fallout radiation, since these women were children in the late 1950s and early 1960s when fallout radiation was greatest in England and Wales. The focus of high thyroid cancer risks in Wales was in areas with high levels of fallout radiation. However, thyroid cancer risks in Wales were not high for more recent cohorts (the ones who were exposed to fallout early in life), and a focus on high risk of benign thyroid diseases was present in Wales well before nuclear weapons existed. The distributions of these benign thyroid diseases, or of factors causing them, seem more likely than fallout to explain the high risk areas for thyroid cancer in the country.