Screening for carcinoma in situ in the contralateral testicle in patients with testicular cancer: a population-based study.

BACKGROUND: Screening programmes for contralateral carcinoma in situ (CIS) testis in patients with unilateral germ-cell cancer (GCC) have never been evaluated. We investigated the effect of screening for contralateral CIS in a large nation-wide, population-based study. PATIENTS AND METHODS: A contralateral single-site biopsy was offered to 4130 patients in whom GCC had been diagnosed in 1984-2007 (screened cohort); 462 patients in whom GCC was diagnosed in 1984-1988 comprised the unscreened cohort. Cases with CIS were offered radiotherapy. Initially CIS-negative biopsies in patients with metachronous GCC were revised according to today's standards. Risk for metachronous GCC was estimated using cumulative incidence and the Cox proportional hazards model. RESULTS: In the screened cohort, contralateral CIS was found in 181 (4.4%) patients. The cumulative incidence of metachronous GCC after 20 years was 1.9% in the screened cohort and 3.1% in the unscreened cohort (P = 0.097), hazard ratio (HR) for the unscreened cohort: 1.59 (P = 0.144). Expert revision with contemporary methodology of CIS-negative biopsy samples from patients with metachronous cancer revealed CIS in 17 out of 45 (38%) cases. Decreased risks for metachronous GCC were related to older age at diagnosis (HR 0.52 per 10 years, P < 0.001) and chemotherapy (HR 0.35, P = 0.002). Limitations include the small number of patients in the unscreened cohort and the retrospective study design. CONCLUSIONS: Our evaluation of a national population-based screening programme for contralateral CIS in patients with testicular cancer showed no significant difference in the risk for metachronous GCC between a screened and an unscreened cohort. Single-site biopsy including modern immunohistochemistry does not identify all cases of CIS.

Biodemographic trajectories of longevity.

Old-age survival has increased substantially since 1950. Death rates decelerate with age for insects, worms, and yeast, as well as humans. This evidence of extended postreproductive survival is puzzling. Three biodemographic insights--concerning the correlation of death rates across age, individual differences in survival chances, and induced alterations in age patterns of fertility and mortality--offer clues and suggest research on the failure of complicated systems, on new demographic equations for evolutionary theory, and on fertility-longevity interactions. Nongenetic changes account for increases in human life-spans to date. Explication of these causes and the genetic license for extended survival, as well as discovery of genes and other survival attributes affecting longevity, will lead to even longer lives.

Etiologic factors of breast cancer elucidated by a study of unselected twins.

The Danish Twin Register consists of the total population of twin pairs born in Denmark during a certain period. Within this population were found 50 monozygotic (MZ) female twins belonging to 45 MZ pairs and 81 dizygotic (DZ) twins belonging to 77 DZ female pairs, of which at least 1 twin had breast cancer (BC) and both twins were alive at the time of the first BC diagnosis. In 5 MZ and 4 DZ pairs, both partners had BC. Pairwise concordance rates were not significantly different between the 2 groups of twins but were of the same magnitude as in a previous study. The heritability, evaluated by genetic determination, was estimated to be 0.30-0.40. The observed number of BC cases developing in the co-twins after the first BC diagnosis in the twin pairs was increased by a factor of nearly 6 in MZ co-twins and by a factor of about 2 in DZ co-twins. For cancer of other sites, the observed and expected numbers were nearly identical in both MZ and DZ co-twins. In 8 of 9 pairs concordant for BC, the lesion was found on the same side. The mean age at diagnosis showed no significant difference between the concordant and discordant pairs. In the 40 MZ pairs with only 1 twin affected, she was more often unmarried and/or nulliparous than her unaffected, genetically identical co-twin, but this finding was not significant. A general tendency for the twin with BC to have the first child at a later age than her unaffected twin sister could not be demonstrated.

Prevalence of fasting hyperglycemia and known non-insulin-dependent diabetes mellitus classified by plasma C-peptide: Fredericia survey of subjects 60-74 yr old.

A Danish population of 5699 individuals (60-74 yr old) was screened by fasting blood glucose (FBG) and interviewed about known diabetes. The distribution of FBG in individuals not known to have diabetes showed no sex difference or significant variation with age. Fasting hyperglycemia (FH), defined as FBG greater than or equal to mM in subjects without a history of diabetes, was found in 1.7% of men and women. Known diabetes (KD) had a prevalence of 3.9 and 5.0% in men and women, respectively. The prevalence rates of FH and KD increased significantly with age. In the two subgroups, plasma C-peptide was measured after overnight fasting and subsequently 6 min after an intravenous injection of glucagon. Based on the distribution of the C-peptide concentrations in non-insulin-treated KD subjects, lower limits for non-insulin-dependent diabetes mellitus (NIDDM) of 0.30 pmol/ml for fasting C-peptide and 0.60 pmol/ml for stimulated C-peptide were arbitrarily chosen. According to these cutoff points, only 38.5% of KD subjects treated with insulin had insulin-dependent diabetes mellitus, corresponding to 9.3% of all KD subjects. After exclusion of these patients, the prevalence of recognized NIDDM was 3.5% in men and 4.5% in women. All FH subjects except one had C-peptide values in the NIDDM interval. A close agreement between fasting and glucagon-stimulated C-peptide was seen. In epidemiological studies with an expected high prevalence of NIDDM, we propose to use fasting C-peptide for classification of patients with insulin-treated diabetes.

Facial clefts in sibs and children of epileptic patients.

The prevalence of facial clefts in sibs and children of 2,072 epileptics ascertained in a defined region was determined by record linkage with a national cleft register, which also provided expected figures. Observed/expected ratios were increased only for cleft lip with or without cleft palate if the mother had manifested epilepsy: it was 4.7 when anticonvulsants were given before and during pregnancy, 2.7 in cases with no treatment, and zero in children born prior to maternal epilepsy. Children of epileptic men and sibs of epileptics showed no increase. The prevalence of isolated cleft palate was not above expectation in any group.

Genetic and environmental influences on functional abilities in Danish twins aged 75 years and older.

BACKGROUND: Functional abilities vary widely among elderly persons. The determinants of this variation are probably multiple and include normal aging processes as well as disease expression. This study estimates the relative importance of genetic and environmental factors to variation in functional abilities in elderly persons. METHODS: We conducted a survey among all Danish twins aged 75 years and older who were identified in the population-based Danish Twin Registry. Interviews were conducted with 77% (7% by proxy responders) of the 3099 individuals in the study population. Functional abilities were assessed by validated Danish survey instruments and were scored on three scales. Heritability (proportion of the population variance attributable to genetic variation) was estimated using structural equation analyses. RESULTS: Structural equation analyses revealed a substantial heritability (34%-47%) for the three functional ability scores among the women aged 80 years and older compared with a more modest heritability (15%-34%) among the women aged 75-79 years. The remaining variation could be attributed to individuals' nonfamilial environments. Comparisons of the functional abilities of twins with living versus deceased co-twins also suggested a difference in the genetic influence for the two age groups. Although heritability estimates were uniformly low in the male participant sample, the size of the sample was not sufficiently large to allow for precise estimates of heritability. CONCLUSION: For women we found that the effect of genetic factors on functional abilities increases with age and accounts for one third to one half of the variation among individuals aged 80 years and older. An understanding of the genetic mechanisms underlying functional abilities in the oldest individuals may enhance the possibilities for improving health in the elderly population by modifying environmental factors.

Pattern of metastases in human breast carcinoma in relation to estrogen receptor status.

The distribution of metastases at the first recurrence of breast cancer was studied in 57 estrogen receptor (ER) positive and in 23 ER negative patients, who constituted a subset of 460 patients with operable breast cancer. The pattern of metastases with respect to localization of metastases and the dominant site of first recurrence was similar in patients with ER positive and ER negative tumours. The recurrence-free survival (RFS) and the overall survival were associated with the ER status in the 460 patients. ER positive patients had both a significantly longer RFS (p = 0.0024) and survival (p = 0.0001) compared to ER negative patients. Survival after recurrence was prolonged in patients with soft tissue recurrences only, and the proportion of dead patients was highest in receptor negative patients with metastases to bone and viscera. In conclusion, we could not demonstrate that ER positive and negative tumours have a propensity for recurrence at specific sites.

A Danish population-based twin study on general health in the elderly.

OBJECTIVES: To study the relative influence of genetic and environmental factors on self-rated health and hospitalization patterns in the elderly. METHODS: A survey among all 3,099 Danish twins ages 75 years and older identified in the Danish Twin Registry. An interview was conducted with 77% of the twins. The number of hospitalizations in the previous 18 years was obtained through register linkage, thereby obtaining health information on 96% of the study population, including all nonresponders. RESULTS: Structural equation modeling suggested that approximately a quarter of the variation in the liability to self-reported health and the number of hospitalizations could be attributed to genetic factors. The remaining variation was most likely due to nonfamilial environment. Analyses of the hospitalization patterns of proxy responders and nonresponders suggest that the estimates of the genetic influence on health outcomes in the study are conservative. DISCUSSION: The present study indicates that variation in general health among the elderly is partly explained by genetic factors.

Mortality among twins after age 6: fetal origins hypothesis versus twin method.

OBJECTIVE: To test the validity of the fetal origins hypothesis and the classic twin method. DESIGN: Follow up study of pairs of same sex twins in which both twins survived to age 6. SETTING: Denmark. SUBJECTS: 8495 twin individuals born 1870-1900, followed through to 31 December 1991. MAIN OUTCOME MEASURES: Mortality calculated on a cohort basis. RESULTS: Mortality among twins and the general population was not significantly different except among females aged 60-89, in whom mortality among twins was 1.14 times (SE 0.03) higher than in the general population. Mortality among female dizygotic twins was 1.77 times (0.18) higher than among monozygotic twins at age 30-59. Otherwise, mortality for monozygotic and dizygotic twins did not consistently differ after age 6. CONCLUSION: According to the fetal origins hypothesis the risk of adult morbidity and mortality is heightened by retardation in intrauterine growth. Twins, and in particular monozygotic twins, experience growth retardation in utero. The findings in the present study suggest that the fetal origins hypothesis is not true for the retardation in intrauterine growth experienced by twins. Furthermore, the data are inconsistent with the underlying assumption of a recent claim that the classic twin method is invalid for studies of adult diseases. The present study is, however, based on the one third of all pairs of twins in which both twins survived to age 6. The possible impact of this selection can be evaluated in future studies of cohorts of younger twins with lower perinatal and infant mortality.

[Study of the Danish Malformation Registry for the incidence of cleft lip and palate during 1983-1987]. / Evaluering af det danske misdannelsesregisters registrering af laebe-ganespalter i perioden 1983-1987.

The Danish Register of Congenital Malformations at the National Board of Health is used for surveillance and research. More than 10% of all patients registered have oral cleft diagnoses. This report evaluates the completeness of the Register of Congenital Malformations as regards registration of oral cleft patients born in Denmark in the period 1983-1987. The register is limited to congenital anomalies diagnosed in hospitals in the child's first year of life. The investigation shows, that the register is suitable for surveillance of clefts, because the completeness of registration was constant during the five-year period 1983-1987. The completeness was more than 90% of all known cases, and probably higher for severe clefts and cases with associated anomalies. Identical diagnosis was found in 93% of all patients registered in The Register of Congenital Malformations with at least one other source of ascertainment. In addition, the investigation disclosed misclassification of a small oral-cleft-subgroup and the need for an additional diagnosis in the coding. The register can only be used for surveillance and research in congenital anomalies, which are usually diagnosed in the child's first year of life.

[Mortality among twins after the age of six: the programming hypothesis versus the twin-method]. / Mortalitet blandt tvillinger efter seksårsalderen: programmeringshypotesen versus tvillingmetoden.

According to the foetal-origins hypothesis the risk of adult morbidity and mortality is heightened by intrauterine growth retardation. Twins, and in particular monozygotic twins, experience growth retardation in utero. A total of 8495 twin individuals born 1870-1900 in Denmark were followed through 1991 and death rates were calculated on a cohort basis. Deaths rates for twins and the general population were not significantly different except for females aged 60-89: mortality for female twins in this age group was 1.14 times (SE 0.03) higher than the general population. Female dizygotic twins experienced death rates 1.77 times (SE 0.18) higher than monozygotic twins at ages 30-59. Otherwise, mortality for monozygotic and dizygotic twins did not consistently differ after age six. The findings in the present study suggest that the foetal-origins hypothesis is not true for the intrauterine growth retardation experienced by twins.

[Clinics for counseling on cancer genetics. Experiences with genetic studies and counseling on familial breast cancer and colorectal cancer]. / Cancergenetisk rådgivningsklinik. Erfaringer med genetisk udredning og rådgivning ved familiaer cancer mammae og familiaer cancer colorectalis.

Five to ten percent of cases of breast cancer and colorectal cancer are familial. These families can be divided into high-risk families and moderate-risk families. Cancer in high-risk families can often be explained by dominant inheritance of a gene causing increased susceptibility to cancer. There is a great demand for genetic counseling in these families, and the structure of and experiences from a familial cancer clinic at Odense University Hospital is described. The establishment of a familial cancer clinic involves three steps: 1) Identification of families with increased cancer susceptibility; 2) Molecular tests to identify gene carriers; 3) Clinical examinations for early detection of tumors. Achievement of these three steps requires the involvement of several medical specialties to ensure patient care. Experience with familial cancer clinics is still limited and the involvement of genetic testing and clinical examination programs at risk individuals are insufficiently examined. The rapidly improving techniques for genetic testing make it urgent that it is implemented as part of already established clinical programs.

A note on ascertainment probability in the Allen/Hrubec twin model.

In their general model of twin concordance Allen and Hrubec recently introduced the concept of secondary ascertainment rate to consider partial ascertainment of secondary cases. This concept is found to be of limited interest because only pairs where valid information can be obtained from both twins should be included in genetic analyses. It is furthermore shown that the validity of the proband method and the Allen/Hrubec model depends on the equivalence of ascertainment in twins from concordant and discordant pairs. However, if this condition is fulfilled, it has been shown how the ascertainment probability in cotwins of probands is related to the overall ascertainment probability in the total population.

Nickel allergy in a female twin population.

The genetic predisposition of nickel allergy was evaluated in 1,546 Danish female twins born between 1906 and 1930. The twins were investigated primarily via a mailed questionnaire and were asked if they noticed redness, itching, or dermatitis when they came in contact with metal clasps or costume jewelry. The material was divided into two equal parts corresponding to the western and eastern parts of Denmark. The majority of the possible positives in the eastern part were examined and patch tested.

Abdominal wall defects in Denmark, 1970-89.

In the last two to three decades, increasing rates of gastroschisis but not of omphalocele have been reported from different parts of the world. The present study represents a register containing 469 children born with abdominal wall defects based on data retrieved from 20 birth cohorts (1970-89) in three nationwide registries. A tentative estimate of the completeness as regards identification of liveborn and stillborn infants is a minimum of 95% and 90% respectively. All cases were reclassified to 166 cases of gastroschisis, 258 of omphalocele and 16 of gross abdominal wall defect. The average point prevalence at birth of gastroschisis was 1.33 per 10 000 live and stillbirths. During the first decade, an increase in prevalence occurred culminating in 1976, followed by a decrease reaching its initial value in 1983 and then a new increase. Overall, no significant linear trend could be demonstrated for the entire period. The average point prevalence at birth for omphalocele was 2.07 and for gross abdominal wall defect 0.12 per 10 000 live and stillbirths with no significant change in the period. The geographical distribution of gastroschisis and omphalocele showed no difference per county.