Clinical Evaluation of Deep Learning for Tumor Delineation on 18F-FDG PET/CT of Head and Neck Cancer.

Artificial intelligence (AI) may decrease 18F-FDG PET/CT-based gross tumor volume (GTV) delineation variability and automate tumor-volume-derived image biomarker extraction. Hence, we aimed to identify and evaluate promising state-of-the-art deep learning methods for head and neck cancer (HNC) PET GTV delineation. Methods: We trained and evaluated deep learning methods using retrospectively included scans of HNC patients referred for radiotherapy between January 2014 and December 2019 (ISRCTN16907234). We used 3 test datasets: an internal set to compare methods, another internal set to compare AI-to-expert variability and expert interobserver variability (IOV), and an external set to compare internal and external AI-to-expert variability. Expert PET GTVs were used as the reference standard. Our benchmark IOV was measured using the PET GTV of 6 experts. The primary outcome was the Dice similarity coefficient (DSC). ANOVA was used to compare methods, a paired t test was used to compare AI-to-expert variability and expert IOV, an unpaired t test was used to compare internal and external AI-to-expert variability, and post hoc Bland-Altman analysis was used to evaluate biomarker agreement. Results: In total, 1,220 18F-FDG PET/CT scans of 1,190 patients (mean age ± SD, 63 ± 10 y; 858 men) were included, and 5 deep learning methods were trained using 5-fold cross-validation (n = 805). The nnU-Net method achieved the highest similarity (DSC, 0.80 [95% CI, 0.77-0.86]; n = 196). We found no evidence of a difference between expert IOV and AI-to-expert variability (DSC, 0.78 for AI vs. 0.82 for experts; mean difference of 0.04 [95% CI, -0.01 to 0.09]; P = 0.12; n = 64). We found no evidence of a difference between the internal and external AI-to-expert variability (DSC, 0.80 internally vs. 0.81 externally; mean difference of 0.004 [95% CI, -0.05 to 0.04]; P = 0.87; n = 125). PET GTV-derived biomarkers of AI were in good agreement with experts. Conclusion: Deep learning can be used to automate 18F-FDG PET/CT tumor-volume-derived imaging biomarkers, and the deep-learning-based volumes have the potential to assist clinical tumor volume delineation in radiation oncology.

Cotinine concentrations in maternal serum and amniotic fluid during pregnancy and risk of testicular germ cell cancer in the offspring: A prospective nested case-control study.

Maternal smoking in pregnancy may increase the risk of testicular germ cell cancer (TGCC) in offspring, but current evidence remains inconclusive. We performed a nested case-control study using cotinine measurements in maternal serum and amniotic fluid as a biomarker for tobacco exposure during pregnancy. A total of 654 males with maternal serum (n = 359, ncases/controls = 71/288) and/or amniotic fluid (n = 295, ncases/controls = 66/229) samples were included. Data on TGCC diagnoses and relevant covariates were derived from nationwide Danish health registries. Cotinine was quantified by liquid chromatography tandem mass spectrometry. An adapted cox regression model estimated the risk of TGCC considering active and inactive tobacco use defined according to cotinine concentrations of <, ≥15 ng/ml. Overall, the concentrations of cotinine were comparable in maternal serum and amniotic fluid (medianserum/amniotic fluid : 2.1/2.6 ng/ml). A strong statistically significant correlation was detected in 14 paired samples (Spearman rho: 0.85). Based on maternal serum cotinine concentrations, exposure to active tobacco use was not associated with risk of TGCC in offspring (HR 0.88, 95% CI 0.51; 1.52). Similarly, based on amniotic fluid cotinine concentrations, exposure to active tobacco use was not associated with risk of TGCC (HR 1.11, 95% CI 0.64; 1.95). However, different risks were observed for seminomas and nonseminomas in both matrices, but none were statistically significant. Our findings did not provide convincing evidence supporting that exposure to tobacco during pregnancy is associated with TGCC.

A Biphasic Pattern of Reproductive Hormones in Healthy Female Infants: The COPENHAGEN Minipuberty Study.

CONTEXT: Minipuberty, a period of a transient activation of the hypothalamic-pituitary-gonadal (HPG) axis in both sexes, enables evaluation of gonadal function in infants suspected of hypogonadism. However, female minipuberty remains poorly elucidated. OBJECTIVE: We aimed to establish continuous reference ranges for the most commonly used reproductive hormones and to evaluate the dynamics of the HPG axis in females aged 0 to 1 year. DESIGN: The COPENHAGEN Minipuberty Study (ClinicalTrials.gov ID: NCT02784184), a longitudinal, prospective cohort study. SETTING: Healthy infants from Copenhagen. PATIENTS OR OTHER PARTICIPANTS: A total of 98 healthy, term female infants followed with 6 examinations including venipuncture during the first year of life. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Serum concentrations of LH, FSH, inhibin B, anti-Müllerian hormone (AMH), estrone (E1), estradiol (E2), and SHBG were quantified using highly sensitive methods in 266 serum samples. RESULTS: Reference ranges were established for LH, FSH, inhibin B, AMH, E1, E2, and SHBG. Two peaks were observed in normalized mean curves for all hormones. The first peaks were timed around postnatal days 15 to 27 followed by a general nadir for all hormones around days 58 to 92. The second peaks occurred around days 107 to 125 for inhibin B, AMH, E1, E2, and SHBG and days 164 to 165 for LH and FSH. CONCLUSIONS: We present age-related, continuous reference ranges of the most commonly used reproductive hormones and present novel data revealing a biphasic and prolonged female minipuberty. CLINICALTRIALS.GOV ID: NCT02784184.

Endocrine Disrupting Chemicals and Risk of Testicular Cancer: A Systematic Review and Meta-analysis.

The incidence of many hormone-dependent diseases, including testicular cancer, has sharply increased in all high-income countries during the 20th century. This is not fully explained by established risk factors. Concurrent, increasing exposure to antiandrogenic environmental endocrine disrupting chemicals (EDCs) in fetal life may partially explain this trend. This systematic review assessed available evidence regarding the association between environmental EDC exposure and risk of testicular cancer (seminomas and nonseminomas). Following PRISMA guidelines, a search of English peer-reviewed literature published prior to December 14, 2020 in the databases PubMed and Embase® was performed. Among the 279 identified records, 19 were eligible for quality assessment and 10 for further meta-analysis. The completeness of reporting was high across papers, but over 50% were considered subject to potential risk of bias. Mean age at diagnosis was 31.9 years. None considered effects of EDC multipollutant mixtures. The meta-analyses showed that maternal exposure to combined EDCs was associated with a higher risk of testicular cancer in male offspring [summary risk ratios: 2.16, (95% CI:1.78-2.62), 1.93 (95% CI:1.49-2.48), and 2.78 (95% CI:2.27-3.41) for all, seminoma, and nonseminoma, respectively]. Similarly, high maternal exposures to grouped organochlorines and organohalogens were associated with higher risk of seminoma and nonseminoma in the offspring. Summary estimates related to postnatal adult male EDC exposures were inconsistent. Maternal, but not postnatal adult male, EDC exposures were consistently associated with a higher risk of testicular cancer, particularly risk of nonseminomas. However, the quality of studies was mixed, and considering the fields complexity, more prospective studies of prenatal EDC multipollutant mixture exposures and testicular cancer are needed.

Age-related renal function decline in Fabry disease patients on enzyme replacement therapy: a longitudinal cohort study.

BACKGROUND: Nephropathy is common in Fabry disease (FD). Prior studies of renal function during enzyme replacement therapy (ERT) have primarily used estimated glomerular filtration rate (eGFR). We studied the attrition of renal function in FD by measured GFR (mGFR) and urine protein excretion, and explored the influence of age. METHODS: This was a long-term observational study of a nationwide, family-screened cohort of FD patients. All Danish genetically verified FD patients on ERT, without end-stage renal disease at baseline and with three or more mGFR values were included. RESULTS: In all, 52 patients with consecutive mGFR values (n = 841) over median 7 years (range 1-13) were evaluated. Blood pressure remained normal and urine protein excretion was unchanged. Plasma globotriaosylceramide (Gb-3) levels normalized while plasma lyso-Gb-3 remained abnormal in 34% of patients. Baseline mGFR was 90 ± 3 mL/min/1.73 m2 and rate of renal function loss 0.9 ± 0.2 mL/min/1.73 m2/year. Baseline eGFR was 97 ± 5 mL/min/1.73 m2 and rate of renal function loss 0.8 ± 0.3 mL/min/1.73 m2/year. mGFR was age- adjusted to renal healthy non-FD subjects, giving a standard deviation score of -0.8 ± 0.2 with an annual slope of -0.03 ± 0.01 (P = 0.099), without differences between genders. Age grouping of age-adjusted data showed exaggerated renal function loss with age. Urine albumin-creatinine ratio (UACR) >300 mg/g was associated with faster renal function loss, independent of baseline mGFR, age and gender. CONCLUSIONS: ERT-treated FD patients did not have a faster attrition of renal function than renal healthy non-FD subjects (background population). The rate of renal function loss with age was independent of gender and predicted by high UACR. We suggest cautious interpretation of non-age-adjusted FD renal data.

A Longitudinal Study of Growth, Sex Steroids, and IGF-1 in Boys With Physiological Gynecomastia.

CONTEXT: Physiological gynecomastia is common and affects a large proportion of otherwise healthy adolescent boys. It is thought to be caused by an imbalance between estrogen and testosterone, although this is rarely evident in analyses of serum. OBJECTIVE: This study aimed to describe the frequency of physiological gynecomastia and to determine possible etiological factors (eg, auxology and serum hormone levels) in a longitudinal setup. DESIGN, SETTINGS, AND PARTICIPANTS: A prospective cohort study of 106 healthy Danish boys (5.8-16.4 years) participated in the longitudinal part of the COPENHAGEN Puberty Study. The boys were examined every 6 months during an 8-year follow-up. Median number of examinations was 10 (2-15). MAIN OUTCOME MEASUREMENTS: Blood samples were analyzed for FSH, LH, testosterone, estradiol, SHBG, inhibin B, anti-Müllerian hormone, IGF-1, and IGF binding protein-3 by immunoassays. Auxological parameters, pubertal development, and the presence of gynecomastia were evaluated at each visit. RESULTS: Fifty-two of 106 boys (49%) developed gynecomastia, of which 10 (19%) presented with intermittent gynecomastia. Boys with physiological gynecomastia reached peak height velocity at a significantly younger age than boys who did not develop gynecomastia (13.5 versus 13.9 years, P = .027), and they had significantly higher serum levels of IGF-1 (P = .000), estradiol (P = .013), free testosterone (P < .001), and FSH (P = .030) during pubertal transition. However, no differences in serum LH or in the estradiol to testosterone ratio were found. CONCLUSIONS: Gynecomastia is frequent in pubertal boys. Increased IGF-1 levels and pubertal growth appear to be associated, whereas changes in estrogen to testosterone ratio seem negligible.

Cancer mortality does not differ between migrants and Danish-born patients.

INTRODUCTION: The aim of this study was to compare cancer mortality among migrant patients with cancer mortality in Danish-born patients. MATERIAL AND METHODS: This was a historical prospective cohort study. All non-Western migrants (n = 56,273) who were granted a right to residency in Denmark between 1 January 1993 and 31 December 1999 were included and matched 1:4 on age and sex with Danish-born patients. Cancer patients in the cohort were identified through the Danish Cancer Registry and deaths and emigrations through the Central Population Register. Using a Cox regression model, mean sex-specific hazard ratio (HR) for all-cause mortality were estimated by ethnicity; adjusting for age, income, co-morbidity and disease stage. RESULTS: No significant differences were observed in mortality for gynaecological cancers between migrant women (HR = 1.12; 95% confidence interval (CI): 0.70-1.80) and Danish-born women. Correspondingly, migrant women (HR = 0.76; 95% CI: 0.49-1.17) showed no significant differences in breast cancer mortality compared with Danish-born women. Regarding lung cancer, neither migrant women (HR = 0.79; 95% CI: 0.45-1.40) nor men (HR = 0.73; 95% CI: 0.53-1.14) presented statistical variances in mortality rates compared with Danish-born patients. Similarly, for colorectal cancer, migrant women (HR = 0.64; 95% CI: 0.27-1.55) and men (HR = 1.58; 95% CI: 0.75-3.36) displayed no significant differences compared with Danish-born patients. CONCLUSION: Different trends were observed according to cancer type, but cancer mortality did not differ significantly between migrants and Danish-born patients. This may imply that the Danish health-care system provides equity in cancer care. FUNDING: The study was funded by the University of Copenhagen and Danielsens Fond. TRIAL REGISTRATION: not relevant.

Duration of residence and disease occurrence among refugees and family reunited immigrants: test of the 'healthy migrant effect' hypothesis.

OBJECTIVES: The 'healthy migrant effect' (HME) hypothesis postulates that health selection has a positive effect on migrants' health outcomes, especially in the first years after migration. We examined the potential role of the HME by assessing the association between residence duration and disease occurrence. METHODS: We performed a historical prospective cohort study. We included migrants who obtained residence permits in Denmark between 1 January 1993 and 31 December 2010 (n = 114,331). Occurrence of severe conditions was identified through linkage to the Danish National Patient Register. Hazard Ratios (HRs) were modelled for disease incidence by residence duration since arrival (0-5 years; 0-10 years; 0-18 years) adjusting for age and sex. RESULTS: Compared with Danish-born individuals, refugees and family reunited immigrants had lower HRs of stroke and breast cancer within 5 years after arrival; however, HRs increased at longer follow-up. For example, HRs of stroke among refugees increased from 0.77 (95% CI: 0.66; 0.91) to 0.96 (95% CI: 0.88; 1.05). For ischaemic heart disease (IHD) and diabetes, refugees and family reunited migrants had higher HRs within 5 years after arrival, and most HRs had increased by end of follow-up. For example, HRs of IHD among family reunited migrants increased from 1.29 (95% CI: 1.17; 1.42) to 1.43 (95% CI: 1.39; 1.52). In contrast, HRs for TB and HIV/AIDS showed a consistent decrease over time. CONCLUSION: Our analyses of the effect of duration of residence on disease occurrence among migrants imply that, when explaining migrants' advantageous health outcomes, the ruling theory of the HME should be used with caution, and other explanatory models should be included.

Inequalities in mortality among refugees and immigrants compared to native Danes--a historical prospective cohort study.

BACKGROUND: Comparisons of mortality patterns between different migrant groups, and between migrants and natives, are relevant to understanding, and ultimately reducing, inequalities in health. To date, European studies on migrants' mortality patterns are scarce and are based solely on country of birth, rather than migrant status. However, mortality patterns may be affected by implications in relation to migrant status, such as health hazards related to life circumstances before and during migration, and factors related to ethnic origin. Consequently, we investigated differences in both all-cause and cause-specific mortality from cancer and cardiovascular disease among refugees and immigrants, compared with the mortality among native Danes. METHODS: A register-based, historical prospective cohort design. All refugees (n = 29,139) and family-reunited immigrants (n = 27,134) who, between 1 January 1993 and 31 December 1999, were granted right of residence in Denmark were included and matched 1:4 on age and sex with native Danes. To identify deaths, civil registration numbers were cross-linked to the Register of Causes of Death (01.01.1994-31.12.2007) and the Danish Civil Registration System (01.01.1994-31.12.2008). Mortality rate ratios were estimated separately for men and women by migrant status and region of birth, adjusting for age and income and using a Cox regression model, after a median follow-up of 10-13 years after arrival. RESULTS: Compared with native Danes, all-cause mortality was significantly lower among female (RR = 0.78; 95%CI: 0.71;0.85) and male (RR = 0.64; 95%CI: 0.59-0.69;) refugees. The rates were also significantly lower for immigrants: women (RR = 0.44; 95%CI: 0.38;0.51) and men (RR = 0.43; 95%CI: 0.37;0.51). Both migrant groups also had lower cause-specific mortality from cancer and cardiovascular diseases. For both all-cause and cause-specific mortality, immigrants generally had lower mortality than refugees, and differences were observed according to ethnic origin. CONCLUSIONS: Mortality patterns were overall advantageous for refugees and immigrants compared with native Danes. Research should concentrate on disentangling the reasons behind migrants' health advantages, in order to enlighten future preventive public-health efforts, for the benefit of the entire population.

Early puberty in internationally adopted girls: hormonal and clinical markers of puberty in 276 girls examined biannually over two years.

BACKGROUND AND AIMS: Retrospective studies have indicated that internationally adopted girls are at high risk of developing precocious puberty. Hypothetically, this could be due to selection bias. The aim of this study was to determine age at reaching pubertal milestones in healthy internationally adopted girls in a prospective, clinical study. METHODS: A longitudinal cohort study including 276 randomly recruited internationally adopted girls. At baseline, age ranged from 4 to 13 years. Participants were followed with biannual examinations over a period of 2 years. Examinations included height, weight, Tanner staging, blood sampling and bone age assessment. Age distribution at entering pubertal stages B2-B5 (breast development), PH1-PH5 (pubic hair development) and menarche was estimated by probit analysis. Data were compared to a reference population of Danish-born girls, studied cross-sectionally. RESULTS: Mean age at B2+ was 9.5 years (95% prediction interval 7.1-12.0 years) and mean age at menarche was 12.1 (10.2-14.0) years in adopted girls, which was significantly lower compared to the reference group (p < 0.0003). 16% of adopted girls entered stage B2 before 8 years of age. The puberty-related rise in LH, FSH and estradiol was detected at earlier ages in adopted girls compared to the reference group. CONCLUSION: Internationally adopted girls have a significantly higher risk of precocious pubertal maturation compared to Danish-born girls.

Narrow intra-individual variation of maternal thyroid function in pregnancy based on a longitudinal study on 132 women.

BACKGROUND: Adaptive alterations in maternal physiology cause changes in thyroid hormone levels throughout pregnancy, and precise biochemical evaluation is thus highly dependent on gestation-specific reference intervals and expected intra-individual variation. OBJECTIVE: The aim of the study was the assessment of the intra-individual variation as well as the longitudinal course of thyroid hormones during normal pregnancy and factors that influence the normal reference range for thyroid function. For this purpose, a longitudinal statistical model was applied. DESIGN: In a cohort of 132 pregnant women, serial blood samples were obtained and ultrasound scans were performed throughout pregnancy. METHODS: Serum levels of TSH, free and total thyroxine (T(4)), free and total triiodothyronine (T(3)) as well as autoantibodies against thyroid peroxidase and thyroglobulin were measured in 979 serum samples. RESULTS: Intra-individual variations of thyroid hormone concentrations were smaller than inter-individual variations (individuality index range: 0.38-0.71). Maternal height was positively associated with free T(4) (FT(4)) (b=0.003; P=0.031) and pre-pregnancy body mass index with T(3) and free T(3) (b=0.017; <0.001 and b=0.007; P<0.001). Smoking was positively associated with T(4) and FT(4), but it was modulated by gestational age. Gestation-specific reference intervals for thyroid function variables from autoantibody-negative participants are presented. CONCLUSIONS: In accordance with the data from nonpregnant adults, intra-individual variations of thyroid hormones were smaller than inter-individual variations also during pregnancy. In the evaluation of thyroid function in pregnancy, the individual longitudinal course of thyroid hormones rather than absolute values should be considered. We present a longitudinal model for the prediction of maternal thyroid function tests in pregnant women.

Recent decline in age at breast development: the Copenhagen Puberty Study.

OBJECTIVE: Recent publications showing unexpectedly early breast development in American girls created debate worldwide. However, secular trend analyses are often limited by poor data comparability among studies performed by different researchers in different time periods and populations. Here we present new European data systematically collected from the same region and by 1 research group at the beginning and end of the recent 15-year period. METHODS: Girls (N = 2095) aged 5.6 to 20.0 years were studied in 1991-1993 (1991 cohort; n = 1100) and 2006-2008 (2006 cohort; n = 995). All girls were evaluated by palpation of glandular breast, measurement of height and weight, and blood sampling (for estradiol, luteinizing hormone, and follicle-stimulating hormone). Age distribution at entering pubertal breast stages 2 through 5, pubic hair stages 2 through 5, and menarche was estimated for the 2 cohorts. RESULTS: Onset of puberty, defined as mean estimated age at attainment of glandular breast tissue (Tanner breast stage 2+), occurred significantly earlier in the 2006 cohort (estimated mean age: 9.86 years) when compared with the 1991 cohort (estimated mean age: 10.88 years). The difference remained significant after adjustment for BMI. Estimated ages at menarche were 13.42 and 13.13 years in the 1991 and 2006 cohorts, respectively. Serum follicle-stimulating hormone and luteinizing hormone did not differ between the 2 cohorts at any age interval, whereas significantly lower estradiol levels were found in 8- to 10-year-old girls from the 2006 cohort compared with similarly aged girls from the 1991 cohort. CONCLUSIONS: We found significantly earlier breast development among girls born more recently. Alterations in reproductive hormones and BMI did not explain these marked changes, which suggests that other factors yet to be identified may be involved.

Testosterone production is better preserved after 16 than 20 Gray irradiation treatment against testicular carcinoma in situ cells.

PURPOSE: To study the effect of 16 Gy radiotherapy (RT) vs. 20 Gy RT on Leydig cell function in men treated with radiotherapy against carcinoma in situ (CIS) of the testis. METHODS AND MATERIALS: Fifty-one men who were treated between 1985 and 2005 were included. Fourteen men had been treated with 20 Gy and 37 with 16 Gy RT. Measurements of sex hormone-binding globulin and basic and stimulated testosterone, as well as luteinizing hormone levels were performed. RESULTS: The follow-up periods for the patients treated without additional chemotherapy were for the 20 Gy and 16 Gy group mean/median/min-max: 9.0/10.0/1.0-20.3 years and 4.0/3.1/0.4-14.1 years, respectively. During the follow-up period, men treated with 16 Gy RT had stable testosterone levels (-1.1%/year, p = 0.4), whereas men treated with 20 Gy had an annual decrease of 2.4% (p = 0.008). For the latter group, the testosterone decrease was most pronounced in the first 5 years, leveling off during the following 5 years. Additionally, more men treated with 20 Gy needed androgen substitution treatment. Our study showed an increased luteinizing hormone level for the men treated with 16 Gy, although this was not significant (p = 0.5). We anticipated a similar increase in the patients treated with 20 Gy but instead observed a decrease (-3.1%, p = 0.01). CONCLUSION: RT at 16 and 20 Gy seem to affect Leydig cell function differently, with 16 Gy RT better preserving testosterone levels and thus being preferred from an endocrinological point of view.

Risk factors for congenital cryptorchidism in a prospective birth cohort study.

BACKGROUND: Risk factors for congenital cryptorchidism were investigated in a prospective birth cohort study in Denmark and Finland from 1997 to 2001. METHODOLOGY AND PRINCIPAL FINDINGS: In total, 2,496 boys were examined for cryptorchidism at birth (cryptorchid/healthy: 128/2,368) and three months old (33/2,215). Information on risk factors was obtained antenatally (questionnaire/interview) or at birth from birth records. Use of nicotine substitutes during pregnancy (n = 40) and infertility treatment by intrauterine insemination (n = 49) were associated with an increased risk for cryptorchidism, adjusted odds ratio (95% confidence interval) (OR (95%CI)) 3.04 (95%CI 1.00-9.27) and 3.01 (95%CI 1.27-7.15), respectively. No association was seen for mothers (n = 79) who had infertility treatment in form of intracytoplasmic sperm injection (ICSI) or in vitro fertilization (IVF) treatment (OR 0.71 95%CI 0.21-2.38). In total, 728 (29%) reported to have smoked during pregnancy, however, no increased risk among maternal smokers was found. Furthermore, we found statistically significant associations between cryptorchidism and low birth weight, prematurity, being small for gestational age, substantial vaginal bleeding, and breech presentation, which are in accordance with other studies. CONCLUSIONS AND SIGNIFICANCE: Our study revealed two novel risk factors for cryptorchidism: intrauterine insemination and the use of nicotine substitutes in pregnancy. This suggests that cryptorchidism may not only be associated to genetic factors, but also to maternal lifestyle and exposure.

Increasing incidence of ophthalmic lymphoma in Denmark from 1980 to 2005.

PURPOSE: To evaluate patient characteristics and incidence of ophthalmic lymphoma in Denmark during the period 1980 to 2005. METHODS: All patients in Denmark with a diagnosis of ophthalmic lymphoma during the period 1980 to 2005 were retrieved from three different population-based registries. Specimens from all patients were collected and reclassified according to the World Health Organization (WHO) classification system. Incidence rates were calculated by using Poisson regression models. RESULTS: A total of 228 patients with a histologically verified diagnosis of ophthalmic lymphoma were included. There was an equal distribution of males and females. The most frequent lymphoma subtype was extranodal marginal zone B-cell lymphoma (MALT [mucosa-associated lymphoid tissue] lymphoma, 55.5%) and most cases were located in the orbit (56.8%). High-grade lymphoma subtypes were found more frequently in males than in females. Incidence rates were highly dependent on the patient's age. For all ages, a statistically significant annual average increase of 3.4% during the 26-year period was found. This increase was primarily due to a rise in the incidence of MALT lymphoma. CONCLUSIONS: In the Danish population ophthalmic lymphoma consists primarily of orbital MALT lymphoma. Although it is a rare disease in mostly elderly patients, the incidence of ophthalmic lymphoma is increasing at a rapid pace.

Secular decline in male testosterone and sex hormone binding globulin serum levels in Danish population surveys.

CONTEXT: Adverse secular trends in male reproductive health have been reported to be reflected in increased testicular cancer risk and decreased semen quality in more recently born men. These secular trends may also be reflected by changes in Leydig cell function. OBJECTIVE: The objective of the study was to examine whether an age-independent time trend in male serum testosterone levels exists. DESIGN AND SETTING: Testosterone and SHBG were analyzed in 5350 male serum samples from four large Danish population surveys conducted in 1982-1983, 1986-1987, 1991-1992, and 1999-2001. Free testosterone levels were calculated. The effects of age, year of birth, and time period on hormone levels were estimated in a general linear statistical model. MAIN OUTCOME MEASURES: Testosterone, SHBG, and calculated free testosterone levels in Danish men in relation to age, study period, and year of birth were measured. RESULTS: Serum testosterone levels decreased and SHBG levels increased with increasing age. In addition to this expected age effect, significant secular trends in testosterone and SHBG serum levels were observed in age-matched men with lower levels in the more recently born/studied men. No significant age-independent effect was observed for free testosterone. Adjustment for a concurrent secular increase in body mass index reduced the observed cohort/period-related changes in testosterone, which no longer were significant. The observed cohort/period-related changes in SHBG levels remained significant after adjustment for body mass index. CONCLUSIONS: The observed age-independent changes in SHBG and testosterone may be explained by an initial change in SHBG levels, which subsequently lead to adjustment of testosterone at a lower level to sustain free testosterone levels.

Testicular carcinoma in situ in subfertile Danish men.

Carcinoma in situ (CIS) testis is the precursor stage for the majority of testicular germ cell tumours (TGCT). Infertility is one of the conditions known to predispose to TGCT, but based on scarce existing data, the prevalence of CIS in this risk group was estimated at only approximately 1%. To establish more objective data, we investigated retrospectively the prevalence of CIS based on testicular biopsies performed in a well-defined group of subfertile males. We included 453 patients who had testicular biopsies performed for infertility reasons during 1995-2005 at the Copenhagen University Hospital (Rigshospitalet). Biopsies were evaluated by two experienced observers independently. CIS was detected in 10 individuals, of whom three had bilateral CIS, corresponding to a prevalence of 2.2% (95% CI 1.1-4.0%). This is greater than the estimated risk of 0.45% for the age- and birth cohort-matched general Danish population. All patients with CIS testis had severe oligozoospermia (

Early pituitary-gonadal activation before clinical signs of puberty in 5- to 8-year-old adopted girls: a study of 99 foreign adopted girls and 93 controls.

CONTEXT: Recent studies have indicated that internationally adopted girls are at high risk of developing precocious puberty. Clinical studies including a contemporary control group are lacking. OBJECTIVE: The objective was to study clinical, biochemical, and ultrasonographic markers of pituitary-gonadal activation in prepubertal adopted girls and a control group in the same age categories. SETTING: The study took place at University Hospital, Copenhagen, Denmark. DESIGN AND PARTICIPANTS: The study included randomly selected internationally adopted girls [(n = 99; mean age, 6.9 (5.1-8.5) yr] and controls of Danish origin [n = 93; mean age, 6.8 (5.2-8.5) yr] who were studied cross-sectionally. METHODS: Height, weight, and pubertal stage were assessed with serum levels of reproductive hormones. Size and morphology of internal genitals were evaluated by ultrasonography. Bone age was evaluated by x-ray of the left hand. RESULTS: Serum values of FSH were significantly higher in prepubertal adopted girls compared with controls [median, 1.4 (95% confidence interval, 0.4-3.6) vs. 1.0 (0.4-2.4) IU/liter; P <0.001]. Serum estradiol was above detection limit (>18 pmol/liter) in 46.5% of prepubertal adopted girls and 20.7% of controls (P = 0.001). In prepubertal adopted girls, the proportion of measurable samples increased significantly with age [odds ratio, 2.5 (95% confidence interval, 1.3-5.0; P = 0.009]. In controls, the odds ratio was 1.0 (0.6-1.7) (P = 0.9). Serum SHBG levels were significantly lower in prepubertal adopted girls compared with controls [99.0 (50.4-153.0) vs. 115.0 (53.1-202.1); P < 0.001]. CONCLUSION: Five- to 8-yr-old adopted girls showed signs of increased pituitary as well as gonadal activity despite prepubertal phenotype in the majority of girls. Our findings suggest that early onset of puberty in adopted girls is centrally driven.

Cryptorchidism and maternal alcohol consumption during pregnancy.

BACKGROUND: Prenatal exposure to alcohol can adversely affect the fetus. We investigated the association between maternal alcohol consumption during pregnancy and cryptorchidism (undescended testis) among newborn boys. METHODS: We examined 2,496 boys in a prospective Danish-Finnish birth cohort study for cryptorchidism at birth (cryptorchid/healthy: 128/2,368) and at 3 months of age (33/2,215). Quantitative information on alcohol consumption (average weekly consumption of wine, beer, and spirits and number of binge episodes), smoking, and caffeine intake was obtained by questionnaire and/or interview once during the third trimester of pregnancy, before the outcome of the pregnancy was known. For a subgroup (n = 465), information on alcohol consumption was obtained twice during pregnancy by interviews. RESULTS: We investigated maternal alcohol consumption both as a continuous variable and categorized. The odds for cryptorchidism increased with increasing weekly alcohol consumption. After adjustment for confounders (country, smoking, caffeine intake, binge episodes, social class, maternal age, parity, maturity, and birth weight) the odds remained significant for women with a weekly consumption of five or more alcoholic drinks (odds ratio = 3.10; 95% confidence interval, 1.05-9.10). CONCLUSIONS: Regular alcohol intake during pregnancy appears to increase the risk of congenital cryptorchidism in boys. The mechanisms for this association are unknown. Counseling of pregnant women with regard to alcohol consumption should also consider this new finding.

CLLU1 expression analysis adds prognostic information to risk prediction in chronic lymphocytic leukemia.

We recently identified a disease-specific gene CLLU1 in chronic lymphocytic leukemia (CLL) and also demonstrated that high CLLU1 expression levels predict poor clinical outcome. To validate this finding, we measured CLLU1 mRNA expression levels by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) in 175 patients with CLL. Analyses of IgV(H) mutational status, ZAP-70 expression, CD38 expression, and chromosomal aberrations were also performed. High levels of CLLU1 expression were associated with shorter overall survival (P < .001), with a 7% increase in risk of early death by each doubling of the CLLU1 expression level. Stratification for age at diagnosis demonstrated a strong prognostic significance of CLLU1 expression in patients younger than 70 years (P < .001), but not in patients aged 70 or older (P = .61). The prognostic significance of IgV(H) mutational status and ZAP-70 expression had a similar age-dependent variation. Multivariate analysis in the younger age group showed that CLLU1 expression analysis added further prognostic information within all prognostic subgroups, with the exception of patients with unmutated IgV(H) CLL. Only CLLU1 expression and IgV(H) mutational status had independent predictive power. Thus, analysis of CLLU1 expression is highly applicable in risk prediction in CLL for patients of an age eligible for risk stratification.