Associations between pregnancy-related factors and birth characteristics with risk of rare uterine cancer subtypes: a Nordic population-based case-control study.

PURPOSE: Uterine sarcomas are a rare group of uterine malignancies. Due to the low incidence and changes in uterine sarcoma classification, risk factors are not well characterized. Our objective was to evaluate risk factors for uterine sarcoma and compare risk factors between uterine sarcoma, malignant mixed Mullerian tumors (MMMTs), and type I endometrial carcinomas. METHODS: This nested case-control study utilized linked data from population-based medical birth and cancer registries in Denmark, Finland, Norway, and Sweden. Up to 10 controls were matched on country and birth year for each uterine cancer case. Using multivariable adjusted multinomial logistic regression, estimates of the associations between pregnancy-related factors and risk of uterine sarcoma, MMMTs, and type I endometrial carcinomas were determined. RESULTS: Having a very-low-birth-weight infant (< 1500 vs. 2500-3999 g: OR [95% CI] 2.83 [1.61-4.96]) was associated with an increased risk of uterine sarcoma. Whereas, having a more recent pregnancy was associated with reduced risks of MMMT (< 10 vs. ≥ 30 years: 0.66 [0.20-2.23]) and type 1 endometrial carcinomas (0.35 [0.30-0.41]) but not uterine sarcomas (1.33 [0.90-1.98], p-heterogeneity < 0.01). CONCLUSION: Our study provides evidence that risk factors for uterine sarcoma and MMMT, previously grouped with uterine sarcomas, vary substantially. Additionally, MMMT and type I endometrial carcinomas are more similar than uterine sarcoma in that pregnancy complications like gestational hypertension and preeclampsia were associated with reduced risks of both but not uterine sarcoma, suggesting different etiologies.

Osteonecrosis of the jaw among patients with cancer treated with denosumab or zoledronic acid: Results of a regulator-mandated cohort postauthorization safety study in Denmark, Norway, and Sweden.

BACKGROUND: Osteonecrosis of the jaw (ONJ) is an adverse effect of antiresorptive treatment. This study estimated incidence proportions and incidence rates of ONJ in cancer patients with bone metastases from solid tumors treated for the prevention of skeletal-related events in routine clinical practice. METHODS: This cohort study in Denmark, Norway, and Sweden in 2011-2018 included 3 treatment cohorts: a denosumab inception cohort (DEIC), a zoledronic acid inception cohort (ZAIC), and a denosumab-switch cohort (DESC). The authors estimated 1- to 5-year incidence proportions and incidence rates of ONJ overall, by cancer site (breast, prostate, or other solid tumor), and by country. ONJ diagnoses were confirmed by adjudication. RESULTS: There were 1340 patients in the DEIC, 1352 in the ZAIC, and 408 in the DESC. The median ages of the 3 cohorts were 70, 69, and 70 years, respectively; the proportions of men were 72.6%, 53.8%, and 48.3%, respectively; and the median follow-up was 19.8, 12.9, and 13.3 months, respectively. The 5-year incidence proportions of ONJ were 5.7% (95% confidence interval [CI], 4.4%-7.3%) in the DEIC, 1.4% (95% CI, 0.8%-2.3%) in the ZAIC, and 6.6% (95% CI, 4.2%-10.0%) in the DESC. The corresponding ONJ incidence rates per 100 person-years were 3.0 (95% CI, 2.3-3.7), 1.0 (95% CI, 0.6-1.5), and 4.3 (95% CI, 2.8-6.3). Incidence proportions and incidence rates were highest in patients with prostate cancer and in Denmark. CONCLUSIONS: This study provides estimates of the risk of medically confirmed ONJ among patients initiating denosumab or zoledronic acid in routine clinical practice in 3 Scandinavian countries. The results varied by cancer site and by country. LAY SUMMARY: Denosumab and zoledronic acid reduce the risk of bone fractures, pain, and surgery in patients with advanced cancers involving bone. Osteonecrosis of the jaw (ONJ)-death of a jawbone-is a known side effect of treatment with denosumab or zoledronic acid. The authors examined almost 2900 denosumab- or zoledronic acid-treated patients with cancer in Denmark, Norway, and Sweden. Over the course of 5 years, ONJ developed in 5.7% of the patients whose initial treatment was denosumab, in 1.4% of the patients whose initial treatment was zoledronic acid, and in 6.6% of the patients who switched from zoledronic acid to denosumab.

Associations of pregnancy-related factors and birth characteristics with risk of endometrial cancer: A Nordic population-based case-control study.

Many pregnancy-related factors are associated with reduced endometrial cancer risk. However, it remains unclear whether pregnancy-related complications (e.g., hypertensive conditions) are associated with risk and whether these associations vary by endometrial cancer subtype. Thus, we evaluated the risk of endometrial cancer, overall and by subtype, in relation to pregnancy-related factors, pregnancy complications and birth characteristics. Utilizing population-based register data from four Nordic countries, we conducted a nested case-control analysis of endometrial cancer risk. We included 10,924 endometrial cancer cases and up to 10 matched controls per case. Odds ratios (ORs) with 95% confidence intervals (CIs) were derived from unconditional logistic regression models. We further evaluated associations by individual histology (i.e., endometrioid, serous, etc.) or, for rare exposures (e.g., pregnancy complications), by dualistic type (Type I [n = 10,343] and Type II [n = 581]). Preexisting and pregnancy-related hypertensive conditions were associated with increased endometrial cancer risk (OR [95% CI]: preexisting hypertension 1.88 [1.39-2.55]; gestational hypertension 1.47 [1.33-1.63]; preeclampsia 1.43 [1.30-1.58]), with consistent associations across dualistic type. Increasing number of pregnancies (≥4 vs. 1 birth: 0.64 [0.59-0.69]) and shorter time since last birth (<10 vs. ≥30 years: 0.34 [0.29-0.40]) were associated with reduced endometrial cancer risk, with consistent associations across most subtypes. Our findings support the role for both hormonal exposures and cell clearance as well as immunologic/inflammatory etiologies for endometrial cancer. This research supports studying endometrial hyperplasia, a precursor condition of endometrial cancer, in the context of pregnancy-related exposures, as this may provide insight into the mechanisms by which pregnancy affects subsequent cancer risk.

Pregnancy-related risk factors for sex cord-stromal tumours and germ cell tumours in parous women: a registry-based study.

BACKGROUND: Non-epithelial ovarian cancers are divided into sex cord-stromal tumours (SCSTs) and germ cell tumours (GCTs). Whereas parity and other pregnancy-related factors are protective for epithelial ovarian cancer, their associations with SCSTs and GCTs remains unclear. METHODS: Using data from the medical birth registries from Denmark, Finland, Norway and Sweden, we compared all parous women with a diagnosis of SCSTs (n = 420) or GCTs (n = 345) 1970-2013 with up to 10 parous controls (SCSTs n = 4041; GCTs n = 2942) matched on the cases' birth year and country. We used conditional logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CIs) of associations between pregnancy-related factors and SCSTs and GCTs. RESULTS: The risk of SCSTs, but not GCTs, decreased with higher age at last birth [≥40 versus <25 years: OR 0.48 (95% CI 0.23-0.98)]. The risk of SCSTs (but not GCTs) also decreased with shorter time since last birth. Number of births, preterm birth, preeclampsia, and offspring size were not associated with risk of SCSTs or GCTs. CONCLUSIONS: We found a decreased risk of SCSTs with higher age at last birth and shorter time since last birth. The risk of SCSTs (but not GCTs) may be influenced by the woman's reproductive history.

Women who develop ovarian cancer show an increase in serum calcium and a decrease in serum albumin. A longitudinal study in the Janus Serum Bank Cohort.

BACKGROUND: Ovarian cancer is associated with high serum calcium and low serum albumin in clinical and epidemiologic studies. Whether high calcium and low albumin predispose to ovarian cancer or reflect existing cancer is unclear. OBJECTIVE: Test the hypothesis that serum calcium increases and serum albumin decreases in women who develop ovarian cancer. METHODS: Two hundred and four women donated sera to the Janus Serum Bank in Norway pre- and post-diagnosis of ovarian cancer, donations separated by approximately 14 years. We measured calcium and albumin in these sera and calculated the albumin-corrected calcium. Sera were adjusted for patient age and storage time. RESULTS: Post-diagnosis, mean age- and storage-adjusted calcium increased, from 2.53 to 2.68 mmol/L (p < .001). Mean age- and storage-adjusted, albumin-corrected calcium increased from 2.3 to 2.7 mmol/L (p < .001). Conversely, mean age- and storage-adjusted albumin decreased, from a mean of 51.3 to 40.9 g/L (p < .001). Significant changes were observed in women with early stage and metastatic cancer. CONCLUSIONS: These data support the hypothesis that calcium and albumin are serum biomarkers of extant ovarian cancer. Longitudinal changes in calcium and albumin may be useful in ovarian cancer early detection.

Birthweight and all-cause mortality after childhood and adolescent leukemia: a cohort of children with leukemia from Denmark, Norway, Sweden, and Washington State.

Background: High birthweight may predispose children to acute lymphoid leukemia, whereas low birthweight is associated with childhood morbidity and mortality. Low and high birthweight have been inconsistently associated with mortality in children with leukemia.Material and methods: In a cohort of childhood and adolescent leukemia (0-19 years) patients from registries in Denmark, Norway, Sweden, and Washington State in the United States (1967-2015), five-year all-cause mortality was assessed by birthweight and other measures of fetal growth using the cumulative incidence function and Cox regression with adjustment for sex, diagnosis year, country, the presence of Down's syndrome or other malformations, and type of leukemia.Results: Among 7148 children and adolescents with leukemia (55% male), 4.6% were low (<2500 g) and 19% were high (≥4000 g) birthweight. Compared with average weight, hazard ratios (HRs) of death associated with low birthweight varied by age at leukemia diagnosis: 1.5 (95% confidence interval (CI): 0.7, 3.2) for patients 0-1 year old, 1.6 (95% CI: 1.0, 2.6) for >1-2 years old; 1.0 (95% CI: 0.6, 1.5) for 3-8 years old; 1.0 (95% CI: 0.6, 1.8) for 9-13 years old; and 1.2 (95% CI: 0.7, 2.1) for 14-19 years old, and were similar for size for gestational age and Ponderal index. In analyses restricted to children born full term (37-41 weeks of gestation), results were only slightly attenuated but risk was markedly increased for infants aged ≤1 year (HR for low birthweight = 3.2, 95% CI: 1.2, 8.8).Conclusion: This cohort study does not suggest that low birthweight or SGA is associated with increased five-year all-cause mortality risk among children with any type of childhood leukemia or acute lymphoblastic leukemia, specifically, beyond infancy.

Maternal reproductive hormones and angiogenic factors in pregnancy and subsequent breast cancer risk.

PURPOSE: Breast cancer risk associated with pregnancy characteristics may be mediated by maternal hormones or angiogenic factors. METHODS: We conducted a prospective breast cancer case-control study among women in the Avon Longitudinal Study of Parents and Children (ALSPAC) and Norwegian Mother and Child Cohort Study (MoBa) related to maternal pregnancy prolactin (n = 254 cases and 374 controls), placental growth factor (PlGF, n = 252 and 371), soluble fms-like tyrosine kinase-1 (sFlt-1, n = 118 and 240) and steroid hormone concentrations (ALSPAC only, n = 173 and 171). Odds ratios (OR) and 95% confidence intervals (CI) for a 1 SD change in analytes were estimated using unconditional logistic regression with matching factors (cohort, mother's birth year, serum/plasma, blood collection timing) and gestational age. RESULTS: Breast cancer ORs (95% CI) were 0.85 (0.51-1.43) for estradiol, 0.86 (0.67-1.09) for testosterone, 0.89 (0.71-1.13) for androstenedione, 0.97 (0.71-1.34) for hCG, 0.93 (0.75, 1.15) for prolactin, 1.00 (0.78-1.27) for PlGF and 1.91 (1.00-3.65 ALSPAC) and 0.94 (0.73-1.21 MoBa) for sFlt-1, and were similar adjusting for potential confounders. Results were similar by blood collection timing, parity, age at first birth or diagnosis, and time between pregnancy and diagnosis. CONCLUSION: These data do not provide strong evidence of associations between maternal hormones or angiogenic factors with subsequent maternal breast cancer risk.

Short-term survival after colorectal cancer in a screened versus unscreened population.

Aims: United States' (US) colorectal cancer (CRC) screening and treatment practices seek to reduce mortality. We examined the survival of US patients compared with patients in the virtually unscreened Norwegian population. Methods: We compared short-term survival after CRC between the US and Norway using relative survival (RS) and excess mortality (EMR) analyses. The CRC patients were aged 50 and older diagnosed in the US (Surveillance, Epidemiology and End Results registry, 2004, N=9511) and in Norway (Cancer Registry of Norway, 2003-2005, N=8256). Results: Death occurred within three years for 39% of the CRC patients. Stage distributions were more favorable for US patients. Stage-specific survival was similar for localized and regional cancers, but more favorable for US distant cancers. In multivariate models of patient, tumor and treatment characteristics, patients (especially below age 80) in the US experienced longer survival (EMR 0.9, CI 0.8-0.9). Stage-specific analyses showed, however, that survival for localized cancers was relatively shorter in the US than in Norway (EMR 1.4, CI 1.1-1.8), but longer for distant cancers (EMR 0.8, CI 0.7-0.8). Conclusions: The enhanced survival for US CRC patients likely reflects a screening-related earlier diagnostic stage distribution, as well as prioritized life extension for patients with metastatic cancers, reflecting vastly different health care systems in the two countries. CRC screening is currently under consideration in Norway. For survival outcomes, the current findings do not discourage such an implementation. Other screening-related aspects such as feasibility and cost-benefit are, however, also relevant and warrant further research within a socialized health system.

Pregnancy complications and subsequent breast cancer risk in the mother: a Nordic population-based case-control study.

Certain features of pregnancy are important risk factors for breast cancer, such as protection afforded by young age at first birth. Preeclampsia, a pregnancy complication, is associated with reduced maternal breast cancer risk. However, questions remain regarding causality, biological mechanisms and the relation of other hypertensive conditions to risk. We conducted a population-based case-control study of breast cancer cases (n = 116,196) in parous women identified through linkage of birth and cancer registries in Denmark, Finland, Norway and Sweden (1967-2013), including up to 10 matched controls per case (n = 1,147,192) sampled from the birth registries (complete data were not available on all variables). Odds ratios (ORs) with 95% confidence intervals (CIs) were derived from unconditional logistic regression models including matching factors (country, maternal birth year) and parity. Hypertension diagnosed before pregnancy (OR 0.87; 95% CI 0.78-0.97), gestational hypertension (OR 0.90; 95% CI 0.86-0.93) and preeclampsia (OR 0.91; 95% CI 0.88-0.95) were associated with reduced breast cancer risk. Results remained similar after adjustment for smoking and maternal body mass index before first pregnancy, and were generally similar stratified by parity, age at breast cancer diagnosis, time since first and last birth, sex of the offspring and calendar time. Except for retained placenta (OR 1.14; 95% CI 0.98-1.32), no other pregnancy complication appeared associated with breast cancer risk. The mechanisms mediating the modest risk reductions for history of preeclampsia or hypertension preceding or arising during pregnancy, and possible increased risk with history of retained placenta are unknown and warrant further laboratory, clinical and epidemiological investigation.

Preterm delivery is associated with an increased risk of epithelial ovarian cancer among parous women.

Epithelial ovarian cancer is a fatal disease of largely unknown etiology. Higher parity is associated with reduced risk of ovarian cancer. However, among parous women, the impact of pregnancy-related factors on risk is not well understood. This population-based case-control study included all parous women with epithelial ovarian cancer in Denmark, Finland, Norway and Sweden during 1967-2013 (n = 10,957) and up to 10 matched controls (n = 107,864). We used conditional logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for pregnancy-related factors and ovarian cancer risk by histological subtype. Preterm delivery was associated with an increased risk [pregnancy length (last pregnancy) ≤30 vs. 39-41 weeks, OR 1.33 (95% CI 1.06-1.67), adjusted for number of births]; the OR increased as pregnancy length decreased (p for trend < 0.001). Older age at first and last birth was associated with a decreased risk [first birth: 30-39 vs. <25 years: adjusted OR 0.76 (95% CI 0.70-0.83); last birth 30-39 vs. <25 years: adjusted OR 0.76 (95% CI 0.71-0.82)]. Increasing number of births was protective [≥4 births vs. 1; OR 0.63 (95% CI 0.59-0.68)] for all subtypes, most pronounced for clear-cell tumors [OR 0.30, (95% CI 0.21-0.44), pheterogeneity < 0.001]. No associations were observed for multiple pregnancies, preeclampsia or offspring size. In conclusion, in addition to high parity, full-term pregnancies and pregnancies at older ages were associated with decreased risk of ovarian cancer. Our findings favor the cell clearance hypothesis, i.e. a recent pregnancy provides protection by clearing of precancerous cells from the epithelium of the ovary/fallopian tubes, mediated by placental or ovarian hormones.

Risk of bladder cancer by disease severity in relation to metabolic factors and smoking: A prospective pooled cohort study of 800,000 men and women.

Previous studies on metabolic factors and bladder cancer (BC) risk have shown inconsistent results and have commonly not investigated associations separately by sex, smoking, and tumor invasiveness. Among 811,633 participants in six European cohorts, we investigated sex-specific associations between body mass index (BMI), mid-blood pressure (BP, [systolic + diastolic]/2), plasma glucose, triglycerides, total cholesterol and risk of BC overall, non-muscle invasive BC (NMIBC) and muscle invasive BC (MIBC). Among men, we additionally assessed additive interactions between metabolic factors and smoking on BC risk. During follow-up, 2,983 men and 754 women were diagnosed with BC. Among men, triglycerides and BP were positively associated with BC risk overall (hazard ratio [HR] per standard deviation [SD]: 1.17 [95% confidence interval (CI) 1.06-1.27] and 1.09 [1.02-1.17], respectively), and among women, BMI was inversely associated with risk (HR: 0.90 [0.82-0.99]). The associations for BMI and BP differed between men and women (pinteraction ≤ 0.005). Among men, BMI, cholesterol and triglycerides were positively associated with risk for NMIBC (HRs: 1.09 [95% CI 1.01-1.18], 1.14 [1.02-1.25], and 1.30 [1.12-1.48] respectively), and BP was positively associated with MIBC (HR: 1.23 [1.02-1.49]). Among women, glucose was positively associated with MIBC (HR: 1.99 [1.04-3.81]). Apart from cholesterol, HRs for metabolic factors did not significantly differ between MIBC and NMIBC, and there were no interactions between smoking and metabolic factors on BC. Our study supports an involvement of metabolic aberrations in BC risk. Whilst some associations were significant only in certain sub-groups, there were generally no significant differences in associations by smoking or tumor invasiveness.

Cancer After Liver Transplantation in Children and Young Adults: A Population-Based Study From 4 Nordic Countries.

Cancer after liver transplantation (LT) constitutes a threat also for young recipients, but cancer risk factors are usually absent in children and large studies on the cancer risk profile in young LT recipients are scarce. Data of patients younger than 30 years who underwent LT during the period 1982-2013 in the Nordic countries were linked with respective national cancer registries to calculate standardized incidence ratios (SIRs). A total of 37 cancer cases were observed in 923 patients with 7846 person-years of follow-up. The SIR for all cancer types, compared with the matched general population, was 9.8 (12.4 for males and 7.8 for females). Cumulative incidence of cancer adjusted for the competing risk of death was 2% at 10 years, 6% at 20 years, and 22% at 25 years after LT. Non-Hodgkin lymphoma was the most common cancer type (n = 14) followed by colorectal (n = 4) and hepatocellular cancer (n = 4). Age was a significant risk factor for cancer, and the absolute risk of most cancers (except for lymphoma) increased considerably in young adults older than 20 years. The cancer risk pattern is different in pediatric and young LT patients compared with adult recipients. The striking increase in cancer incidence in young adulthood after the second decade of life deserves further consideration in transition programs.

Paternal characteristics associated with maternal periconceptional use of folic acid supplementation.

BACKGROUND: Maternal predictors of folic acid (FA) supplementation use to reduce offspring risk of neural tube defects are well known, while paternal determinants for maternal FA use are less known. Such knowledge is important to increase women's compliance to recommended periconceptional FA use. METHODS: In a nation-wide study of 683,785 births registered in the Medical Birth Registry of Norway during 1999-2010, the associations between paternal characteristics (age, education, occupation, country of origin) and maternal FA use were estimated by relative risks (RR) with 95% confidence intervals (CI), using log-binomial regression. RESULTS: Maternal FA use before and during pregnancy (adequate FA use) was found in 16% of the births. The association between paternal age and adequate FA use was inversely U-shaped; adjusted RRs for adequate FA use were 0.35 (95% CI 0.28-0.43) and 0.72 (95% CI 0.71-0.74) for paternal age < 20 and ≥ 40 years, respectively, comparing age 30-34 years. Compulsory education (1-9 years) among fathers was compared to tertiary education; the RR was 0.69 (95% CI 0.68-0.71) for adequate FA use. The lower risk of adequate FA use for paternal compulsory education was present in all categories of maternal education. Occupation classes other than "Higher professionals" were associated with decreased risk of adequate FA use, compared with the reference "Lower professionals". RR for adequate FA use was 0.58 (95% CI 0.56-0.60) comparing fathers from "Low/middle-income countries" with fathers born in Norway. CONCLUSION: Adequate FA use in the periconceptional period was lower when fathers were younger or older than 30-34 years, had shorter education, had manual or self-employed occupations, or originated from low/middle-income countries. Partners may contribute to increase women's use of periconceptional FA supplementation.

Parity, hormones and breast cancer subtypes - results from a large nested case-control study in a national screening program.

BACKGROUND: Breast cancer comprises several molecular subtypes with different prognoses and possibly different etiology. Reproductive and hormonal factors are associated with breast cancer overall, and with luminal subtypes, but the associations with other subtypes are unclear. We used data from a national screening program to conduct a large nested case-control study. METHODS: We conducted a nested case-control study on participants in the Norwegian Breast Cancer Screening Program in 2006 - 2014. There was information on estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) for 4748 cases of breast cancer. Breast cancer subtypes were defined as luminal A-like (ER+ PR+ HER2-), luminal B-like (ER+ PR- HER2- or ER+ PR+/PR-HER2+), HER2-positive (ER- PR- HER2+) and triple-negative (ER- PR- HER2-). Conditional logistic regression was used to estimate odds ratios (ORs) of breast cancer associated with age at first birth, number of pregnancies, oral contraceptive use, intrauterine devices and menopausal hormone therapy. Analyses were adjusted for age, body mass index, education, age at menarche, number of pregnancies and menopausal status. RESULTS: Number of pregnancies was inversely associated with relative risk of luminal-like breast cancers (p-trend ≤0.02), and although not statistically significant, with HER2-positive (OR = 0.60, 95% CI 0.31-1.19) and triple-negative cancer (OR = 0.70, 95% CI 0.41-1.21). Women who had ≥4 pregnancies were at >40% lower risk of luminal-like and HER2-positive cancers than women who had never been pregnant. However, there was a larger discrepancy between tumor subtypes with menopausal hormone use. Women who used estrogen and progesterone therapy (EPT) had almost threefold increased risk of luminal A-like cancer (OR = 2.92, 95% CI 2.36-3.62) compared to never-users, but were not at elevated risk of HER2-positive (OR = 0.88, 95% CI 0.33-2.30) or triple-negative (OR = 0.92, 95% CI 0.43 - 1.98) subtypes. CONCLUSIONS: Reproductive factors were to some extent associated with all subtypes; the strongest trends were with luminal-like subtypes. Hormone therapy use was strongly associated with risk of luminal-like breast cancer, and less so with risk of HER2-positive or triple-negative cancer. There are clearly some, but possibly limited, etiologic differences between subtypes, with the greatest contrast between luminal A-like and triple-negative subtypes. TRIAL REGISTRATION: Not applicable.

Risk of familial classical Hodgkin lymphoma by relationship, histology, age, and sex: a joint study from five Nordic countries.

We aimed to provide the familial risk of classical Hodgkin lymphoma (HL) by relationship, histology, age at diagnosis, and sex. A cohort of 57,475 first-degree relatives of 13,922 HL patients diagnosed between 1955 and 2009 in 5 European countries was observed for HL incidence. The overall lifetime cumulative risk (CR) of HL in first-degree relatives of a patient with HL was 0.6%, which represents a threefold (standardized incidence ratio [SIR], 3.3; 95% confidence interval [CI], 2.8-3.9) increased risk over the general population risk. The risk in siblings (6.0-fold; 95% CI, 4.8- to 7.4-fold) was significantly higher than in parents and/or children (2.1-fold; 95% CI, 1.6- to 2.6-fold). Very high lifetime risk of HL was found for those with multiple affected first-degree relatives (13-fold; 95% CI, 2.8- to 39-fold) and for same-sex twins (57-fold; 95% CI, 21- to 125-fold). We found high familial risks between some concordant histologic subtypes of HL such as lymphocyte-rich (81-fold; 95% CI, 30- to 177-fold) and nodular sclerosis (4.6-fold; 95% CI, 2.9- to 7.0-fold) and also between some discordant subtypes. The familial risk in sisters (9.4-fold; 95% CI, 5.9- to 14-fold) was higher than in brothers (4.5-fold; 95% CI, 2.9- to 6.7-fold) or unlike-sex siblings (5.9-fold; 95% CI, 4.3- to 8.1-fold). The lifetime risk of HL was higher when first-degree relatives were diagnosed at early ages (before age 30 years). This study provides tangible absolute risk estimates for relatives of HL patients, which can be used as a sex-, age-, and family history-based risk calculator for classical HL by oncologists and genetic counselors.

Trends in Incidence of Neuroendocrine Neoplasms in Norway: A Report of 16,075 Cases from 1993 through 2010.

BACKGROUND: Epidemiological studies show an increasing trend in the incidence of neuroendocrine neoplasms (NENs). A significant number of NENs occur in less common primary sites, but they are often excluded from the population-based studies. We studied the incidence trends of all NENs in Norway according to different primary sites. MATERIALS AND METHODS: Our analyses were based on cancer cases diagnosed between 1993 and 2010 and reported to the national population-based Cancer Registry of Norway. A total of 65 morphological codes were identified as neuroendocrine and stratified into 3 different groups of aggressiveness: low, intermediate and high. RESULTS: We identified 16,075 NENs of which 49.5% were in women. The median age at diagnosis was 65 years. The most common primary sites were the lung (48.1%) and the gastroenteropancreatic system (18.0%). Stage at diagnosis was local in 40.4% of the cases, regional in 17.5% and distant in 42.1%. The stage distribution was stable throughout the study period. The age-standardized (European) incidence rate (per 100,000 person-years) increased from 13.3 in 1993 to 21.3 in 2010 with an estimated annual increase of 5.1% in women and 2.1% in men. The increase was most pronounced for tumors of intermediate aggressiveness from 3.3 in 1993 to 7.3 in 2010. The largest annual increases were estimated for the adrenal gland (8.8%), the pancreas (6.9%) and the lungs (6.1%). CONCLUSION: The incidence of NENs increased. Most primary tumors were found in the lungs or in the gastroenteropancreatic system. The increase in the incidence differed according to the primary site, gender and tumor aggressiveness.

Prostate-specific antigen testing for prostate cancer: Depleting a limited pool of susceptible individuals?

After the introduction of the prostate specific antigen (PSA) test in the 1980s, a sharp increase in the incidence rate of prostate cancer was seen in the United States. The age-specific incidence patterns exhibited remarkable shifts to younger ages, and declining rates were observed at old ages. Similar trends were seen in Norway. We investigate whether these features could, in combination with PSA testing, be explained by a varying degree of susceptibility to prostate cancer in the populations. We analyzed incidence data from the United States' Surveillance, Epidemiology, and End Results program for 1973-2010, comprising 511,027 prostate cancers in men ≥40 years old, and Norwegian national incidence data for 1953-2011, comprising 113,837 prostate cancers in men ≥50 years old. We developed a frailty model where only a proportion of the population could develop prostate cancer, and where the increased risk of diagnosis due to the massive use of PSA testing was modelled by encompassing this heterogeneity in risk. The frailty model fits the observed data well, and captures the changing age-specific incidence patterns across birth cohorts. The susceptible proportion of men is [Formula: see text] in the United States and [Formula: see text] in Norway. Cumulative incidence rates at old age are unchanged across birth cohort exposed to PSA testing at younger and younger ages. The peaking cohort-specific age-incidence curves of prostate cancer may be explained by the underlying heterogeneity in prostate cancer risk. The introduction of the PSA test has led to a larger number of diagnosed men. However, no more cases are being diagnosed in total in birth cohorts exposed to the PSA era at younger and younger ages, even though they are diagnosed at younger ages. Together with the earlier peak in the age-incidence curves for younger cohorts, and the strong familial association of the cancer, this constitutes convincing evidence that the PSA test has led to a higher proportion, and an earlier timing, of diagnoses in a limited pool of susceptible individuals.

Lung cancer incidence associated with radon exposure in Norwegian homes. / Lungekreftforekomst knyttet til radoneksponering i norske boliger.

BACKGROUND: Radioactive radon gas is generated from uranium and thorium in underlying rocks and seeps into buildings. The gas and its decay products emit carcinogenic radiation and are regarded as the second most important risk factor for lung cancer after active tobacco smoking. The average radon concentration in Norwegian homes is higher than in most other Western countries. From a health and cost perspective, it is important to be able to quantify the risk of lung cancer posed by radon exposure. MATERIAL AND METHOD: We estimated the radon-related risk of lung cancer in Norway based on risk estimates from the largest pooled analysis of European case-control studies, combined with the hitherto largest set of data on radon concentration measurements in Norwegian homes. RESULTS: Based on these estimates, we calculate that radon is a contributory factor in 12 % of all cases of lung cancer annually, assuming an average radon concentration of 88 Bq/m3 in Norwegian homes. For 2015, this accounted for 373 cases of lung cancer, with an approximate 95 % confidence interval of 145 ­ 682. INTERPRETATION: Radon most likely contributes to a considerable number of cases of lung cancer. Since most cases of radon-associated lung cancer involve smokers or former smokers, a reduction of the radon concentration in homes could be a key measure to reduce the risk, especially for persons who are unable to quit smoking. The uncertainty in the estimated number of radon-associated cases can be reduced through a new national radon mapping study with an improved design.

Supplemental folic acid in pregnancy and childhood cancer risk.

BACKGROUND: We investigated the association between supplemental folic acid in pregnancy and childhood cancer in a nation-wide study of 687 406 live births in Norway, 1999-2010, and 799 children diagnosed later with cancer. METHODS: Adjusted hazard ratios (HRs) compared cancer risk in children by approximated periconceptional folic acid levels (folic acid tablets and multivitamins (0.6 mg), only folic acid (0.4 mg), only multivitamins (0.2 mg)) and cancer risk in unexposed. RESULTS: Any folic acid levels were not associated with leukemia (e.g., high-level folic acid HR 1.25; 95% CI 0.89-1.76, PTrend 0.20), lymphoma (HR 0.96; 95% CI 0.42-2.21, PTrend 0.51), central nervous system tumours (HR 0.68; 95% CI 0.42-1.10, PTrend 0.32), neuroblastoma (HR 1.05; 95% CI 0.53-2.06, PTrend 0.85), Wilms' tumour (HR 1.16; 95% CI 0.52-2.58, PTrend 0.76), or soft-tissue tumours (HR 0.77; 95% CI 0.34-1.75, PTrend 0.90). CONCLUSIONS: Folic acid supplementation was not associated with risk of major childhood cancers.

Reproductive history and risk of colorectal adenocarcinoma in parous women: a Nordic population-based case-control study.

BACKGROUND: Data are conflicting regarding the role of endogenous sex hormones in colorectal carcinogenesis. In this large population-based study, we pooled data from birth and cancer registries in four Nordic countries, to evaluate the risk of colorectal adenocarcinoma in relation to women's reproductive history. METHODS: We conducted a population-based case-control study among women registered in Nordic birth registries. The study included colorectal adenocarcinoma cases diagnosed in Denmark, Finland, Norway, and Sweden during 1967-2013 and up to 10 matched controls per case, in total 22 185 cases and 220 246 controls. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were derived from conditional logistic regression models. We had limited information available on possible confounders. RESULTS: We found no evidence for associations between colorectal adenocarcinoma and parity, age at first and last birth, and time since first and last birth. The risk estimates were also close to unity for specific cancer subsites (proximal and distal colon and rectum). As well, when the analyses were stratified on menopausal status, parity, and mother's year of birth, no indication of associations was found. CONCLUSIONS: In this large, Nordic population-based study, no evidence for associations was found between women's reproductive history and colorectal adenocarcinoma in parous women.