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Summary Background Thyroid cancer tends to be diagnosed at a younger age (median age 51 years) compared with most other malignancies (such as breast cancer [62 years] or lung cancer [71 years]). The incidence of thyroid cancer is higher in women than men diagnosed from early adolescence. However, few in-utero and early life risk exposures associated with increased risk of thyroid cancer have been identified. Methods In this population-based nested case-control study we used registry data from four Nordic countries to assess thyroid cancer risk in offspring in relation to maternal medical history, pregnancy complications, and birth characteristics. Patient with thyroid cancer (cases) were individuals born and subsequently diagnosed with first primary thyroid cancer from 1973 to 2013 in Denmark, 1987 to 2014 in Finland, 1967 to 2015 in Norway, or 1973 to 2014 in Sweden. Each case was matched with up to ten individuals without thyroid cancer (controls) based on birth year, sex, country, and county of birth. Cases and matched controls with a previous diagnosis of any cancer, other than non-melanoma skin cancer, at the time of thyroid cancer diagnosis were excluded. Cases and matched controls had to reside in the country of birth at the time of thyroid cancer diagnosis. Conditional logistic regression models were used to calculate odds ratios (ORs) with 95% CIs. Results Of the 2437 cases, 1967 (81·4%) had papillary carcinomas, 1880 (77·1%) were women, and 1384 (56·7%) were diagnosed before age 30 years (range 0–48). Higher birth weight (OR per kg 1·14 [95% CI 1·05–1·23]) and congenital hypothyroidism (4·55 [1·58–13·08]); maternal diabetes before pregnancy (OR 1·69 [0·98–2·93]) and postpartum haemorrhage (OR 1·28 [1·06–1·55]); and (from registry data in Denmark) maternal hypothyroidism (18·12 [10·52–31·20]), hyperthyroidism (11·91 [6·77–20·94]), goiter (67·36 [39·89–113·76]), and benign thyroid neoplasms (22·50 [6·93–73·06]) were each associated with an increased risk of thyroid cancer in offspring. Interpretation In-utero exposures, particularly those related to maternal thyroid disorders, might have a long-term influence on thyroid cancer risk in offspring. Funding Intramural Research Program of the National Cancer Institute (National Institutes of Health).

Testicular germ cell tumors (TGCT) are the most common tumor in young white men and have a high heritability. In this study, the international Testicular Cancer Consortium assemble 10,156 and 179,683 men with and without TGCT, respectively, for a genome-wide association study. This meta-analysis identifies 22 TGCT susceptibility loci, bringing the total to 78, which account for 44% of disease heritability. Men with a polygenic risk score (PRS) in the 95th percentile have a 6.8-fold increased risk of TGCT compared to men with median scores. Among men with independent TGCT risk factors such as cryptorchidism, the PRS may guide screening decisions with the goal of reducing treatment-related complications causing long-term morbidity in survivors. These findings emphasize the interconnected nature of two known pathways that promote TGCT susceptibility: male germ cell development within its somatic niche and regulation of chromosomal division and structure, and implicate an additional biological pathway, mRNA translation., Testicular germ cell tumors are highly heritable, and the authors present the largest genome association study, identifying 22 novel loci, which account for a third of those identified to date. Implicated pathways include male germ cell development and differentiation, and chromosomal segregation.

OBJECTIVE To identify minimally invasive biomarkers to help differentiate dogs with gastric carcinoma from those with chronic gastritis. DESIGN Prospective study. ANIMALS 15 dogs with gastric carcinoma, 29 dogs with chronic gastritis, and 7 healthy dogs. PROCEDURES Dogs with clinical signs of upper gastrointestinal tract disease for > 14 days that underwent gastroscopy or necropsy for collection of gastric biopsy specimens for histologic evaluation were prospectively enrolled. Gastric carcinoma and chronic gastritis were diagnosed on the basis of histologic findings. Additionally, gastric biopsy specimens were collected endoscopically from 7 healthy (control) dogs while they were anesthetized for a routine neutering procedure. Prior to being anesthetized for gastroscopy or euthanized, all dogs underwent a physical examination, and a blood sample was collected for quantification of select serum biomarker concentrations. Histologic findings, body condition score (BCS), and serum biomarker concentrations were compared among the 3 groups. RESULTS Dogs with gastric carcinoma were significantly older and had a significantly lower BCS, lower serum folate concentration, and greater serum C-reactive protein (CRP) concentration, compared with dogs with chronic gastritis and control dogs. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that age > 8 years, BCS < 4, serum CRP concentration > 25 mg/L, and an abnormally low serum folate concentration might be useful noninvasive biomarkers for identification of dogs with gastric carcinoma. For underweight older dogs with signs of upper gastrointestinal tract disease and high serum CRP and low serum folate concentrations, gastric biopsy specimens should be obtained and evaluated so that a prompt definitive diagnosis can be made and appropriate treatment initiated.

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. heterogeneity < 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.

Kidney transplantation in recipients with a previous malignancy is often deferred 2 to 5 years after cancer treatment due to fear of cancer recurrence. In Norway, the required waiting period has been 1 year.We compared patient and graft survival of recipients with pretransplant cancer to the outcomes of matched recipients without such cancer (comparators) using Cox regression.From 1963 to 2010, 377 (6.4%) of 5867 recipients had a pretransplant cancer. During a median follow-up of 6.8 years, 256 recipients died, 35 (13.7%) from recurrent cancer and 27 (10.5%) from de novo cancer. Uncensored and death-censored graft loss occurred in 263 and 46 recipients, respectively. All-cause mortality was similar as in comparators (hazard ratio [HR], 1.06; 95% confidence interval [CI], 0.93-1.20]; P = 0.40), death-censored graft loss was lower (HR, 0.63; 95% CI, 0.47-0.84; P = 0.002), and uncensored graft loss was similar (HR, 0.99; 95% CI, 0.87-1.12; P = 0.87). Cancer mortality was higher than in comparators (HR, 1.97; 95% CI, 1.51-2.56; P0.001), particularly during the first 5 years of follow-up (HR, 3.44; 95% CI, 2.36-5.03; P0.01). Waiting period was not associated with recurrent cancer mortality or all-cause mortality (both P0.45). Results were similar within cancer subgroups, with most data in patients with a history of kidney cancer, prostate cancer, urothelial cancer, and skin squamous cell carcinoma.Kidney transplant recipients with a pretransplant cancer had a similar overall patient and graft survival as recipients without such cancer. Cancer mortality was increased, particularly during the first 5 years after transplantation. A short waiting period was not associated with mortality.

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 (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.

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 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.

ObjectiveTo examine associations between birth defects and cancer from birth into adulthood.DesignPopulation based nested case-control study.SettingNationwide health registries in Denmark, Finland, Norway, and Sweden.Participants62 295 cancer cases (0-46 years) and 724 542 frequency matched controls (matched on country and birth year), born between 1967 and 2014.Main outcome measuresRelative risk of cancer in relation to major birth defects, estimated as odds ratios with 99% confidence intervals from logistic regression models.ResultsAltogether, 3.5% (2160/62 295) of cases and 2.2% (15 826/724 542) of controls were born with major birth defects. The odds ratio of cancer for people with major birth defects compared with those without was 1.74 (99% confidence interval 1.63 to 1.84). For individuals with non-chromosomal birth defects, the odds ratio of cancer was 1.54 (1.44 to 1.64); for those with chromosomal anomalies, the odds ratio was 5.53 (4.67 to 6.54). Many structural birth defects were associated with later cancer in the same organ system or anatomical location, such as defects of the eye, nervous system, and urinary organs. The odds ratio of cancer increased with number of defects and decreased with age, for both non-chromosomal and chromosomal anomalies. The odds ratio of cancer in people with any non-chromosomal birth defect was lower in adults (≥20 years: 1.21, 1.09 to 1.33) than in adolescents (15-19 years: 1.58, 1.31 to 1.90) and children (0-14 years: 2.03, 1.85 to 2.23). The relative overall cancer risk among adults with chromosomal anomalies was markedly reduced from 11.3 (9.35 to 13.8) in children to 1.50 (1.01 to 2.24). Among adults, skeletal dysplasia (odds ratio 3.54, 1.54 to 8.15), nervous system defects (1.76, 1.16 to 2.65), chromosomal anomalies (1.50, 1.01 to 2.24), genital organs defects (1.43, 1.14 to 1.78), and congenital heart defects (1.28, 1.02 to 1.59) were associated with overall cancer risk.ConclusionsThe increased risk of cancer in individuals with birth defects persisted into adulthood, both for non-chromosomal and chromosomal anomalies. Further studies on the molecular mechanisms involved are warranted.

Background Cisplatin-based chemotherapy (CBCT) is part of standard treatment of several cancers. In testicular cancer (TC) survivors, an increased risk of developing metabolic syndrome (MetS) is observed. In this epigenome-wide association study, we investigated if CBCT relates to epigenetic changes (DNA methylation) and if epigenetic changes render individuals susceptible for developing MetS later in life. We analyzed methylation profiles, using the MethylationEPIC BeadChip, in samples collected ~ 16 years after treatment from 279 Norwegian TC survivors with known MetS status. Among the CBCT treated (n = 176) and non-treated (n = 103), 61 and 34 developed MetS, respectively. We used two linear regression models to identify if (i) CBCT results in epigenetic changes and (ii) epigenetic changes play a role in development of MetS. Then we investigated if these changes in (i) and (ii) links to genes, functional networks, and pathways related to MetS symptoms. Results We identified 35 sites that were differentially methylated when comparing CBCT treated and untreated TC survivors. The PTK6–RAS–MAPk pathway was significantly enriched with these sites and infers a gene network of 13 genes with CACNA1D (involved in insulin release) as a network hub. We found nominal MetS-associations and a functional gene network with ABCG1 and NCF2 as network hubs. Conclusion Our results suggest that CBCT has long-term effects on the epigenome. We could not directly link the CBCT effects to the risk of developing MetS. Nevertheless, since we identified differential methylation occurring in genes associated with conditions pertaining to MetS, we hypothesize that epigenomic changes may also play a role in the development of MetS in TC survivors. Further studies are needed to validate this hypothesis.

Introduction/Background Non-epithelial ovarian cancers are rare but affect women of all ages. The etiology is unknown. Non-epithelial ovarian cancers are divided into two major subgroups: sex cord-stromal tumors (SCSTs) and germ cell tumors (GCTs). Whereas parity is protective for epithelial ovarian cancer, its association with non-epithelial ovarian cancer and its subtypes remains less clear, as are associations with other pregnancy-related factors. Methodology All parous women with births recorded in the medical birth registries from the Nordic countries with a subsequent diagnosis of SCSTs (n=420) and GCTs (n=345) during 1967–2013 were compared with up to 10 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 (CI)of associations of pregnancy-related factors. Results Number of births was not associated with risk of SCSTs or GCTs. Older age at last birth was inversely associated with the risk of SCSTs (age 30–39 versus Conclusion In this large population-based case-control study among parous women, number of births was not protective for risk of SCSTs and GCTs.The inverse associations with greater age at last birth and shorter time since last birth observed for SCSTs, however, suggest that these subtypes may be influenced by the woman’s reproductive history. Disclosure Ingrid Glimelius have received Honoraria from Janssen for projects unrelated to the current 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 (

Objective To investigate whether exposure to hyperemesis gravidarum (HG) is associated with increased maternal long‐term mortality. Design Population‐based cohort study. Setting Medical Birth Registry of Norway (1967–2002) linked to the Cause of Death Registry. Population Women in Norway with singleton births in the period 1967–2002, with and without HG. Women were followed until 2009 or death. Methods Cox proportional hazard regression model was applied to estimate hazard ratios (HRs) with 95% confidence interval (CI). Main outcome measures The primary outcome was all‐cause mortality during follow up. Secondary outcomes were cause‐specific mortality (cardiovascular mortality, deaths due to cancer, external causes or mental and behavioural disorders). Results Of 999 161 women with singleton births, 13 397 (1.3%) experienced HG. During a median follow up of 26 years (25 902 036 person‐years), 43 470 women died (4.4%). Women exposed to HG had a lower risk of long‐term all‐cause mortality compared with women without HG (crude HR 0.82; 95% CI 0.75–0.90). When adjusting for confounders, this reduction was no longer significant (adjusted HR 0.92; 95% CI 0.84–1.01). Women exposed to HG had a similar risk of cardiovascular death as women not exposed (adjusted HR 1.04; 95% CI 0.83–1.29), but a lower long‐term risk of death from cancer (adjusted HR 0.86; 95% CI 0.75–0.98). Conclusion In this large population‐based cohort study, HG was not associated with an increased risk of long‐term all‐cause mortality. Women exposed to HG had no increase in mortality due to cardiovascular disease, but had a reduced risk of death from cancer. Tweetable abstract Population‐based cohort study: Hyperemesis was not associated with an increased risk of long‐term mortality., Tweetable abstract Population‐based cohort study: Hyperemesis was not associated with an increased risk of long‐term mortality.

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.

An understanding of the origin of cancer is critical for cancer prevention and treatment. Complex biological mechanisms promote carcinogenesis, and there is increasing evidence that pregnancy-related exposures influence fetal growth cell division and organ functioning and may have a long-lasting impact on health and disease susceptibility in the mothers and offspring. Nulliparity is an established risk factor for breast, ovarian, endometrial, and possibly pancreatic cancer, while the risk of kidney cancer is elevated in parous compared with nulliparous women. For breast, endometrial and ovarian cancer, each pregnancy provides an additional risk reduction. The associations of parity with thyroid and colorectal cancers are uncertain. The timing of reproductive events is also recognized to be important. Older age at first birth is associated with an increased risk of breast cancer and older age at last birth is associated with a reduced risk of endometrial cancer. The risks of breast and endometrial cancers increase with younger age at menarche and older age at menopause. The mechanisms, and hormone profiles, that underlie alterations in maternal cancer risk are not fully understood and may differ by malignancy. Linking health-registries and pooling of data in the Nordic countries have provided opportunities to conduct epidemiologic research of pregnancy exposures and subsequent cancer. We review the maternal risk of several malignancies, including those with a well-known hormonal etiology and those with less established relationships. The tendency for women to have fewer pregnancies and at later ages, together with the age-dependent increase in the incidence of most malignancies, are expected to affect the incidence of pregnancy-associated cancer. This article is protected by copyright. All rights reserved.

Reproductive factors have been shown to influence cancer risk. Several pathological conditions during pregnancy have also been associated with subsequent altered cancer risk in the mother. Hyperemesis gravidarum (hyperemesis) is an early pregnancy condition characterized by severe nausea and vomiting resulting in weight loss and metabolic disturbances. Studies have reported associations between hyperemesis and cancer, but results are inconsistent. In this nested case-control study we linked the population-based medical birth registries and cancer registries in Norway, Sweden and Denmark in order to examine overall cancer risk and risk of specific cancer types in women with a history of hyperemesis, using conditional logistic regression. In total, 168,501 cases of cancer in addition to up to 10 cancer-free controls per case were randomly sampled, matched on year of birth and birth registry (n 5 1,721,626). Hyperemesis was defined through the International Classification of Diseases. Analyses were adjusted for potential confounders. Hyperemesis was inversely associated with overall cancer risk with adjusted relative risk (aRR) of 0.93 (95% CI: 0.88–0.99), with cancer in the lungs (aRR: 0.60, 95% CI: 0.44–0.81), cervix (aRR: 0.66, 95% CI: 0.49–0.91) and rectum (aRR: 0.48, 95% CI: 0.29–0.78). Thyroid cancer was positively associated with hyperemesis (aRR 1.45, 95% CI: 1.06–1.99) and risk increased with more than one hyperemetic pregnancy (aRR 1.80, 95% CI: 1.23–2.63). Hormonal factors, in particular human chorionic gonadotropin, are likely to be involved in mediating these effects. This study is the first to systematically address these associations and provides valuable knowledge on potential long-term consequences of hyperemesis.

Background: Mammographic density (MD) is one of the strongest known breast cancer risk factors. Twin studies have suggested that a large part of the variation in MD is genetically determined. We hypothesized that breast cancer susceptibility variants may affect MD, and that their effects may be modified by nongenetic factors. Methods: We assessed MD, using a computer-assisted method, on 2,348 postmenopausal Caucasian women (50–69 years) who participated in the Norwegian Breast Cancer Screening Program (NBCSP) in 2004 or 2006–07. We used linear regression (additive models) to determine the association between each SNP and MD, adjusting for age, body mass index (BMI), and study. We evaluated MD associations with 17 established breast cancer SNPs, overall, and by strata defined by non-genetic factors. Results: Two variants, 6q25.1-rs9383938 and TXNRD2-rs8141691, were statistically significantly associated with percent MD (P = 0.019 and 0.03, respectively), with the 6q25.1-rs9383938 association being consistent with the SNP effect on breast cancer risk. The effect of 6q25.1-rs3734805 on percent MD varied between parous and nulliparous women (Pinteraction = 0.02), whereas the effects of 9q31.2-rs865686 and MRPS30:FGF10-rs4415084 differed across strata of BMI (Pinteraction = 0.01 and 0.005, respectively). There was no evidence of effect modification by estrogen and progestin therapy use or alcohol consumption. Conclusion: This study provides novel evidence of shared genetic risk factors between MD and breast cancer and of possible MD genetic–environmental interactions. Impact: Although the results may be chance findings, they nevertheless highlight the need to investigate interactions with nongenetic factors in studies on the genetics of MD. Cancer Epidemiol Biomarkers Prev; 23(9); 1752–63. ©2014 AACR.

Introduction Testicular germ cell cancer, hereafter called testicular cancer (TC), is the most common malignancy in young men in lagre parts of the world. Cisplatin-based chemotherapy (CBCT) has contributed to an increase in TC survival rates over the last decades. However, cisplatin exposure has been shown to result in drug-induced DNA hypermethylation. The aim of the present study is to study the effects of CBCT on DNA methylation in cisplatin-treated vs untreated TC survivors. Material and methods We included 279 Norwegian TC survivors, where 103 underwent orchiectomy, and 176 orchiectomy and additional CBCT. The two groups were matched on age at blood sampling. The TC survivors were re-examined on average 16 years after the orchiectomy. Whole genome DNA methylation profiles were measured with Illumina`s MethylationEPIC BeadChip and analysed with the R package minfi. We used a linear regression model adjusting for smoking, age and cell type composition to identify CBCT differentially methylated CpG sites. Additionally, genes with p-value Results and discussions Out of the initial 866,836 CpG sites, 8 62 400 were included in our analysis. Thirty-three and 14 differentially methylated CpG sites were associated with CBCT after adjusting for multiple testing with False Discovery Rate (FDR) and Bonferroni correction, respectively. Eighty-five genes had a FDR adjusted p-value Conclusion Our results suggest that CBCT has long-term effects on the epigenome. Overall these results can contribute to elucidate what cellular mechanism are behind later consequences for TC survivors, like organotoxicity and metabolic syndrome. Our results should be further explored in a larger study of TC survivors treated with CBCT.

Introduction Testicular germ cell tumour (TGCT) is a malignancy present in males with the highest incidence rates in younger age ranges. The aetiology is still largely unknown; however, several genome-wide association studies have identified up to 30 independent loci influencing TGCT risk, confirming its inherited genetic susceptibility. Machine learning can be utilised as a modelling technique to identify patterns within genetic and lifestyle data that allows classification and identification of biomarkers. We aim to identify potential biomarkers and perform accurate classifications in the small non-coding RNAs (sncRNAs) of 147 pre-diagnostic serum samples. Material and methods The serum samples were obtained from the Janus Serum Bank, with life-style covariates, such as smoking habits, BMI and exercise habits also recorded for each sample. A total of 69 TGCT samples and 78 control sample sncRNA reads were used to train machine learning algorithms including linear regression, LASSO, decision trees and neural networks. These cases and controls are matched by age at blood sampling. Results and discussions Preliminary results from LASSO and decision tree methods show differentiation in the miRNA/piRNA patterns between the control and the TGCT samples after adjusting individual read counts for age at sampling. Classification performance was better when trained using piRNAs, 58% of control samples were classified as normal and 60% of TGCT cases being classified as TGCT patients. Further inclusion of life-style covariates in the model as well as age and time of diagnosis is still to be performed to increase classification performance further. By using interpretable machine learning methods, we aim to identify biomarkers that allow the accurate classification of the samples. Conclusion These results show that the piRNA composition seen in pre-diagnostic serum samples may contain potential biomarkers that can lead to accurate classification of whether a patient was at increased risk of testicular cancer before the initial diagnosis. Preliminary results should be further expanded with different sncRNA datasets and lifestyle covariates.

Using a 2-level hierarchical frailty model, we analyzed population-wide data on testicular germ-cell tumor (TGCT) status in 1,135,320 two-generational Norwegian families to examine the risk of TGCT in family members of patients. Follow-up extended from 1954 (cases) or 1960 (unaffected persons) to 2008. The first-level frailty variable was compound Poisson-distributed. The underlying Poisson parameter was randomized to model the frailty variation between families and was decomposed additively to characterize the correlation structure within a family. The frailty relative risk (FRR) for a son, given a diseased father, was 4.03 (95% confidence interval (CI): 3.12, 5.19), with a borderline significantly higher FRR for nonseminoma than for seminoma (P = 0.06). Given 1 affected brother, the lifetime FRR was 5.88 (95% CI: 4.70, 7.36), with no difference between subtypes. Given 2 affected brothers, the FRR was 21.71 (95% CI: 8.93, 52.76). These estimates decreased with the number of additional healthy brothers. The estimated FRRs support previous findings. However, the present hierarchical frailty approach allows for a very precise definition of familial risk. These FRRs, estimated according to numbers of affected/nonaffected family members, provide new insight into familial TGCT. Furthermore, new light is shed on the different familial risks of seminoma and nonseminoma.

Genome-wide association studies (GWAS) have transformed understanding of susceptibility to testicular germ cell tumors (TGCTs), but much of the heritability remains unexplained. Here we report a new GWAS, a meta- A nalysis with previous GWAS and a replication series, totaling 7,319 TGCT cases and 23,082 controls. We identify 19 new TGCT risk loci, roughly doubling the number of known TGCT risk loci to 44. By performing in situ Hi-C in TGCT cells, we provide evidence for a network of physical interactions among all 44 TGCT risk SNPs and candidate causal genes. Our findings implicate widespread disruption of developmental transcriptional regulators as a basis of TGCT susceptibility, consistent with failed primordial germ cell differentiation as an initiating step in oncogenesis. Defective microtubule assembly and dysregulation of KIT-MAPK signaling also feature as recurrently disrupted pathways. Our findings support a polygenic model of risk and provide insight into the biological basis of TGCT.

The in utero origins of breast cancer are an increasing focus of research. However, the long time period between exposure and disease diagnosis, and the lack of standardized perinatal data collection makes this research challenging. We assessed perinatal factors, as proxies for in utero exposures, and breast cancer risk using pooled, population-based birth and cancer registry data. Birth registries provided information on perinatal exposures. Cases were females born in Norway, Sweden or Denmark who were subsequently diagnosed with primary, invasive breast cancer (n = 1419). Ten controls for each case were selected from the birth registries matched on country and birth year (n = 14,190). Relative risks (RRs) and 95% confidence intervals (CIs) were estimated using unconditional regression models. Breast cancer risk rose 7% (95% CI 2–13%) with every 500 g (roughly 1 s.d.) increase in birth weight and 7% for every 1 s.d. increase in birth length (95% CI 1–14%). The association with birth length was attenuated after adjustment for birth weight, while the increase in risk with birth weight remained with adjustment for birth length. Ponderal index and small- and large-for-gestational-age status were not better predictors of risk than either weight or length alone. Risk was not associated with maternal education or age, gestational duration, delivery type or birth order, or with several pregnancy complications, including preeclampsia. These data confirm the positive association between birth weight and breast cancer risk. Other pregnancy characteristics, including complications such as preeclampsia, do not appear to be involved in later breast carcinogenesis in young women.

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.British Journal of Cancer advance online publication 4 October 2016; doi:10.1038/bjc.2016.315 www.bjcancer.com.

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 $$39.9\,\%\,\left( {95\,\%\,{\text{CI}}\, 38.2, 41.6\,\% } \right)$$ in the United States and $$30.4\,\%\, \left( {95\,\%\, {\text{CI}} \,28.9, 32.0\,\% } \right)$$ 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.

The Armitage–Doll model with random frailty can fail to describe incidence rates of rare cancers influenced by an accelerated biological mechanism at some, possibly short, period of life. We propose a new model to account for this influence. Osteosarcoma and Ewing sarcoma are primary bone cancers with characteristic age–incidence patterns that peak in adolescence. We analyze Surveillance, Epidemiology and End Result program incidence data for whites younger than 40 years diagnosed during the period 1975–2005, with an Armitage–Doll model with compound Poisson frailty. A new model treating the adolescent growth spurt as the accelerated mechanism affecting cancer development is a significant improvement over that model. We also model the incidence rate conditioning on the event of having developed the cancers before the age of 40 years and compare the results with those predicted by the Armitage–Doll model. Our results support existing evidence of an underlying susceptibility for the two cancers among a very small proportion of the population. In addition, the modeling results suggest that susceptible individuals with a rapid growth spurt acquire the cancers sooner than they otherwise would have if their growth had been slower. The new model is suitable for modeling incidence rates of rare diseases influenced by an accelerated biological mechanism. Copyright © 2012 John Wiley & Sons, Ltd.

The etiology of testicular germ cell cancer (TGCC) is still poorly understood, but biological and epidemiological evidence suggest that TGCC originates early in life. The aim of the present study was to analyze heterogeneity in TGCC risk within Norway, comparing county of birth to county of diagnosis, in order to assess the relative contribution of risk factors acting early and later in life. A further aim was to present the Norwegian TGCC incidence rates (1958-2007).All TGCC cases (n = 7130) reported to the Cancer Registry of Norway, 1958-2007, were analyzed by county of diagnosis in 10-year intervals. The relative risk of TGCC based on county of birth, was estimated by Poisson regression analysis of all new TGCC cases (n = 1943), based on the mother's county of residence at the time of the son's birth, 1967-2007, obtained by linkage between the Cancer Registry and the Medical Birth Registry of Norway.Between the first (1958-67) and last (1998-2007) 10-year period, the average incidence rate more than tripled from 3.3 to 10.5 per 100 000 person-years (world adjusted), respectively. The average incidence rate during 1968-2007 was highest in the county of Rogaland (8.6) and lowest in Hedmark (5.3), the ratio between them being 1.6. The relative risk of TGCC based on county of birth (1967-2007) varied between 1.43 (Møre og Romsdal) and 0.95 (Buskerud), giving a ratio of 1.5.The ratio between the relative risk in the highest and lowest county was basically similar when comparing counties of birth with counties of diagnosis. Thus, our data do not shed light on the relative contribution of risk factors acting early versus later in life. The incidence rate of TGCC in Norway is among the highest in the world, and the increase in incidence rate does not seem to level off.

Testicular cancer (TC) survival rates have increased substantially over the last decades, largely due to the introduction of cisplatin (CP) chemotherapy. This treatment is, however, associated with increased risk of developing metabolic syndrome (MetS), defined according to the National Cholesterol Education Program. We aimed to investigate if CP treatment were associated with epigenetic changes, and whether these changes render TC survivors susceptible for developing MetS later in life. We included 279 Norwegian TC survivors with and without CP treatment and MetS, matched on age at blood sampling (Table 1). The TC survivors were re-examined on average 16 years after the orchiectomy, and for some patients, CP treatment. Whole genome DNA methylation profiles were measured with MethylationEPIC BeadChip and analyzed with the R package minfi. We used a linear regression model adjusting for smoking, age and cell type composition to identify CP differentially methylated CpG sites and logistic regression adjusting for smoking and age to identify differentially methylated CpG sites associated with MetS. Gene enrichment analyses were based on Fisher's exact test using KEGG and Reactome pathways. 32 and 15 differentially methylated CpG sites were associated with CP treatment after adjusting for multiple testing with False Discovery Rate (FDR) and Bonferroni correction, respectively. The PTK6-RAS-MAPk pathway was significantly enriched with the FDR significant CpGs (p-value < 0.1). We could not identify FDR significant differentially methylated CpGs associated with MetS with our sample size. In conclusion, our results suggest that CP treatment has long-term effects on the epigenome. Genes involved in double-strand break repair, consistent with the cytotoxicity of CP treatment, are among the differentially methylated CpGs. Our top list of differentially methylated CpGs associated with MetS (lowest unadjusted p-values), should be further explored in a larger sample set of TC survivors. Table 1: Overview of sample characteristicsCP+ MetS+CP- MetS+CP+ MetS-CP- MetS-N613411569Mean age at surgery31312730Mean age at sample collection49484443Time between surgery and sample collection17181714 Citation Format: Trine B. Rounge, Cecilie Bucher-Johannessen, Christian M. Page, Trine B. Haugen, Sophie D. Fosså, Hege S. Haugnes, Tom Grotmol. Cisplatin treatment of testicular cancer introduces long-term changes to the epigenome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4325.

Both subtypes of estrogen receptor (ER), ERalpha and ERbeta, are normally present in the mammary gland. The role of ERalpha as a prognostic marker in breast cancer is well established due to the beneficial effect of providing tamoxifen as adjuvant therapy. The role of ERbeta, however, is less clear. To gain insight into the importance of ERbeta in breast cancer, 145 primary breast cancers were examined by immunohistochemistry for ERbeta, and the expression level was compared with ERalpha and progesterone receptor (PR) status. Especially, we wanted to examine the significance of ERbeta in the contrasting ERalpha+/PR+ and ERalpha-/PR- subgroups. In the ERalpha+/PR+ subgroup (dual positive), the survival difference between patients with low, medium and high ER beta level was statistically significant (p = 0.004), with more than 70% of patients with medium and high ERbeta levels surviving 100 months, compared with less than 30% in the group with low ERbeta level. Further, for ERalpha+/PR+ patients there was a reduced risk of fatal outcome by multivariate analysis with increasing ERbeta levels (p(trend) < 0.01 [univariate analysis]; p(trend) = 0.05 [multivariate analysis]). The risk was 31% and 27% for medium and high ERbeta levels, respectively, compared with low ERbeta level, adjusting for standard prognostic factors such as tumor diameter, nuclear tumor grade (quantified by mean nuclear area), lymph node status, and patient age at operation. For patients with ERalpha-/PR- tumors (dual negative), however, there was no association between ERbeta levels and patient outcome. Our findings indicate that ERbeta expression provides independent prognostic information for breast cancers with ERalpha/PR-positive status, a feature typical among screen-detected breast cancers. The role of ERbeta needs to be further evaluated especially in this group of breast cancers.

The distinct geographic variation in the global incidence of nasopharyngeal carcinoma reflects a complex etiology involving viral, environmental, and genetic components. The high to intermediate rates observed in endemic areas contrast markedly with the uniformly low rates seen in much of the world. An interesting epidemiologic observation is the early peak in age-incidence curves observed in certain geographically disparate populations, suggestive of distinct causal entities and the possible exhaustion of susceptible individuals from the population at a certain age. The aim of this study was to systematically evaluate the age-incidence profiles of NPC worldwide on partitioning populations according to level of risk, in an effort to provide clues about the importance of early-in-life factors and genetic susceptibility. Using data from 23 high-quality population-based cancer registries for the period 1983-1997, a key finding was the consistent pattern of bimodality that emerged across low-risk populations, irrespective of geographic location. Continual increases in NPC risk by age up to a first peak in late adolescence/early adulthood (ages 15-24 years) were observed, followed by a second peak later in life (ages 65-79 years). No such early peak in NPC incidence by age group was evident among the high-risk populations studied. These findings are discussed according to existing lines of biological and epidemiologic evidence related to level of population risk, age at diagnosis, and histologic subtype. A modified model for NPC tumor development is proposed on the basis of these observations. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2356–65)

BACKGROUND: The role of vitamin D in breast cancer etiology is unclear. There is some, but inconsistent, evidence that vitamin D is associated with both breast cancer risk and mammographic density (MD). We evaluated the associations of MD with month the mammogram was taken, and with vitamin D intake, in a population of women from Norway--a country with limited sunlight exposure for a large part of the year. METHODS: 3114 women aged 50-69, who participated in the Norwegian Breast Cancer Screening Program (NBCSP) in 2004 or 2006/07, completed risk factor and food frequency (FFQ) questionnaires. Dietary and total (dietary plus supplements) vitamin D, calcium and energy intakes were estimated by the FFQ. Month when the mammogram was taken was recorded on the mammogram. Percent MD was assessed using a computer assisted method (Madena, University of Southern California) after digitization of the films. Linear regression models were used to investigate percent MD associations with month the mammogram was taken, and vitamin D and calcium intakes, adjusting for age, body mass index (BMI), study year, estrogen and progestin therapy (EPT), education, parity, calcium intakes and energy intakes. RESULTS: There was no statistical significant association between the month the mammogram was taken and percent MD. Overall, there was no association between percent MD and quartiles of total or dietary vitamin D intakes, or of calcium intake. However, analysis restricted to women aged

Some cancer types level off or decrease in incidence at older age groups, not following the Weibull hazard rate. This stagnation can be explained by the frailty model, which describes the population effect of mixing individuals who are susceptible, with high risk of cancer, with those that are "non-susceptible", with a low risk of cancer even in the oldest age groups. The aim of the study was to apply a frailty model on colorectal cancer incidence data for the Norwegian population aged 40-99 years, diagnosed 1956-2000. The model provided an acceptable fit to the data. The estimated proportion of susceptibles increased from about 5% to about 24% from the first cohort (1851-1855) to the last cohort (1946-1950), in line with the rise in incidence of the disease during this period. According to the frailty modelling, the estimated number of genetic events necessary for a malignant lesion to develop in the colorectum is seven to eight, which accords with the present knowledge regarding colorectal carcinogenesis. The frailty phenomenon may thus be present in this cancer form. The findings indicate that it is possible to model the development of colorectal cancer in the population based on large heterogeneity in risk between individuals, in such a manner that a small group of individuals are susceptible to develop the disease, whereas the remaining majority have a low susceptibility.

There is increasing recognition that conditions in utero are of importance for later cancer risk in several organs, particularly the testis and breast. A review of the most recent literature on this topic is therefore warranted. The PubMed database was searched for relevant recent literature on intrauterine conditions associated with cancer risk later in life, with particular emphasis on the testis, breast, but also studies pertaining to other organs were included. Epidemiological and experimental data support the hypothesis that factors acting in utero play a role in the development of cancer in the testis and breast. For other organs, such as the prostate, urinary system and colorectum, the results are inconclusive. While conditions during foetal life are associated with later cancer risk in the testis and breast, the biological mechanisms are for the most part elusive. They are, however, likely to involve hormonal disturbances, number of cells at risk, and genetic or epigenetic events.

The origin of testicular germ cell cancer (TGCC) is believed to be carcinoma in situ cells developed in utero. Clinically, TGCCs are divided into two major histological groups, seminomas and non-seminomas, where the latter group includes non-seminomatous TGCCs with seminomatous components (mixed S/NS TGCC). Recent studies, however, have suggested that non-seminomas and mixed S/NS TGCCs could have certain differences in aetiology, and in this study the TGCCs were divided into three, rather than the conventional two histological groups. A large case-control study was undertaken on data on all live-born boys registered in the Medical Birth Registry of Norway during the period 1967-1998 (n=961 396). Among these were 1087 TGCC cases registered in the Cancer Registry of Norway until February 2004. We found several risk factors for TGCC, including low parity, low gestational age, epilepsy and retained placenta. Several of the variables studied seemed to be risk factors for specific histological groups, e.g. parity 0 vs. 2 and low gestational age being associated with increased risk of non-seminomas, but not of mixed S/NS TGCC, and low maternal age being associated with increased risk of mixed S/NS TGCC, but not of non-seminomatous TGCC. Therefore, our results might suggest that non-seminomas and mixed S/NS TGCCs have partially different risk factors, whose associations may be obscured by combining these two histological groups. The histological groups were not significantly different, however. Most of our findings on risk factors for TGCC are in agreement with at least some previous studies. An unexplainable exception is low birth weight being associated with reduced risk of TGCC in our study.

Between 1955 and 1963, an estimated number of 150 million people in various parts of the world, including Norway, received poliomyelitis vaccine possibly contaminated with infectious simian virus 40 (SV40). Human studies have investigated the hypothesised association between SV40 and various cancers, but the results have so far been contradicting. The aim of the present study was to examine Norwegian cancer incidence data to assess a possible association between birth cohorts assumed to have been subjected to the vaccine and the incidence rate of lymphoproliferative disorders (excluding Hodgkin's lymphoma), further subdivided into non-Hodgkin's lymphoma (NHL), lymphocytic leukemia and plasma cell neoplasms. Between 1953 and 1997, the incidence rate of lymphoproliferative diseases combined increased about 3-fold in both males and females. Subgroup analysis showed that this increase was largely attributable to NHL. Age-period-cohort modelling of the subgroups, as well as of all groups combined, showed that the cohort effect was more prominent than the period effect. However, the variations in incidence patterns across the birth cohorts did not fit with the trends that would be expected if a SV40 contaminated vaccine did play a causative role. Thus, our data do not support the hypothesis of an association between the vaccine and any subgroup of lymphoproliferative diseases.

It has been proposed that hypospadias, cryptorchidism and testicular cancer, as well as decreasing sperm quality are symptoms of an underlying entity called testicular dysgenesis syndrome (TDS). We wanted to study the risk factors for hypospadias and compare them with those of the other conditions belonging to TDS. A large case-control study was undertaken on data on all live-born boys registered in the Medical Birth Registry of Norway during the period 1967-1998 (n = 961 396; hypospadias cases = 2382). Logistic regression analysis was used to study the association between potential risk factors and hypospadias, estimated by odds ratio (OR). The risk factors for hypospadias were divided into four categories: (i) maternal characteristics, e.g. low parity [p(trend) < 0.001], hypertension (OR = 1.49) and bleeding (OR = 1.39) during index pregnancy, and (pre)eclampsia (OR = 1.84); (ii) complications during delivery, e.g. retained placenta (OR = 1.67) or Caesarean section (OR = 1.36); (iii) characteristics of the newborn, e.g. low birth weight [p(trend) < 0.001], small for gestational age (OR = 2.16), and presence of congenital malformations other than hypospadias (OR = 2.72), e.g. inguinal hernia (OR = 5.65); (iv) prevalence among relatives of hypospadias cases, e.g. brother with hypospadias (OR = 20.81). The novel finding of retained placenta as a risk factor indicates that early malfunction of placenta could be a causative factor for hypospadias. When comparing with previously published risk factors for hypospadias, cryptorchidism and testicular cancer, we found that the following risk factors were common to all three conditions: low parity, low birth weight, low gestational age, inguinal hernia, bleeding during pregnancy and Caesarean section. In conclusion, our results support the notion that the conditions of TDS share risk factors.

Background and aims: The purpose of this study was to evaluate the utility of easily measured clinical variables at flexible sigmoidoscopy (FS) screening that might predict a proximal advanced neoplasm (PAN). Methods: We studied 1833 subjects with biopsy verified adenomas at FS who subsequently underwent full colonoscopy. Results: A total of 387 (21%) subjects had proximal colonic neoplasms (PCN) and 85 (5%) had PAN. In univariate comparison, the risk of PAN increased more than threefold in the presence of a distal adenoma measuring either ≥10 mm in diameter or containing villous components. Multiplicity of distal adenomas, severe dysplasia, or age ≥60 years increased the risk of PAN more than twofold. In the multivariate model, the presence of a distal adenoma ≥10 mm, villousness, and multiplicity maintained their significance as predictive variables for increased risk of proximal neoplasms, whereas sex and severe dysplasia lost their significance. By recommending colonoscopy only to individuals with multiple (>1) adenomas or any high risk adenoma at FS, we would have reduced the number of colonoscopies by 1209 (66%) but would have missed 32 (38%) participants with PAN and 217 (56%) with PCN. By using a 60 cm endoscope instead of an ordinary colonoscope at FS, nine (2%) participants with advanced neoplasms, including three patients with cancer, would have been missed. Conclusion: The present study supports the concept of defining “any adenoma” as a positive FS, qualifying for colonoscopy. We recommend the use of an ordinary colonoscope instead of a 60 cm sigmoidoscope for FS screening examinations.

The Norwegian Colorectal Cancer Prevention study is an ongoing flexible sigmoidoscopy (FS) screening trial for colorectal cancer. Twenty-one thousand average-risk individuals, aged 50-64 years, living in two separate areas in Norway were randomly drawn from the Population Registry and invited to once-only screening flexible sigmoidoscopy. Examinations were performed over 3 years, at 2 centres, by 8 different endoscopists, using the same type of equipment. The aim of the present study was to investigate possible differences between endoscopists in detecting individuals with polyps, adenomas and advanced lesions (adenomas with severe dysplasia and/or villous components and/or size larger than 9 mm and carcinoma) in flexible sigmoidoscopy screening.The present trial comprises data from 8822 individuals, aged 55-64 years, who have undergone a flexible sigmoidoscopy. In the study period, all lesions detected by the different endoscopists were registered. Tissue samples were taken from all lesions detected.Detection rates varied significantly between endoscopists, ranging from 36.4% to 65.5% for individuals with any polyp, from 12.7% to 21.2% for any adenoma and from 2.9% to 5.0% for advanced lesions. In a multiple logistic regression model, the performing endoscopist was a strong independent predictor for detection of individuals with polyps (P0.001 ), adenomas (P0.001) and advanced lesions (P = 0.01).Detection rates for colorectal lesions vary significantly between endoscopists in colorectal cancer screening. Establishing systems for monitoring performance in screening programmes is important. Supervised training and re-certification for endoscopists with poor performance should be considered.

Background: Randomized controlled trials of sufficient power testing the long-term effect of screening for colorectal neoplasia only exist for faecal occult blood testing (FOBT). There is indirect evidence that flexible sigmoidoscopy (FS) may have a greater yield. The aim of this study was to determine the diagnostic yield of screening with FS or a combination of FS and FOBT in an average-risk population in an urban and combined urban and rural population in Norway. Methods: 20,780 men and women (1:1), aged 50-64 years, were invited for once-only screening (FS only or a combination of FS and FOBT (1:1)) by randomization from the population registry. A positive FS was defined as a finding of any neoplasia or any polyp &#83 10 &#114 mm. A positive FS or FOBT qualified for colonoscopy. Results: Overall attendance was 65%. Forty-one (0.3%) cases of CRC were detected. Any adenoma was found in 2208 (17%) participants and 545 (4.2%) had high-risk adenomas. There was no difference in diagnostic yield between the ...

Background: To eliminate the risk of combustion during electrosurgical procedures and to reduce patient discomfort, carbon dioxide (CO2) insufflation has been recommended during colonoscopy. However, air insufflation is still the standard method, perhaps due to the lack of suitable equipment and shortage of randomised studies. Aims: This randomised controlled trial was conducted to assess patient tolerance and safety when using CO2 insufflation during colonoscopy. Patients: Over an eight month period a successive series of patients referred for a baseline colonoscopy due to findings in a flexible sigmoidoscopy screening trial were randomly assigned to the use of either air or CO2 insufflation during colonoscopy. Methods: End tidal CO2 (ETCO2), a non-invasive parameter of arterial pCO2, was registered before and repeatedly during and after the examination. The patient's experience of pain during and after the examination was registered using a visual analogue scale (VAS). Sedation was not used routinely. Results: CO2 insufflation was used in 121 patients (51%) and air in 119 patients (49%). The groups were similar in age, sex, and caecal intubation rate. No rise in ETCO2 was registered. There were statistically significant differences in VAS scores between the groups with less pain reported when using CO2. Conclusions: This randomised study of unsedated patients shows that CO2 insufflation is safe during colonoscopy with no rise in ETCO2 level. CO2 was found to be superior to air in terms of pain experienced after the examination.

Background: A randomized sample of 14,000 men and women, aged 55-64 years, resident in the City of Oslo and Telemark County, were drawn from the population registry to be offered a flexible sigmoidoscopy (FS) screening examination. A questionnaire was designed to modify routines and evaluate patient satisfaction. Methods: Consecutive participants (4956) were given a questionnaire immediately after the FS to be filled in and returned by mail on the following day. Participants were asked questions about service, practical issues, and the level of pain during the FS and post-examination discomfort. They were also encouraged to give their comments in free text. Results: Questionnaire replies were received from 4574 (92%) out of 4956 participants. The vast majority reported to have experienced no (70%) or slight (21%) pain during the examination. Women reported pain and post-examination discomfort more often than men. Pain was also associated with age of the patient and length of bowel examined, but not with t...

In the past three decades, the incidence of colorectal cancer (CRC) in Norway has doubled, surpassing all other Nordic countries for both men and women to become the most frequently diagnosed cancer. A small-scale, randomized study on flexible sigmoidoscopy (FS) screening in Telemark, Norway, has shown a reduction in accumulated CRC incidence after 13 years. The aim of our study was to evaluate the effect on CRC mortality and morbidity by screen detection of CRC and removal of precursor lesions (polypectomy), and to test out the management and organization mimicking a countrywide screening service. A total of 13,823 men and women (1:1), age 55-64 years, were drawn randomly from the population registries in Oslo (urban) and the county of Telemark (mixed urban and rural) and invited to have a screening examination. The rest of the relevant age cohorts constituted the control groups. In the screening group, 535 individuals were excluded according to exclusion criteria, rendering 13,288 individuals eligible for screening examination.A once only screening model was used. In the screening group, individuals were randomized to have a once only FS or a combination of FS and faecal occult blood test (FOBT).The overall attendance rate was 8,849 out of 13,288 (67%); 73% in Telemark and 60% in Oslo. Attendance for FS only was 68% and 65% for combined FSFOBT.The present FSIFSFOBT screening study obtained a high acceptance rate for both screening modalities. The attendance rate was stable throughout the trial, suggesting an acceptable model for management of future countrywide screening.

Flexible sigmoidoscopy is currently recommended as a screening modality for colorectal cancer. However, a substantial number of patients experience discomfort because of the procedure. possibly limiting compliance and thus screening success. During endoscopy, air is commonly used to insufflate the bowel. Carbon dioxide rather than air insufflation has been shown to reduce procedure-related pain and discomfort in colonoscopy. The aim of the present study was to evaluate whether carbon dioxide insufflation reduces discomfort during and after flexible sigmoidoscopy for colorectal cancer screening.In a randomized, double-blinded design, 230 consecutive participants in a population-based flexible sigmoidoscopy colorectal cancer screening trial were assigned to have their examination performed with either carbon dioxide or air insufflation. Patients were asked to grade discomfort experienced both during and in the hours after the procedure on a visual analogue scale.Carbon dioxide insufflation significantly reduced the amount of discomfort at 1, 3 and 6 h after the sigmoidoscopy. One hour after the examination. 84% of patients in the CO2 group reported no discomfort, compared to 64% in the air group (P = 0.006). No differences between the groups were observed during the examination.Carbon dioxide insufflation significantly reduced post-examination discomfort. The use of carbon dioxide rather than air insufflation may contribute to better public acceptance for flexible sigmoidoscopy screening.

The concept of frailty plays a major role in the statistical field of survival analysis. Frailty variation refers to differences in risk between individuals which go beyond known or measured risk factors. In other words, frailty variation is unobserved heterogeneity. Although understanding frailty is of interest in its own right, the literature on survival analysis has demonstrated that existence of frailty variation can lead to surprising artefacts in statistical estimation that are important to examine. We present literature that demonstrates the presence and significance of frailty variation between individuals. We discuss the practical content of frailty variation, and show the link between frailty and biological concepts like (epi)genetics and heterogeneity in disease risk. There are numerous suggestions in the literature that a good deal of this variation may be due to randomness, in addition to genetic and/or environmental factors. Heterogeneity often manifests itself as clustering of cases in families more than would be expected by chance. We emphasize that apparently moderate familial relative risks can only be explained by strong underlying variation in disease risk between families and individuals. Finally, we highlight the potential impact of frailty variation in the interpretation of standard epidemiological measures such as hazard and incidence rates.

Weight-bearing stress may be a risk factor for both human and canine primary bone cancer. A cohort of Leonbergers (LB) was followed from birth to death and the cause of death recorded. We hypothesised that dogs dying due to primary bone cancer would be larger; measured by bodyweight (BW) and the circumference of the distal radius and ulna (CDRU) than those of the same breed that died of other causes. Information obtained from breeders, owners and veterinary surgeons were questionnaire-based. The dogs were examined by a veterinary surgeon at pre-specified “observational ages” (3, 4, 6, 12, 18, and 24m). Data were recorded, including BW and CDRU. The study population consisted of 196 LB, 9 of which died due to primary bone cancer (6 males, 3 females). Individual growth curves, showing BW and CDRU during the first 2 years of life, were made for these 9 dogs and compared to gender-specific mean values for LB that died from other causes. These curves showed that LB succumbing to primary bone cancer generally had a higher BW during the growth period than the remaining dogs, and that this difference appeared to be largest in the male LB. Male LB that developed primary bone cancer later in life also had a larger CDRU during most part of this period, as compared to those that did not develop this disease. Logistic regression showed a statistically significant effect of BW on the odds ratio of developing primary bone cancer at 12m and 18m and of CDRU at 18m, and a Poisson regression verified consistency of these results. At these ages, an increase in BW of 1 kg yielded a nearly 20% higher risk of developing primary bone cancer, while a 1 cm larger CDRU was associated with a nearly 70% increased risk. These findings support that weight-bearing stress during the period of high proliferative activity in the long bones associated with growth may increase the risk of canine primary bone cancer.

BACKGROUND: We investigated perinatal factors in relation to bone cancer subtypes, osteosarcoma (OS), Ewing Sarcoma (ES) and chondrosarcoma (CS).MATERIALS AND METHODS: All cases in Norway (1970-2009), Sweden (1974-2009) and Denmark (1980-2010)RESULTS: Higher maternal education was associated with a 40% increase in OS risk (95% CI 1-93%). The RR for OS was 3.22 (95% CI 1.37-7.59) comparing offspring of hypertensive mothers with those of mothers with a normotensive pregnancy, and Cesarean section was associated with a 29% risk reduction (95% CI 0-50%). When gestational age, birth weight and birth length were assessed simultaneously, there were no associations with any of the bone tumor subtypes.CONCLUSION: These results provided little evidence of an important role of pregnancy factors in the etiology of bone cancers. Higher maternal education may be associated with factors, possibly early nutrition or other correlates of socioeconomic status, that increase OS risk in offspring. The elevated OS risk associated with gestational hypertension and reduced risk associated with Cesarean section warrant replication.

Hypergastrinaemia is observed commonly in human patients with gastric carcinoma and is associated with atrophic gastritis and Helicobacter pylori infection, both of which predispose to development of gastric tumours. Increased expression of gastrin is also described as a prognostic indicator for gastric carcinoma in man. Gastric carcinoma is rare in dogs and generally carries a grave prognosis. In this study, the expression of gastrin was investigated immunohistochemically in gastric biopsy samples from 64 dogs with gastric carcinoma. Serum gastrin concentrations were measured in 15 of these dogs and compared with those of seven healthy control dogs. Tumour tissue expressed gastrin in 8% (5/64) of the dogs with gastric carcinoma. There was no significant difference in serum gastrin concentrations between dogs with gastric carcinoma and healthy controls (P = 0.08). Expression of gastrin in gastric carcinomas is less common in dogs than in man and may therefore not be relied on as a prognostic marker in this species. Serum gastrin concentration alone is also not a useful biomarker for gastric carcinoma in dogs.

There is substantial evidence for the beneficial effect of screening programmes aimed at reducing mortality from colorectal cancer (CRC). The effect on all-cause mortality, however, may not necessarily be beneficial. In the present study we used the follow-up results 13 years after a flexible sigmoidoscopy screening to evaluate the long-term effects of informing participants about findings at flexible sigmoidoscopy (FS) screening. There were no severe complications and there was no long-term difference in deaths related to whether there had been any mucosal rupture (biopsy or snare resection) or not. As a group, those who attended in 1983 and were informed that they had polyps tended to improve their smoking habits more than those informed that they had no polyps. Similarly, and in spite of more people giving up smoking, the group with polyps had a trend towards a smaller increase in BMI (+0.7 (95% CI 0.2-1.1)) than the polyp-free group (+1.2 (95% CI 0.9-1.6)) (P = 0.07). The observations suggest that flexible sigmoidoscopy screening may face an educational challenge to avoid unfavourable changes in the lifestyle of screenees, an effect that may more than outweigh the beneficial effect of screening.

Objectives: The aim of the present prospective study was to identify possible risk factors of testicular cancer (TC) in relation to gestation and birth.Methods: Based on data from compulsory birth and cancer registration in Norway, odds ratios (ORs) of TC were estimated.

OBJECTIVE: The etiology of childhood cancers is largely unknown. Studies have suggested that birth characteristics may be associated with risk. Our goal was to evaluate the risk of childhood cancers in relation to fetal growth. METHODS: We conducted a case-control study nested within Nordic birth registries. The study included cancer cases diagnosed in Denmark, Finland, Norway, and Sweden among children born from 1967 to 2010 and up to 10 matched controls per case, totaling 17 698 cases and 172 422 controls. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were derived from conditional logistic regression. RESULTS: Risks of all childhood cancers increased with increasing birth weight (Ptrend ≤ .001). Risks of acute lymphoid leukemia and Wilms tumor were elevated when birth weight was >4000 g and of central nervous system tumors when birth weight was >4500 g. Newborns large for gestational age were at increased risk of Wilms tumor (OR: 2.1 [95% CI: 1.2–3.6]) and connective/soft tissue tumors (OR: 2.1 [95% CI: 1.1–4.4]). In contrast, the risk of acute myeloid leukemia was increased among children born small for gestational age (OR: 1.8 [95% CI: 1.1–3.1]). Children diagnosed with central nervous system tumors at 39 cm had the highest risk (OR: 4.7 [95% CI: 2.5–8.7]). CONCLUSIONS: In this large, Nordic population-based study, increased risks for several childhood tumors were associated with measures of fetal growth, supporting the hypothesis that tumorigenesis manifesting in childhood is initiated in utero.

Do cancer and cancer treatment influence patients' subsequent pregnancies and outcomes for the offspring? In this study, we compared birth outcomes in 3,915 female and male survivors and 144,653 controls from the general population with similar parity, by merging data from the Cancer Registry and the Medical Birth Registry of Norway. The cancer survivors were diagnosed at age 16-45 in the period 1967-2004. Subgroups of nulliparous survivors (childless before cancer) and primiparous (one pregnancy before and one after cancer) were analyzed, using logistic regression to compare birth outcomes with controls, focusing perinatal death, congenital anomalies, preterm birth (