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A growing number of estrogen receptor beta (ER beta) splice variants are reported. Several of these have been discovered in testis, but with few exceptions little is known about their cellular localization. The aim of this study was to identify and elucidate the mRNA expression pattern of the different ER beta splice variants in human testicular cells. Northern analysis was performed on whole testis and fractions enriched in germ cells from untreated men and from estrogen-treated men undergoing sex change surgery. Probes were constructed in order to systematically screen for and identify various ER beta splice variants. Several ER beta bands were observed in the human testis, in which splice variants constituted the major part of total ER beta transcripts. Interestingly, only two ER beta wild-type transcripts were detected. These seem to be virtually absent from the haploid germ cells and are probably mainly located in somatic cells and/or primary spermatocytes. Several novel ER beta deletion variants were found in high levels in the haploid germ cell fractions and were nearly absent in testicular cells from the estrogen-treated men. The cell-dependent distribution raises the question whether splice variants may have specific functions in spermatogenesis, and whether the differential splicing of ER beta is regulated in a cell-specific manner.

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.

Testicular tumors in humans are reported to be significantly increasing in incidence. Embryo exposure to environmental estrogens has been proposed as one of the possible underlying causes. In mice, genetic, immunological, and experimental evidence suggest that germ cell testicular tumors may derive from primordial germ cells (PGCs), the embryonic precursors of gametes. Here we show that relatively high concentrations of estrogens stimulate mouse PGC growth in vitro through the somatic cells of the gonadal ridges. Moreover, we found that estrogens stimulate the transcription of the Steel gene and the production of c-Kit ligand in gonadal somatic cells, and that this growth factor is likely to be responsible for the observed stimulation of PGC growth via an Akt/PTEN pathway. Finally, we show that estrogen stimulation of gonadal somatic cells in culture, in combination with PTEN down-regulation in PGCs and the presence of leukemia inhibitory factor in the culture medium, result in high frequency of PGC transformation in tumorigenic cells. Based on these results, we present a novel experimental in vitro model for tumorigenic germ cell transformation and identify molecular pathways likely involved in development of germ cell tumors after estrogen exposure.

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 ...

The World Health Organization (WHO) laboratory manual (1992) states the normal values for pH in liquefied semen to be between 7.2 and 8.0. This implies an adjustment compared with the previous version (WHO, 1987) in which the upper limit was 7.8, whereas in the WHO clinical manual (1993) the normal range of values is still stated to be in the range of 7.2-7.8. In this study pH was measured in ejaculates from 207 men in couples undergoing infertility examination. The pH was measured within 30 and 60 min after ejaculation with both pH paper and pH meter. The mean pH values were consistently well above 8.0 regardless of analysis method and time after ejaculation. Since semen analysis is part of clinical assessment of male infertility and includes pH measurement, our findings suggest that the range of normal values needs to be revised further.

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.

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 = 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.

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.

In order to study the possible placental transfer of the Fusarium mycotoxin zearalenone (ZON), Sprague Dawley rats were treated with a single dose (0.74 mg/kg b.w.) of ZON i.v. on day 12 or day 18 of pregnancy, or intragastrically (i.g.) on day 18 of pregnancy. Samples of placenta, foetus, and maternal liver and spleen were collected for chemical analyses 0.3 h after treatment on day 12, and 0.3, 4, and 24 h after treatment on day 18. Three rats were used for each pregnancy day, administration route, and exposure time. The concentrations of ZON and its metabolites alpha- and beta-zearalenol (-ZOL) were determined quantitatively by high-performance liquid chromatography (HPLC) after incubation with beta-glucuronidase and purification on immunoaffinity columns. Tissue distribution was studied by means of whole body autoradiography at 4 and 24 h after treatment with tritiated ZON (750 microCi/kg b.w; 7.4 mg/kg b.w.) on day 18 of pregnancy. ZON and alpha-ZOL were transferred into the foetus on both gestational days. However, a delay in distribution into the foetus, relative to the maternal tissue, was observed. Beta-ZOL was below the detection limit in the foetus. No specific site of foetal accumulation of ZON or its metabolites was apparent. In the maternal tissues, the highest levels of ZON and of alpha- and beta-ZOL were found in the liver.

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.

Long-term effects of brief in utero exposure to diethylstilboestrol (DES) during a foetal period known to be critical for gonadal development were evaluated. Rats were exposed to DES (100 μg/kg body-weight) from day 17 to 19 of pregnancy. All of the DES-treated pregnant rats (11/11) ate parts or whole of their offspring during the first day after birth (p = 0.03). Surviving male offspring were examined on day 63 post-partum. DES induced a reduction in weight of the testis (p = 0.06) and ventral prostate (p = 0.07), even after this short exposure. DES tended to reduce the number of Sertoli cells (p = 0.13). Our findings indicate that even a short in utero exposure of rats to DES during a critical period for gonadal development results in cannibalism and reduced testis and ventral prostate weight.

The in vivo estrogenic potency of zearalenone (ZEA), a mycotoxin produced by different strains of Fusarium fungi, and its metabolites (alpha- and beta-zearalenol), have been studied in fish. Estrogenicity was evaluated using an in vitro competitive receptor binding assay and in vivo induction of vitellogenesis and zonagenesis, two estrogen receptor (ER)-mediated responses that are integral aspects of fish oogenesis. The ER binding affinities of alpha-zearalenol and ZEA in rainbow trout (Oncorhynchus mykiss) were approximately 1/150 and 1/300 to that of estradiol, respectively. Juvenile salmon (Salmo salar) were exposed to a single intraperitoneal injection of ZEA, alpha-zearalenol and beta-zearalenol (each at 1 and 10 mg/kg) and compared to fish injected with estradiol-17 beta (E2; 5 mg/kg) and controls. Using indirect enzyme-linked immunosorbent assay (ELISA) with homologous antibodies, a dose-dependent induction of vitellogenin (Vtg) and eggshell zona radiata proteins (Zr-proteins) were observed 7 days after exposure to ZEA and alpha-zearalenol. beta-Zearalenol did not elevate plasma Vtg levels, but a non-significant elevation of plasma Zr-proteins levels was observed at the highest dose (10 mg/kg). Generally, alpha-zearalenol and ZEA possess estrogenic potencies that are approximately 50% compared to that of E2, and their order of estrogenic potency (in both in vitro receptor competitive binding and in vivo induction of Vtg and Zr-proteins levels) is: alpha-zearalenol > ZEA > beta-zearalenol. Our results show that blood plasma analysis of Vtg and Zr-proteins levels provides a suitable in vivo fish model for assessing the estrogenic potencies of ZEA and its metabolites.

Mounting evidence confirms that hepatic biosynthetic processes are essential for female sexual maturation in fish, which is directly controlled by estrogens. These oogenetic events (zonagenesis and vitellogenesis) are induced in both sexes by estrogens. In this paper, we report the induction of zona radiata (zr) proteins and vitellogenin in primary hepatocytes from Atlantic salmon (Salmo salar L.) exposed to xenoestrogens and mycotoxins. Cells were treated with doses of 1, 5, and 10 microM 4-nonylphenol (4-NP), o, p'-DDT, lindane ([gamma]-HCH), and bisphenol A (BPA), which all induced zr proteins and vitellogenin in an approximate dose-dependent manner. Hepatocytes were also treated with combinations of xenoestrogens at 1 or 2 microM, resulting in elevated levels of both zr proteins and vitellogenin, compared to single treatment. The estrogenic activity of the mycotoxin zearalenone (ZEA) and its metabolites [alpha]-ZEA) and ss-zearalenol (ss-ZEA)], with regard to zonagenesis and vitellogenesis, was assessed in this assay system. Mycotoxins were used at concentrations of 10, 100, or 1,000 nM. All induced zr proteins and vitellogenin, with [alpha]-ZEA being the strongest inducer. When cells were treated with xenoestrogens or mycotoxins in combination with an estrogen receptor inhibitor (ICI 182,780), the induction of both zr proteins and vitellogenin was inhibited in all cases. Thus, the reported estrogen effects are bonafide estrogen responses. Zona radiata proteins were more responsive than vitellogenin to both xenoestrogens and mycotoxins. The versatility and sensitivity of the hepatocyte assay demonstrates that biosynthesis of zr proteins provides a new supplementary method for estimating xenoestrogenicity and mycotoxin action. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7

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 (

STUDY QUESTION Is there an association between testicular germ cell tumor (TGCT) and genetic polymorphisms in AKT1, PTEN and the 8q24 locus? SUMMARY ANSWER Our findings suggest that genetic variation in PTEN may influence the risk of TGCT. WHAT IS KNOWN ALREADY There is strong evidence that genetic variation influences the risk of TGCT. The oncogene, AKT1, the tumor suppressor gene, PTEN and the chromosome 8q24 locus play important roles in cancer development in general. STUDY DESIGN, SIZE, DURATION We have conducted a population-based Norwegian-Swedish case-parent study, based on cases diagnosed in 1990-2008, including 831 triads (TGCT case and both parents), 474 dyads (TGCT case and one parent) and 712 singletons (only the TGCT case). In addition we expanded the study to include 3922 unrelated male controls from the TwinGene project. PARTICIPANTS/MATERIALS, SETTING, METHODS We genotyped 26 single nucleotide polymorphisms (SNPs) in AKT1, PTEN and the 8q24 locus. First, triads and dyads were included in a likelihood-based association test. To increase the statistical power, case singletons and controls from the TwinGene project were included in a single test for association. We examined if the allelic effect on TGCT risk differed by histological subgroup, country of origin or parent of origin. Odds ratios (ORs) and 95% confidence intervals (CI) were calculated with Bonferroni correction (P bonf) for multiple testing. MAIN RESULTS AND THE ROLE OF CHANCE In the case-parent analyses, none of the 26 SNPs were significantly associated with TGCT. Of the 23 SNPs investigated in the combined study, one SNP in PTEN (rs11202586) remained associated with TGCT risk after adjusting for multiple testing (OR = 1.16, 95% CI = 1.06-1.28, P bonf = 0.040). We found no difference in risk according to histological subgroup, parent of origin or between countries. LIMITATIONS, REASONS FOR CAUTION Our study is strengthened by the population-based design and large sample size, which gives high power to detect risk alleles. The reported association was not highly significant, and although it was based on an a priori hypothesis of this tumor suppressor gene being implicated in the etiology of TGCT, replication studies, as well as functional studies of this polymorphism, are warranted. WIDER IMPLICATIONS OF THE FINDINGS We report, to our knowledge, a novel association between TGCT and a marker in the tumor suppressor gene PTEN. Previous studies have linked PTEN to TGCT etiology, and there is also a link between PTEN and KITLG, which contains TGCT susceptibility loci revealed through recent genome-wide studies.

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 (37 gestational weeks) and low birth weight (LBW,2,500 g). We adjusted for maternal age, birth period and educational level. Nulliparous female survivors' offspring had increased risk of preterm birth (OR = 1.30 [95% CI 1.05-1.61]) but similar risks of LBW and perinatal death as their controls. Primiparous female survivors differed from their controls, with higher frequency of preterm birth (OR = 1.89 [95% CI 1.40-2.56]) and LBW at term (OR = 2.02 [95% CI 1.15-3.55]). A borderline significant increase of perinatal death was seen among offspring of primiparous female survivors, with OR = 1.92 (95% CI 0.98-3.76). Offspring of male survivors did not differ from their controls. For all cancer types combined, no increased risk of congenital anomalies was seen among either female or male survivors' offspring. Pregnant female cancer survivors should be offered close follow-up, as there is an increased risk of adverse birth outcomes, in particular among those with higher parities.

Introduction Mammographic density (MD) is one of the strongest known breast cancer risk factors. Estrogen and progestin therapy (EPT) has been associated with increases in MD. Dense breast tissue is characterized by increased stromal tissue and (to a lesser degree) increased numbers of breast epithelial cells. It is possible that genetic factors modify the association between EPT and MD, and that certain genetic variants are particularly important in determining MD in hormone users. We evaluated the association between MD and 340 tagging single nucleotide polymorphisms (SNPs) from about 30 candidate genes in hormone metabolism/growth factor pathways among women who participated in the Norwegian Breast Cancer Screening Program (NBCSP) in 2004. Methods We assessed MD on 2,036 postmenopausal women aged 50 to 69 years using a computer-assisted method (Madena, University of Southern California) in a cross-sectional study. We used linear regression to determine the association between each SNP and MD, adjusting for potential confounders. The postmenopausal women were stratified into HT users (EPT and estrogen-only) and non-users (never HT). Results For current EPT users, there was an association between a variant in the prolactin gene (PRL; rs10946545) and MD (dominant model, Bonferroni-adjusted P (Pb) = 0.0144). This association remained statistically significant among current users of norethisterone acetate (NETA)-based EPT, a regimen common in Nordic countries. Among current estrogen-only users (ET), there was an association between rs4670813 in the cytochrome P450 gene (CYP1B1) and MD (dominant model, Pb = 0.0396). In never HT users, rs769177 in the tumor necrosis factor (TNF) gene and rs1968752 in the region of the sulfotransferase gene (SULT1A1/SULT1A2), were significantly associated with MD (Pb = 0.0202; Pb = 0.0349). Conclusions We found some evidence that variants in the PRL gene were associated with MD in current EPT and NETA users. In never HT users, variants in the TNF and SULT1A1/SULT1A2 genes were significantly associated with MD. These findings may suggest that several genes in the hormone metabolism and growth factor pathways are implicated in determining MD.

Background Nonmalignant mammary tumors (NMT) are common in intact female dogs. Little is known about the clinical significance of these tumors, and the effect of ovariohysterectomy (OHE) on their development. Hypothesis Ovarian hormone ablation through OHE decreases the risk of new tumors and thereby improves long-term prognosis for dogs with NMT. Animals Eighty-four sexually intact bitches with NMT. Methods Dogs were allocated to undergo OHE (n = 42) or not (n = 42) at the time of NMT removal in a randomized clinical trial. Tumor diagnosis was confirmed histologically in all subjects. Information about new tumor development was collected via follow-up phone calls and recheck examinations. Separate survival analyses were performed with the endpoints new tumor development and death. Cause of death was classified as related or unrelated to mammary tumor. In addition to OHE status, the influence of age, body weight, breed, tumor size, tumor number, tumor duration, type of surgery, and tumor histology was investigated. Results New mammary tumor(s) developed in 27 of 42 (64%) intact dogs and 15 of 42 (36%) ovariohysterectomized dogs (hazard ratio 0.47, P = .022). Nine of the 42 dogs (21%) which developed new tumors were euthanized because of mammary tumor. Survival was not significantly different between the 2 treatment groups. In the intact group, nine dogs subsequently developed ovarian–uterine diseases. Conclusion Ovariohysterectomy performed at the time of mammary tumor excision reduced the risk of new tumors by about 50% among dogs with NMT. Survival was not significantly affected. Adjuvant OHE should be considered in adult dogs with mammary tumors.

The question of a possible precursor--product relationship between oval cells and hepatocytes was examined in rats treated for 2 weeks with 2-acetylaminofluorene (2-AAF) with a two-thirds partial hepatectomy (PH) performed after the first week of 2-AAF treatment (modified Solt-Farber model). Liver cells were pulse-chase labelled with bromodeoxyuridine (BrdU) on day 6 post PH. On day 7 post PH the nonparenchymal (NPC) fraction, which contains the oval cells, exhibited a labelling index (LI) approximately 10 times higher than that of the hepatocytes as analysed by flow cytometry (FCM), the majority of the proliferating cells being oval cells. At later time points, there was no significant increase in the LI of diploid hepatocytes, and no detectable shift of BrdU-labelled cells from the NPC fraction to the hepatocyte fraction, suggesting that no extensive conversion of BrdU-labelled oval cells to hepatocytes was taking place. Throughout the experimental period there was a significant increase in the diploid hepatocyte cell fraction, from 12% on day 7 to 25% on day 13 post PH. Diploid hepatocytes pulse-labelled on days 7 or 9 post PH had a high LI (7-8%), in contrast to the low LI (1%) of tetra- and octoploid cells. Proliferation of diploid hepatocytes may thus explain the large increase in the diploid hepatocyte fraction observed from days 9 through 15 post PH. Our results, therefore, provide no reason to invoke oval cells as precursors of hepatocytes in the modified Solt-Farber carcinogenesis model.

Background: Primary bone cancer comprises three major histologic types: osteosarcoma (OS), Ewing sarcoma (ES), and chondrosarcoma (CS). Given the limited knowledge about the etiology of primary bone cancer, we undertook an age-period-cohort (APC) analysis to determine whether incidence varied by birth cohort or calendar period. The purpose was to examine the temporal development of each bone cancer type and generate etiologic hypotheses via the observed birth cohort-related changes. Methods: An APC model was fitted to incidence data for U.S. whites for OS, ES, and CS obtained from nine registries of the Surveillance, Epidemiology, and End Results program, which covers about 10% of the U.S. population, 1976–2005. Results: The incidence of OS decreased between 1976 and 2005 among those aged over 60 years, a decline that occurred among patients with OS as their primary malignancy only. From 1986–1995 to 1996–2005, the incidence rate of CS among females of 20 to 69 years rose by about 50%, with rates increasing among consecutive cohorts born during 1935–1975. CS rates among males were stable, as were rates of ES. Conclusion: The risk reduction in OS as a primary malignancy at older ages could possibly be related to diminished exposure over time to bone-seeking radionuclides. The CS increase among females corresponds to birth cohorts with rising exposures to oral contraceptives and menopausal hormonal therapy. Impact: As the estrogen signaling pathway has been shown to stimulate proliferation of normal and malignant chondrocytes, estrogen exposure may increase the risk for CS. Further studies are warranted to clarify its possible etiological significance. Cancer Epidemiol Biomarkers Prev; 20(8); 1770–7. ©2011 AACR.

Background Osteosarcoma (OS) is a bone malignancy which occurs primarily in adolescents. Since it occurs during a period of rapid growth, genes important in bone formation and growth are plausible modifiers of risk. Genes involved in DNA repair and ribosomal function may contribute to OS pathogenesis, because they maintain the integrity of critical cellular processes. We evaluated these hypotheses in an OS association study of genes from growth/hormone, bone formation, DNA repair, and ribosomal pathways. Methods We evaluated 4836 tag-SNPs across 255 candidate genes in 96 OS cases and 1426 controls. Logistic regression models were used to estimate the odds ratios (OR) and 95% confidence intervals (CI). Results Twelve SNPs in growth or DNA repair genes were significantly associated with OS after Bonferroni correction. Four SNPs in the DNA repair gene FANCM (ORs 1.9-2.0, P = 0.003-0.004) and 2 SNPs downstream of the growth hormone gene GH1 (OR 1.6, P = 0.002; OR 0.5, P = 0.0009) were significantly associated with OS. One SNP in the region of each of the following genes was significant: MDM2, MPG, FGF2, FGFR3, GNRH2, and IGF1. Conclusions Our results suggest that several SNPs in biologically plausible pathways are associated with OS. Larger studies are required to confirm our findings.

In contrast to research in adults, there have been limited studies on testicular germ-cell cancer among boys aged15 years. The aim of the study was to investigate the association between perinatal characteristics and childhood testicular germ-cell cancer.We identified 152 patients with childhood germ-cell cancer among boys (15 years) born in Norway, Sweden, Finland and Denmark between 1967 and 2006 using the cancer and medical birth registries. For each case we sampled 10 population controls matched on year and country of birth. We used conditional logistic regression analysis to estimate odds ratios for cancer risk.There was a weak, positive association between high (≥4000 g) birth weight and childhood testicular germ-cell cancer (adjusted OR=1.25; 95% CI: 0.83-1.90) compared with normal birth weight, and a correspondingly elevated risk for low birth weight (adjusted OR=1.41; 95% CI: 0.43-4.56). For Ponderal Index (PI) there was an increased risk for low and high values compared to those in the middle category (adjusted OR=1.64; 95% CI: 1.03-2.62 and 1.67; 95% CI: 0.93-2.99), respectively. There was no association between birth length and childhood testicular germ-cell cancer. The adjusted OR for testicular cancer among first born was 1.40; 95% CI: 0.96-2.05. Greater maternal age and less maternal education appeared to increase the risk, but the estimates were not statistically significant.We found a U-shaped association between fetal growth, measured as the PI, and childhood testicular germ-cell cancer. Our findings support the notion that abnormal fetal growth rate confers a risk in pediatric testicular cancer [corrected].

Histologically verified tumours submitted to the Norwegian Canine Cancer Register from 1990 to 1998 were studied (n=14,401). The proportion of testicular tumours (n=345) was 2.4%, and the breakdown of histological tumour diagnoses is presented. The frequency of the most common histopathological types was 33% interstitial (Leydig), 26.4% Sertoli and 33.9% seminomas/germ cell tumours. The average age at diagnosis was 10 years, but was significantly lower for Sertoli cell tumours (8.6 years) than for the other tumour types. Following a histopathological re-evaluation, 22.5% of the original tumor diagnoses were modified. Proportional morbidity ratios were calculated and individuals from the breeds Shetland sheepdog and Collie were five times more likely to have testicular tumours than the overall average for the registry. Breed differences in the distribution of histopathologic types were observed. Shetland sheepdog and Collie were most commonly diagnosed with Sertoli cell tumours, while all tumours from Norwegian elkhound in this material were seminomas.

The aim of this study was to test whether atrial natriuretic factor (ANF) exerts any effect on human intestinal ion transport, and the porcine intestine was used as a positive control of ANF's effects. Tissues from human proximal (n = 6) and distal (n = 6) colons, and from distal ileum (n = 6) were mounted in Ussing chambers, and short circuit current (Isc) was measured subsequent to serosal application of ANF (10(-6) M), 8-Br-cyclic guanosine monophosphate (8-Br-cGMP) (10(-4) M), and theophylline (10(-2) M). ANF did not affect Isc whereas 8-Br-cGMP increased Isc by 28 (8-53), 16 (3-36), and 16 (5-41) microA cm-2 in the distal colon (DC), proximal colon (PC) and distal ileum (DI), respectively. Likewise, transepithelial potential difference (PD) became more negative by 5.0 (0.6-8.9), 2.5 (0.4-4.0) and 0.9 (0.3-2.3) mV in DC, PC, and DI, respectively, subsequent to addition of 8-Br-cGMP. Isc and PD were further increased by theophylline. Additional radio-isotope flux studies in human colon revealed that ANF did not affect electroneutral sodium and chloride transport either. For comparison, ANF (10(-6) M) was administered to large intestinal tissues from young pigs in which ANF induced a significant increase in Isc which was comparable to the 8-Br-cGMP response in humans. The porcine Isc response was partly inhibited by chloride-free solution on the serosal side, by serosal application of bumetanide (10(-4) M) and BaCl2 (10(-3) M), and mucosal application of the chloride-channel blocker diphenylamine-2-carboxylate (DPC) (10(-3) M). Mucosal amiloride (10(-5) M) pre-treatment reduced baseline Isc but did not affect the porcine intestinal Isc response to ANF. In vitro radio-autography demonstrated specific binding sites for ANF in porcine distal colon, whereas no apparent labelling was observed in human distal colon. These findings suggest that the lack of effect of ANF on sodium and chloride transport in human distal ileum and colon is probably due to lack of ANF receptors. In the porcine intestine, however, the Isc response induced by ANF seems to involve stimulation of electrogenic chloride secretion, whereas electrogenic sodium absorption seems unaffected.

The purpose of the study was to identify overall incidence and risk of developing a metachronous contralateral testicular germ cell tumor (TGCT) and compare the risk for patients treated before and after 1980 (cisplatin became available for patients with metastatic TGCT). Our hypothesis was that the risk of metachronous TCGT would be reduced for patients with metastatic disease diagnosed after 1980. We included 7,102 men with unilateral TGCT, recorded in the Cancer Registry of Norway. Allowing for competing risk, cumulative incidence and adjusted hazard ratio (HR) were estimated for different subgroups, and the diagnostic periods 1953-1979 (I) and 1980-2007 (II). Relative risks were assessed by standardized incidence ratio (SIR). In Period I and Period II, 38 and 137 males, respectively, were diagnosed with metachronous contralateral TGCT. Corresponding 20-year cumulative incidences were 1.9% and 3.9%. In Period II, risk of a second TGCT was halved [HR = 0.5, 95% confidence interval (95% CI) = 0.33-0.77] for patients with metastatic compared to localized disease. For patients presenting with localized and metastatic disease, the SIRs for Period I were 14.6 (95% CI = 9.6-21.2) and 25.3 (95% CI = 12.1-46.5), respectively. In Period II, the corresponding numbers were 19.0 (95% CI = 15.6-22.9) and 9.8 (95% CI = 6.4-14.5). In conclusion, the risk of metachronous contralateral TGCT was halved for patients with metastatic compared to localized disease in Period II, whereas this protective effect of extent of disease lacked significance for Period I. These findings support our hypothesis that cisplatin-based chemotherapy reduced the risk of a second TGCT for patients with metastatic TGCT diagnosed after 1980.

The aim of the present study was to examine the possible role of microtubules in chloride secretion by distal rat colon stimulated by prostaglandin (PGE2) and theophylline. Distal colonic tissue from male rats was mounted in Ussing chambers, and short-circuit current (Isc) was measured to assess chloride secretion. Three microtubule inhibitors, colchicine, nocodazole, and taxol, all inhibited the stimulated Isc and reduced the 60-min integrated secretory response to PGE2 and theophylline (▪Iscdt) by 39–52%, whereas the inactive colchicine analog lumicolchicine did not. Atropine and tetrodotoxin had no effect on stimulated chloride secretion. To confirm the source of Isc, unidirectional22Na+ and36Cl− fluxes were measured in tissues exposed to lumicolchicine (control) or colchicine. Control tissues absorbed both chloride [5.0 (1.1–8.6) (median and 95% confidence interval) μeq/cm2/hr] and sodium [2.8 (0.9–7.2) μeq/cm2/hr], and this net absorption was reduced by 96% and 79%, respectively, by treatment with PGE2 and theophylline due to an increase in serosal-to-mucosal chloride and sodium movement. Colchicine-treated tissues exhibited similar net basal chloride and sodium absorption that was reduced by 71% and 75%, respectively, by treatment with PGE2 and theophylline. Thus the PGE2- and theophylline-induced increase in chloride secretion was significantly reduced by colchicine (P

har vært økende helt siden registreringen startet tidlig på 1950-tallet. Data fra Oslo har i denne statistikkenalltid vært presentert samlet som et fylke. I denne artikkelen vises hyppighet av kolorektal kreft fordelt påkjønn og 25 bydeler samt for fire regioner i Oslo. Utviklingen over tid fra 1956 til 1995 er vist for Oslo og Norge.Den økende hyppighet av både tykktarm- og endetarmkreft gjennom flere tiår ser ut til å avta noe. Dette gjeldersærlig for tykktarmkreft for kvinner og endetarmkreft for menn i hele landet. Det er store variasjoner mellombydelene i Oslo for begge krefttyper og kjønn. Det er ingen signifikant samvariasjon på bydelsnivå mellom mennog kvinner for hver av de to kreftformene. Det er heller ingen samvariasjon mellom sosioøkonomiske faktorer ibydelene og hyppighet av kolorektal kreft.Sykdommens utvikling fra adenomatøs polypp til adenocarcinom over en lang periode på 10-15 år gjør den velegnettil screening. En planlagt screeningundersøkelse for kolorektal kreft i Telemark og Oslo er nærmere beskrevet.Resultatene av prosjektet forventes å danne grunnlaget for en samlet nasjonal strategi mot kolorektal kreft.Stensvold I, Grotmol T, Glattre E.SAMMENDRAGKreft i tykktarm og endetarm (kolorektal kreft) er den hyppigste kreftform i Norge for begge kjønn samlet. Hyppigheten Colorectal cancer – secular trend from 1956 through 1995: Results fromTelemark and Oslo and new screening for colorectal cancer prevention.Nor J Epidemiol ENGLISH SUMMARYColorectal cancer is the most common cancer form in Norway for both genders combined. The incidence rate hasbeen increasing ever since the registration started in the early 1950s. Data from Oslo have always been presentedas one county in the registry. This paper presents the incidence rates for colorectal cancer split by genders and the25 areas in Oslo. In addition, the secular trend from 1956 through 1995 is shown for both Oslo and Telemarkcounties as well as for the whole country. The increasing incidence rates of both colon and rectal carcinomas haveapparently levelled off over the last 10 years. This applies particularly to colon carcinoma in women and rectalcarcinoma in men for the whole country.There was a large variation between the 25 areas of Oslo for both cancer forms and between genders. Therewas no significant correlation between men and women for either of the two cancer forms at the area level inOslo. Nor was there any correlation between socioeconomic factors in areas of Oslo and the incidence rate ofcolorectal cancer.The vast majority of colorectal carcinomas develop from an adenomatous polyp over a period of 10 to 15 years.This long time span makes the disease well suited for screening. A prospective, randomized sigmoidoscopyscreening for colorectal cancer prevention in Telemark and Oslo is being planned, and the present data from thesecounties serve as important background information before the screening is scheduled to start in January 1999.1998; 8 (1): 37-43.

Medisinsk fødselsregister og Kreftregisteret inneholder personidentifiserbare data som via fødselsnummeret kan kobles sammen innenfor de rammer som lovverket gir. Denne sammenkoblingen gir oss interessante muligheter til å studere fødselskarakteristikas betydning for risikoen for å få kreft senere i livet. På den måten vil vi også kunne få informasjon om hvilke mekanismer som er med å påvirke vår kreftrisiko. Det gir oss også muligheter til å studere hvilke konsekvenser kreftforekomst med påfølgende behandling kan ha både for senere svangerskap og barn som blir født.Per 2006 er det akkumulert 12 443 krefttilfeller blant de barn som er registrert i Medisinsk fødselsregister siden det ble etablert i 1967. Selv om dette er et betydelig antall krefttilfeller, er de fordelt på mange krefttyper, noe som har begrenset nytteverdien i kreftforskningen så langt. Imidlertid vil forskningsmuligheteneøke med alderen til registeret. Også andre nordiske land har muligheter for slike koblinger, og til sammen gir dette unike muligheter til å gjennomføre interessant forskning.I denne fremstillingen gis en kort presentasjon av gjennomførte og pågående vitenskapelige studier basert på sammenkobling mellom data fra Medisinsk fødselsregister og Kreftregisteret.

OBJECTIVE: To determine the risk of colorectal cancer after screening with flexible sigmoidoscopy. DESIGN: Randomised controlled trial. SETTING: Population based screening in two areas in Norway-city of Oslo and Telemark county (urban and mixed urban and rural populations). PARTICIPANTS: 55 736 men and women aged 55-64 years. INTERVENTION: Once only flexible sigmoidoscopy screening with or without a single round of faecal occult blood testing (n=13 823) compared with no screening (n=41 913). MAIN OUTCOME MEASURES: Planned end points were cumulative incidence and mortality of colorectal cancer after 5, 10, and 15 years. This first report from the study presents cumulative incidence after 7 years of follow-up and hazard ratio for mortality after 6 years. RESULTS: No difference was found in the 7 year cumulative incidence of colorectal cancer between the screening and control groups (134.5 v 131.9 cases per 100 000 person years). In intention to screen analysis, a trend towards reduced colorectal cancer mortality was found (hazard ratio 0.73, 95% confidence interval 0.47 to 1.13, P=0.16). For attenders compared with controls, a statistically significant reduction in mortality was apparent for both total colorectal cancer (hazard ratio 0.41, 0.21 to 0.82, P=0.011) and rectosigmoidal cancer (0.24, 0.08 to 0.76, P=0.016). CONCLUSIONS: A reduction in incidence of colorectal cancer with flexible sigmoidoscopy screening could not be shown after 7 years' follow-up. Mortality from colorectal cancer was not significantly reduced in the screening group but seemed to be lower for attenders, with a reduction of 59% for any location of colorectal cancer and 76% for rectosigmoidal cancer in per protocol analysis, an analysis prone to selection bias. TRIAL REGISTRATION: Clinical trials NCT00119912.

The incidence of nasopharyngeal carcinoma (NPC) varies widely according to age at diagnosis, geographic location, and ethnic background. On a global scale, NPC incidence is common among specific populations primarily living in southern and eastern Asia and northern Africa, but in most areas, including almost all western countries, it remains a relatively uncommon malignancy. Specific to these low-risk populations is a general observation of possible bimodality in the observed age-incidence curves. We have developed a multiplicative frailty model that allows for the demonstrated points of inflection at ages 15-24 and 65-74. The bimodal frailty model has 2 independent compound Poisson-distributed frailties and gives a significant improvement in fit over a unimodal frailty model. Applying the model to population-based cancer registry data worldwide, 2 biologically relevant estimates are derived, namely the proportion of susceptible individuals and the number of genetic and epigenetic events required for the tumor to develop. The results are critically compared and discussed in the context of existing knowledge of the epidemiology and pathogenesis of NPC.

Ultrastructural studies performed on pigs revealed that numerous cytoplasmic tubulovesicles were present in resting pancreatic duct cells. Elevation of systemic arterial PCO2 from 5.5 to 11 kPa increased the number of vesicles more than twofold. Following secretin administration, concurrent with the onset of HCO3- secretion (JHCO3), the cytoplasm became devoid of vesicles, and the basolateral plasma membrane surface area more than doubled. Similar phenomena were observed in bile duct cells. After pretreatment with the microtubules-inhibiting drug colchicine, secretin failed to reduce duct cell vesicle density, and JHCO3 was reduced by c. 50% compared to the control. These ultrastructural changes resemble those described in other H+/HCO3(-)-transporting organs such as the distal nephron and the urinary bladder. Our findings are compatible with the notion that cytoplasmic vesicles containing H(+)-ATPases are incorporated into the basolateral plasma membrane of secretory cells during secretin stimulation. Active transport of H+ into interstitial fluid might therefore be the driving force underlying JHCO3.

BackgroundThe risk of sporadic colorectal cancer (CRC) is mainly associated with lifestyle factors, particularly dietary factors. Diets high in red meat and fat and low in fruit and vegetables are associated with an increased risk of CRC. The dietary effects may be modulated by genetic polymorphisms in biotransformation genes. In this study we aimed to evaluate the role of dietary factors in combination with genetic factors in the different stages of colorectal carcinogenesis in a Norwegian population.MethodsWe used a case-control study design (234 carcinomas, 229 high-risk adenomas, 762 low-risk adenomas and 400 controls) to test the association between dietary factors (meat versus fruit, berries and vegetables) genetic polymorphisms in biotransformation genes (GSTM1,GSTT1,GSTP1Ile105Val,EPHX1Tyr113His andEPHX1His139Arg), and risk of colorectal carcinomas and adenomas. Odds ratio (OR) and 95% confidence interval (95% CI) were estimated by binary logistic regression.ResultsA higher ratio of total meat to total fruit, berry and vegetable intake was positively associated with both high and low-risk adenomas, with approximately twice the higher risk in the 2ndquartile compared to the lowest quartile. For the high-risk adenomas this positive association was more obvious for the common allele (Tyr allele) of theEPHX1codon 113 polymorphism. An association was also observed for theEPHX1codon 113 polymorphism in the low-risk adenomas, although not as obvious.ConclusionAlthough, the majority of the comparison groups are not significant, our results suggest an increased risk of colorectal adenomas in individuals for some of the higher ratios of total meat to total fruit, berry and vegetable intake. In addition the study supports the notion that the biotransformation enzymes GSTM1, GSTP1 and EPHX1 may modify the effect of dietary factors on the risk of developing colorectal carcinoma and adenoma.

Summary It is well known that men with testicular cancer also have reduced fertility before diagnosis. It is unclear, however, whether their parents also have reduced fertility. We performed a population-based record linkage study comparing parental fertility among 3711 testicular cancer cases and 371 100 control males. The cases were diagnosed from 1961 to 2001, and the data were analysed by logistic regression. Included indicators of parental fertility were number of children, rate of unlike-sex twins as a proxy for dizygotic twinning rate, and proportion of boys. The number of children was reduced across increasing sibship size among both mothers [odds ratio (OR) = 0.95, p(trend) = 0.003] and fathers [OR = 0.97, p(trend) = 0.057] of subjects with testicular cancer. The proportion of unlike-sex twins was also reduced among their mothers [(OR = 0.56, p = 0.049 (adjusted for year of birth)] and fathers [(OR = 0.56, p = 0.049 (adjusted for year of birth)]. The results were only marginally changed when also adjusting for respective parental age. Our study indicates that parents of testicular cancer cases have reduced fertility. This suggests that genetic factors are important in the association between testicular cancer and reduced fertility.

Background & Aims: A potential downside of colorectal cancer screening is that a "health certificate effect" might have negative effects on lifestyle. The aim of the present randomized controlled trial was to evaluate lifestyle changes in a group of individuals offered flexible sigmoidoscopy screening compared with a control group and also in relation to screening outcome. Methods: Men and women aged 50–55 years were drawn by randomization from the population registry to be invited for flexible sigmoidoscopy screening (n = 6961) or not to be invited (n = 7000). Both groups were asked to fill in a questionnaire on selected lifestyle indicators at baseline and 3 years later. From both rounds, 3598 pairs of completed questionnaires were available for analysis from the screening group and 3462 from the control group. Results: Both groups revealed a desirable change in most lifestyle indicators. A weight gain in the screening group was, on average, 0.24 kg higher than in the control group ( P = .023). The screening group had poorer improvement in score for smoking (mean difference, 0.05; P = .013) and exercise habits (mean difference, −0.12; P = .001) and a lower increase in servings/day of fruit, berries, and vegetables (mean difference, −0.10; P = .001) compared with controls. The weight gain in screen-negative individuals (ie, no neoplasia) was, on average, 0.5 kg ( P = .020) more than for screen positives. Conclusions: The present study has demonstrated a possible health certificate effect of flexible sigmoidoscopy screening and screening outcome on lifestyle. Although modest, these findings indicate a potential need for patient education in screening programs.

Context: Betaine is formed from the essential nutrient choline or is supplied from the diet. It serves as a substrate in the betaine-homocysteine methyltransferase reaction and thereby provides methyl groups for the homocysteine-methionine cycle, which is regulated by enzymes dependent on folate, vitamin B12, riboflavin (vitamin B2), or vitamin B6.Objective: We investigated how betaine affected total homocysteine (tHcy) concentration within the frame of variable B-vitamin status and according to the methylenetetrahydrofolate reductase (MTHFR) 677C->T genotype.Design/Setting/Patients: This is a population-based study with a cross-sectional design. It includes 10,601 healthy men and women aged 50–64 yr.Outcome Measures: Plasma samples were analyzed for tHcy, betaine, choline, dimethylglycine, riboflavin, and vitamin B6, whereas folate and vitamin B12 were analyzed in serum.Results: Betaine was a strong determinant of plasma tHcy in subjects with low serum folate and the MTHFR TT genotype. The association was further strengthened at low levels in the circulation of the other B-vitamins (B2, B6, and B12). Thus, in subjects with the combination of serum folate in the lowest quartile, low vitamin B2, B6, and B12 status, and the MTHFR TT genotype, the difference in tHcy (mean, 95% confidence interval) across extreme plasma betaine quartiles was 8.8 (1.3–16.2) μmol/liter.Conclusion: Betaine may thus be an important one-carbon source, particularly in MTHFR 677 TT subjects with inadequate B-vitamin status.

Small non-coding RNAs play essential roles in tumorigenesis. However, their role in testicular germ cell tumor (TGCT), the most common malignancy in young males in most western countries, is largely unknown. In particular, a comprehensive analysis of the small RNA composition, including microRNAs (miRNAs), PIWI-interacting RNAs (piRNAs), and tRNA-derived small RNAs and their interactions, are lacking. tRNA-derived small RNAs have been shown to bind to the piRNA-associated protein HIWI2, indicating crosstalk between small RNA pathways. We have employed small RNA sequencing on 22 human TGCT samples from 5 histological subtypes, 3 carcinoma in situ, and 12 normal testis samples. The sequences from each sample group were analyzed according to sequence length, base composition, and their association with repeats, exons, tRNAs, piRNAs, and miRNAs. Most sequences 24-32 nucleotides in length, displayed piRNA characteristics. Expression analyses of the small RNA contigs demonstrated global loss of small RNAs in TGCT compared to normal testis. A large proportion of the 33-36 nt RNA sequences derives from mature tRNAs, predominantly from the 5′ end. We did not identify differences in the expression of 5′ tRNA halves between normal and cancer tissue samples; however, 3 shorter 5′ tRNA fragments showed differential expression. Although components of the same pathways might be involved in piRNA and tRNA-derived small RNAs biogenesis, expression differences in TGCT samples suggest independent regulation of key components in response to the carcinogenic process. Our results show subtype-specific microRNA expression, as well as a global loss of piRNAs in all TGCT histological subtypes when compared to normal testicular tissue. In addition, we document the presence of large amounts of tRNA-derived sequences in both TGCT and normal samples, which may provide new insight into the association between the tRNA fragments and piRNA biogenesis. These results may be valuable in the identification of new biomarkers for TGCT. Citation Format: Trine B. Rounge, Kari Furu, Rolf Skotheim, Trine B. Haugen, Espen Enerly, Tom Grotmol. Small RNA profiling of human testicular germ cell tumor tissue samples shows abundant tRNA fragments and global loss of piRNA. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-296. doi:10.1158/1538-7445.AM2015-LB-296

The latest figures from the Cancer Registry of Norway show that Norway has the highest incidence rate of testicular cancer in the world. They also show that the incidence rate continues to increase, as it has for the last decades in the western world. The reasons for this increase, which might also be true for urogenital abnormalities in men and reduced sperm quality, are uncertain. Data suggest, however, that these anomalies originate in foetal life, and that contributing factors are genetic, pregnancy-related and environmental. The potential importance of environmental factors must be taken seriously, and the authorities must take action to strengthen the research in this area.

BACKGROUND: Lifestyle is a well-established risk factor for colorectal cancer (CRC) and is also found to be associated with occurrence of adenomas. In the present study we evaluated risk factors for both low-risk adenomas and advanced neoplasia in asymptomatic individuals using a single-paged questionnaire. Aiming to see if the questionnaire was a useful tool in picking up high-risk individuals. METHODS: A cross-sectional study was carried out within a randomised controlled colorectal cancer screening trial (n = 6961). The population comprised men and women born between 1946 and 1950. Before screening in year 2001 they were asked to fill in a questionnaire about their present lifestyle. Cases were categorised according to the most severe findings at screening. Analyses were then conducted to find risk factors associated with the presence of either low-risk adenomas or advanced neoplasia. RESULTS: The response rate among attendees was 97% (3998/4111). Among these, 3447 (86%) had no neoplasia, 443 (11%) had low-risk adenomas, and 108 (3%) had advanced neoplasia. Low-risk adenomas were significantly associated with current smoking, and obesity. Participants with advanced neoplasia had a two-fold increased risk of not adhering to any of the selected lifestyle recommendations compared to controls. However, current smoking was the only variable that reached statistical significance in the multivariate analysis for these lesions. A dose-response relationship to the consumption of cigarettes per day was shown, where OR was 2.04 (CI 1.07-3.89) for the lowest consumption category. CONCLUSION: The present findings indicate that a short questionnaire may be adequate in picking up the most consistent associations between lifestyle risk factors and colorectal neoplasia. Smoking and BMI were found to be the most significant risk factors for neoplasia, but adhering to recommendations on diet, and physical activity seems also to be of importance. Denne artikkelen ser på livsstil i forhold til funn av adenomer og cancer påvist ved screening. Styrken i denne studien ligger i at livsstilsdata ble registrert før screening, dvs. før noen visste om det forelå adenomer/cancer eller ikke. Dermed unngikk man vanlig observer bias som begrenser case/control studier på dette. Studien viste at røyking og BMI (kroppsmasseindeks) var sterkest assosiert med forekomst av avansert neoplasi (store adenomer, adenomer med grov dysplasi eller villøse komponenter eller cancer), men det på holde seg til anbefalt kosthold og ikke røyke hadde også betydning.

The aim of the present study was to evaluate to what extent lifestyle-related variables predict participation for flexible sigmoidoscopy (FS) screening when the compliance is relatively high. During 2001, a randomized sample of 6961 men and women, born between 1946 and 1950, were invited to have a flexible sigmoidoscopy screening examination. Attendees (n = 4111) were asked to fill in a questionnaire focusing on physical activity, body weight, smoking habits and diet. The questionnaire was sent by mail to non-attendees (n = 2628) and a randomized corresponding control group not invited to screening (n = 7000). Sixty-one percent attended for screening. The questionnaire response rate among attendees, non-attendees and controls was 97, 11 and 61%, respectively. Attendees were more physically active (P < 0.001), and showed more adherence to general dietary recommendations, compared with controls. Opposing their healthy exercise and dietary habits, however, attendees were more likely to be moderate smokers compared with controls. The present offer of FS screening, achieving a relatively high compliance rate, may have reached attendees using screening as a supplement to an already healthy lifestyle, but also those who seek amelioration through health checks for risks behaviour that they are perfectly well aware of, such as smoking.

Background and study aim Valid tissue sampling of colorectal adenomas is crucial for their management in terms of treatment and follow-up. The aim of this study was to assess the validity of a cold biopsy sample as representative for the whole polypectomy specimen, with regard to histopathological features. Patients and methods As part of the Norwegian Colorectal Cancer Prevention trial, 442 participants (60% men) who fulfilled the criterion of colonoscopic recovery of adenoma that had been biopsied at flexible sigmoidoscopy, had their adenomas subsequently removed by polypectomy (snare resection) at colonoscopy. Logistic regression analysis was used to determine which variables contributed to the histopathological discrepancy between cold biopsy and polypectomy specimens. Results Among the 532 colorectal adenomas biopsied at flexible sigmoidoscopy and removed by colonoscopy, the assessment of intraepithelial neoplasia (dysplasia) status was changed in 51 adenomas (10%), and 38 (7%) of them had been underestimated at biopsy compared with polypectomy. Likewise, the assessment of villousness was changed in 45 adenomas (9%), being upgraded in 26 (6%) at polypectomy compared with biopsy. In a multivariate model, the diameter of neoplasia at polypectomy was positively associated with increased risk of the underestimation of intraepithelial neoplasia and/or villousness influencing a diagnosis of advanced colorectal neoplasia, when cold biopsy and polypectomy specimens were compared ( Ptrend=0.01). Among 56 cases of advanced neoplasia, 35 (63%) showed only low-grade intraepithelial neoplasia on biopsy. Conclusions Biopsy-based diagnosis underestimated histopathological diagnosis in about 10% of colorectal adenomas detected by flexible sigmoidoscopy screening, but advanced neoplasia was underestimated in more than 60%. Efforts must be made to obtain polypectomy specimens to secure precise diagnosis.

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.