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Studies have suggested that prostate cancer (PCa) patients receiving androgen deprivation therapy (ADT) are at increased risk of developing or exacerbating cardiovascular disease (CVD). We aimed to explore the association between ADT for PCa and subsequent CVD and all-cause mortality in this nationwide, longitudinal study. We also evaluated the role of cardiovascular risk and ADT duration to determine effect modification. Norwegian registry data were used to identify patients with PCa from 2008-18 and who received primary ADT in the first year after diagnosis. The associations between ADT and composite cardiovascular events, and the individual components of myocardial infarction, stroke and heart failure, in addition to atrial fibrillation and all-cause mortality, were explored using time-varying Cox regression models. We included 30 923 PCa patients, of whom 8449 (27%) received primary ADT. Mean follow-up was 2.9 and 3.8 years for CVD events and mortality, respectively. We found an association between ADT and composite CVD (adjusted HR 1.13: 95% CI 1.05-1.21), myocardial infarction (1.18: 1.05-1.32), stroke (1.21: 1.06-1.38), heart failure (1.23: 1.13-1.35) and all-cause mortality (1.49: 1.39-1.61). These associations persisted in those with low and moderate CVD risk and ADT longer than 7 months. A relationship between ADT and composite CVD and all-cause mortality was observed, especially in those with moderate CVD risk and longer treatment duration. Future studies with more detailed cancer data are needed to verify the clinical relevance of these results, especially when considering all-cause mortality within the context of treatment guidelines and benefits of ADT. publishedVersion

Angiogenesis is necessary for tumor growth and has been targeted in breast cancer; however, it is unclear which patients will respond and benefit from antiangiogenic therapy. We report noninvasive monitoring of patient response to neoadjuvant chemotherapy given alone or in combination with anti‐vascular endothelial growth factor (bevacizumab) in a randomized clinical trial. At four time points during neoadjuvant chemotherapy ± bevacizumab of receptor tyrosine‐protein kinase erbB‐2‐negative breast cancers, we measured metabolites and inflammation‐related markers in patient's serum. We report significant changes in the levels of several molecules induced by bevacizumab, the most prominent being an increase in pentraxin 3 (PTX3) and von Willebrand factor (VWF). Serum levels of AXL, VWF and pulmonary and activation‐regulated cytokine (PARC/CCL18) reflected response to chemotherapy alone or in combination with bevacizumab. We further analyzed serum cytokines in relation to tumor characteristics such as gene expression, tumor metabolites and tumor infiltrating leukocytes. We found that VWF and growth‐differentiation factor 15 tumor mRNA levels correlated with their respective serum protein levels suggesting that these cytokines may be produced by tumors and outflow to the bloodstream while influencing the tumor microenvironment locally. Finally, we used binomial logistic regression which allowed to predict patient's response using only 10 noninvasive biomarkers. Our study highlights the potential of monitoring circulating levels of cytokines and metabolites during breast cancer therapy © 2019 The Authors. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Previous studies on metabolic factors and bladder cancer (BC) risk have shown inconsistent results and have commonly not investigated associations separately by sex, smoking, and tumor invasiveness ...

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.

The prevalence of clinically relevant HPV types and their specific risk for progression and regression in women with atypical squamous cells of uncertain significance (ASCUS) and low-grade squamous intraepithelial lesions (LSIL) were studied in a routine screening population. A 4-year cohort of women (n = 820) with ASCUS/LSIL and a positive HPV test in triage were followed for 6-9 years. The progression risks for CIN2+/CIN3+ were determined for single (71.2%) and multiple HPV infections (28.8%). The CIN2+ progression risk for all HPV 16, all HPV 35, single HPV 16 and single HPV 35 infections were 65.3% (95% CI: 59.6-71.0), 64.4% (95% CI: 50.4-78.4), 63.8% (95% CI: 56.2-71.4) and 73.7% (95% CI: 53.9-93.5), respectively. Based on CIN2+ progression risks four main groups were defined; the HPV 16 group, the HPV 31/33/35 group, the HPV 18/45/51/52 group and the HPV 39/56/58/59/66/68 group with progression risks of 65.3% (95% CI: 59.6-71.0), 62.1% (95% CI: 54.8-69.4), 52.6 (95% CI: 45.9-59.3) and 39.5 (95% CI: 33.0-46.0), respectively. In multivariate analyses, women in the age group 40-49 years had an increased risk of CIN2+ progression. As for CIN3+, HPV 16 had a higher progression risk than other HPV risk groups (p

Suicide risk in adult cancer patients is found to be elevated, but limited information exists regarding risks of suicide and non-suicidal violent deaths when diagnosed with cancer in young age. We investigate suicide and violent deaths in a national cohort including individuals diagnosed with cancer before age 25. Through the linkage of different national registries (Cancer Registry of Norway, Norwegian Causes of Death Registry, and the National Registry) a cohort of all live births in Norway during 1965-1985 was defined and followed up through 2008. Individuals diagnosed with cancer before age 25 and the cancer-free references were compared using an extended Cox proportional hazard regression model. The cohort comprised 1,218,013 individuals, including 5,440 diagnosed with cancer before age 25. We identified 24 suicides and 14 non-suicidal violent deaths in the cancer group. The hazard ratio (HR) of suicide in the cancer group was 2.5 (95% confidence interval (CI) 1.7-3.8), and was increased both when diagnosed with cancer in childhood (0-14 years of age); HR=2.3 (95% CI 1.2-4.6), and during adolescence/young adulthood (15-24 years); HR=2.6 (95% CI 1.5-4.2). Survivors of bone/soft tissue sarcomas, CNS tumors and testicular cancer were at particular risk. The risk of non-suicidal violent death was not increased in the cancer survivors (HR=1.0; 95% CI 0.6-1.7). Although based on small numbers and the absolute risk of suicide being low, these are novel findings with important implications for establishing adequate follow-up including suicide prevention strategies for young cancer survivors. This article is protected by copyright. All rights reserved.© 2016 UICC. Language: en

Previous studies on metabolic factors and bladder cancer (BC) risk have shown inconsistent results and have commonly not investigated associations separately by sex, smoking, and tumor invasiveness. Among 811,633 participants in six European cohorts, we investigated sex-specific associations between body mass index (BMI), mid-blood pressure (BP, [systolic + diastolic]/2), plasma glucose, triglycerides, total cholesterol and risk of BC overall, non-muscle invasive BC (NMIBC) and muscle invasive BC (MIBC). Among men, we additionally assessed additive interactions between metabolic factors and smoking on BC risk. During follow-up, 2,983 men and 754 women were diagnosed with BC. Among men, triglycerides and BP were positively associated with BC risk overall (hazard ratio [HR] per standard deviation [SD]: 1.17 [95% confidence interval (CI) 1.06-1.27] and 1.09 [1.02-1.17], respectively), and among women, BMI was inversely associated with risk (HR: 0.90 [0.82-0.99]). The associations for BMI and BP differed between men and women (p

The prevalence of clinically relevant HPV types and their specific risk for progression and regression in women with atypical squamous cells of uncertain significance (ASCUS) and low-grade squamous intraepithelial lesions (LSIL) were studied in a routine screening population. A 4-year cohort of women (n = 820) with ASCUS/LSIL and a positive HPV test in triage were followed for 6-9 years. The progression risks for CIN2+/CIN3+ were determined for single (71.2%) and multiple HPV infections (28.8%). The CIN2+ progression risk for all HPV 16, all HPV 35, single HPV 16 and single HPV 35 infections were 65.3% (95% CI: 59.6-71.0), 64.4% (95% CI: 50.4-78.4), 63.8% (95% CI: 56.2-71.4) and 73.7% (95% CI: 53.9-93.5), respectively. Based on CIN2+ progression risks four main groups were defined; the HPV 16 group, the HPV 31/33/35 group, the HPV 18/45/51/52 group and the HPV 39/56/58/59/66/68 group with progression risks of 65.3% (95% CI: 59.6-71.0), 62.1% (95% CI: 54.8-69.4), 52.6 (95% CI: 45.9-59.3) and 39.5 (95% CI: 33.0-46.0), respectively. In multivariate analyses, women in the age group 40-49 years had an increased risk of CIN2+ progression. As for CIN3+, HPV 16 had a higher progression risk than other HPV risk groups (p 0.05). In multiple infections only HPV 16 had a significant additive CIN3+ progression risk (p 0.05) as compared to other HPV risk groups. In summary, HPV types 16 and 35, including the HPV risk group 31/33/35, had a similar CIN2+ progression risk, but only HPV 16 had a higher risk for CIN3+ progression.

The connexins constitute a family of integral membrane proteins that form channels between adjacent cells. These channels are assembled in plasma membrane domains known as gap junctions and enable cells to directly exchange ions and small molecules. Intercellular communication via gap junctions plays important roles in regulating cell growth and differentiation and in maintaining tissue homeostasis. This type of cell communication is often impaired during cancer development, and several members of the connexin protein family have been shown to act as tumor suppressors. Emerging evidence suggests that the connexin protein family has important roles in colorectal cancer development. In the normal colonic epithelial tissue, three connexin isoforms, connexin 26 (Cx26), Cx32 and Cx43, have been shown to be expressed at the protein level. Colorectal cancer development is associated with loss of connexin expression or relocalization of connexins from the plasma membrane to intracellular compartments. Downregulation of connexins in colorectal carcinomas at the transcriptional level involves cancer-specific promoter hypermethylation. Recent studies suggest that Cx43 may constrain growth of colon cancer cells by interfering with the Wnt/β-catenin pathway. There is also increasing evidence that the connexins may have potential as prognostic markers in colorectal cancer. This review discusses the role of connexins in colorectal cancer pathogenesis, as well as their potential as prognostic markers and targets in the prevention and treatment of the disease.

Methyl group donors and intermediates of one-carbon metabolism affect DNA synthesis and DNA methylation, and may thereby affect prostate carcinogenesis. Choline, the precursor of betaine, and the one-carbon metabolite sarcosine have been associated with increased prostate cancer risk. Within JANUS, a prospective cohort in Norway (n = 317,000) with baseline serum samples, we conducted a nested case-control study among 3,000 prostate cancer cases and 3,000 controls. Using conditional logistic regression, odds ratios (ORs) and 95% confidence intervals (CIs) for prostate cancer risk were estimated according to quintiles of circulating betaine, dimethylglycine (DMG), sarcosine, glycine and serine. High sarcosine and glycine concentrations were associated with reduced prostate cancer risk of borderline significance (sarcosine: highest vs. lowest quintile OR = 0.86, CI = 0.72-1.01, p(trend) = 0.03; glycine: OR = 0.83, CI = 0.70-1.00, p(trend) = 0.07). Serum betaine, DMG and serine were not associated with prostate cancer risk. However, individuals with a high glycine/serine ratio were at decreased prostate cancer risk (OR = 0.74, CI = 0.69-0.85, p(trend) < 0.001). This population-based study suggested that men with high serum sarcosine or glycine concentrations have modestly reduced prostate cancer risk. Ratios of metabolites reflecting one-carbon balance may be associated with prostate cancer risk, as demonstrated for the glycine/serine ratio, and should be explored in future studies.

Suicide risk in adult cancer patients is found to be elevated, but limited information exists regarding risks of suicide and non-suicidal violent deaths when diagnosed with cancer in young age. We investigate suicide and violent deaths in a national cohort including individuals diagnosed with cancer before age 25. Through the linkage of different national registries (Cancer Registry of Norway, Norwegian Causes of Death Registry and the National Registry) a cohort of all live births in Norway during 1965-1985 was defined and followed up through 2008. Individuals diagnosed with cancer before age 25 and the cancer-free references were compared using an extended Cox proportional hazard regression model. The cohort comprised 1,218,013 individuals, including 5,440 diagnosed with cancer before age 25. We identified 24 suicides and 14 non-suicidal violent deaths in the cancer group. The hazard ratio (HR) of suicide in the cancer group was 2.5 (95% confidence interval (CI) 1.7-3.8), and was increased both when diagnosed with cancer in childhood (0-14 years of age); HR = 2.3 (95% CI: 1.2-4.6), and during adolescence/young adulthood (15-24 years); HR = 2.6 (95% CI: 1.5-4.2). Survivors of bone/soft tissue sarcomas, CNS tumors and testicular cancer were at particular risk. The risk of non-suicidal violent death was not increased in the cancer survivors (HR = 1.0; 95% CI: 0.6-1.7). Although based on small numbers and the absolute risk of suicide being low, these are novel findings with important implications for establishing adequate follow-up including suicide prevention strategies for young cancer survivors.

A positive association between overweight/obesity and endometrial cancer has been observed. It has been hypothesized that obesity is mostly associated with a subtype described as estrogen-dependent (Type I tumors), constituting about 80% of the endometrial tumors. Few epidemiologic studies have, however, analyzed different histological subtypes separately. The present study aimed at exploring the relations between body size and histological subtypes of cancer of the uterine corpus. Height and weight were measured in over 1 million Norwegian women aged 20-74 during 1963-2001. During follow-up, 9,227 cancers of the uterine corpus were diagnosed. The tumors were classified as Type I tumors (mostly endometrial adenocarcinomas with subgroups), Type II tumors (papillary, serous, and clear cell adenocarcinomas and some poorly differentiated carcinomas), sarcomas, and mixed tumors. Relative risks (RRs) of cancer of the uterine corpus were estimated using Cox proportional hazards regression. Compared with women with normal BMI, overweight and obese women had an overall RR of cancer of the uterine corpus of 1.36 (95% CI: 1.29-1.42) and 2.51 (95% CI: 2.83-2.66). The increase in risk was most pronounced for Type I tumors, but was also seen for Type II tumors, sarcomas and mixed tumors. The overall RR of corpus uteri cancer associated with a 10-cm increase in height was 1.09 (95% CI: 1.05-1.13), and was mostly observed for Type I tumors.

Human papillomavirus (HPV) types 16 and 18 are the major risk factors for cervical carcinoma, whereas HPV types 6 and 11 cause benign genital lesions. We wanted to study the joint effect of simultaneous infections with the oncogenic and non-oncogenic HPV types on risk of subsequent development of cervical carcinoma. A cohort of 530,000 women who had donated blood samples to Nordic serum banks between 1973 and 1994 was followed up by linkage to national cancer registries. We identified 182 prospective cases with invasive cervical carcinoma and selected 538 matched controls at random. HPV 6, 11, 16, 18 and 33 seropositivity was used as a marker for the different HPV infections, and seropositivity for Chlamydia trachomatis and cotinine were used as markers for risk-taking sexual behavior and smoking respectively. The adjusted odds ratio (OR) of cervical squamous-cell carcinoma (SCC) was 2.2 for HPV6/11 among HPV16 seronegatives and 5.5 for HPV16 among HPV6/11 seronegatives. Assuming multiplicative joint effect, the expected OR for seropositivity to both HPV6/11 and HPV16 would have been 12, but the observed OR was 1.0. The antagonistic interaction was statistically significant (p = 0.001) and present also under deterministic considerations of possible misclassification bias. Antagonistic interactions were also detected for combinations of HPV16 and HPV18 and of HPV16 and HPV33. The results are in line with the concept that HPV-specific immunity protects against SCC and support primary prevention of SCC by vaccination against the HPVs.

The Scandinavian countries exhibit some of the highest incidence rates of ovarian cancer in the world. Prognosis is poor, and the crude 5-year relative survival was 36% in the Nordic countries in the 1980s. Histology-specific prognostic trends in 5-year relative survival of patients with ovarian cancer and borderline tumours were examined, based on data from the population-based Cancer Registry of Norway. Relative risks (RRs) of dying were derived from Cox regression models. Logistic regression analysis on the proportion of cases with a localised tumour was performed. The 5-year relative survival rate of patients with ovarian cancer increased steadily from 1954 to 1993, being most pronounced in women below the age of 65 at the time of diagnosis. No improvement was seen for women older than 75. For all patients with ovarian cancer, an RR of dying of 0.48 (95% CI = 0.44–0.53) was estimated in 1989–1993 compared with 1954–1958. For patients with epithelial cancer, an RR of 0.63 (95% CI = 0.57–0.69) was seen in 1989–1993 compared with 1970–1973. Patients with mucinous, endometrioid and clear cell tumours had the highest odds of having a localised tumour. The age-adjusted 5-year relative survival rate of patients with borderline tumours was almost constant between 1970 and 1993, at about 93%. The prognosis of patients with ovarian cancer in Norway has improved since the 1950s. The very favourable prognosis of patients with borderline tumours has remained unchanged since the 1970s. Int. J. Cancer 75:663–670, 1998.© 1998 Wiley-Liss, Inc.

In order to study the relationship between benign breast changes, a family history of breast cancer and breast cancer, extratumoral breast tissue from 1259 breast-cancer patients in the WHO Collaborative Study of Neoplasia and Contraceptives was classified histologically. The occurrence of ductal hyperplasia, ductal atypia, sclerosing adenosis, adenosis, lobular atypia, lactational metaplasia, cysts, apocrine metaplasia, apocrine hyperplasia and atypia, duct ectasia and the epithelial-stromal ratio was evaluated as absent, mild, moderate or marked, along with registration of the quality and number of slides. Information on occurrence of cancer in the family was available for patients' mothers and grandmothers. Logistic-regression analyses showed that the prevalence odds ratios for lactational metaplasia, cysts, duct ectasia and calcification were significantly increased in patients with a family history of breast cancer. Apocrine metaplasia and hyperplasia were not significantly increased. The prevalence rates of ductal atypia (ductal carcinoma in situ and atypical ductal hyperplasia), ductal hyperplasia, sclerosing adenosis, adenosis and high epithelial-stromal ratio did not differ significantly among patients with or without a family history of breast cancer. A family history of other types of cancer did not influence the occurrence of any of the benign components. The findings in the present study are strikingly similar to those in our earlier comparison of extra-tumoral breast tissue in patients from countries with high and low risk of breast cancer. It is reasonable to conclude from this that a history of breast cancer in a woman's mother or grandmother and the factors leading to higher risk of breast cancer in some countries than in others have similar effects on the morphologic evolution of breast cancer through benign and pre-cancerous changes.

With the aim of elucidating the relationships between breast cancer, risk factors and benign breast changes, extratumoral breast tissue in 1,506 women from the WHO Collaborative study of neoplasia and steroid contraceptives was studied histologically. Patients came from 3 countries with a high incidence of breast cancer (Israel, East Germany and Australia) and 6 low-risk countries (Thailand, China, Philippines, Mexico, Chile and Colombia). Ductal atypia, ductal hyperplasia, adenosis, lobular atypia, apocrine metaplasia, apocrine hyperplasia, apocrine atypia, cysts, duct ectasia, inflammatory reaction, calcification, lactational change and epithelial-stromal ratio were classified as absent/mild/moderate/marked. Prevalence odds ratios were calculated by logistic regression analyses. Increasing frequency with age was found for ductal hyperplasia, sclerosing adenosis, apocrine metaplasia and cysts, while adenosis, lactational change and the epithelial-stromal ratio decreased with age. No significant difference between high- and low-risk countries was found for ductal hyperplasia or sclerosing adenosis. Compared with cases from high-risk countries, those from low-risk countries had a significantly lower prevalence of apocrine metaplasia, apocrine hyperplasia and cysts, and a significantly higher prevalence of ductal atypia. When seen in conjunction with other studies, the results suggest that ductal hyperplasia and sclerosing adenosis have similar roles in cancer development in high- and low-risk countries and that the factors responsible for international differences in breast cancer may exert their effect by influencing the initial development of these changes. They also suggest a delayed progression from noninvasive to invasive carcinoma in low-risk countries.

Methyl group donors and intermediates of one-carbon metabolism affect DNA synthesis and DNA methylation, and may thereby affect prostate carcinogenesis. Choline, the precursor of betaine, and the one-carbon metabolite sarcosine have been associated with increased prostate cancer risk. Within JANUS, a prospective cohort in Norway (n = 317,000) with baseline serum samples, we conducted a nested case-control study among 3,000 prostate cancer cases and 3,000 controls. Using conditional logistic regression, odds ratios (ORs) and 95% confidence intervals (CIs) for prostate cancer risk were estimated according to quintiles of circulating betaine, dimethylglycine (DMG), sarcosine, glycine and serine. High sarcosine and glycine concentrations were associated with reduced prostate cancer risk of borderline significance (sarcosine: highest vs. lowest quintile OR = 0.86, CI = 0.72-1.01, p(trend) = 0.03; glycine: OR = 0.83, CI = 0.70-1.00, p(trend) = 0.07). Serum betaine, DMG and serine were not associated with prostate cancer risk. However, individuals with a high glycine/serine ratio were at decreased prostate cancer risk (OR = 0.74, CI = 0.69-0.85, p(trend)0.001). This population-based study suggested that men with high serum sarcosine or glycine concentrations have modestly reduced prostate cancer risk. Ratios of metabolites reflecting one-carbon balance may be associated with prostate cancer risk, as demonstrated for the glycine/serine ratio, and should be explored in future studies.

Initial studies have indicated diabetes and obesity to be risk factors for hepatocellular carcinoma; but the association between other metabolic risk factors and primary liver cancer (PLC) has not been investigated. The metabolic syndrome and cancer project (Me-Can) includes cohorts from Norway, Austria and Sweden with data on 578,700 subjects. We used Cox proportional hazard models to calculate relative risks (RRs) of PLC by body mass index (BMI), blood pressure and plasma levels of glucose, cholesterol and triglycerides as continuous standardized variables (z-score with mean = 0 and standard deviation (SD) = 1) and their standardized sum of metabolic syndrome (MetS) z-score. RRs were corrected for random error in measurements. During an average follow-up of 12.0 years (SD = 7.8), 266 PLCs were diagnosed among cohort members. RR of liver cancer per unit increment of z-score adjusted for age, smoking status and BMI and stratified by birth year, sex and sub-cohorts, was for BMI 1.39 (95% confidence interval (CI) 1.24-1.58), mid blood pressure 2.08 (0.95-4.73), blood glucose 2.13 (1.55-2.94) cholesterol 0.62 (0.51-0.76) and serum triglycerides 0.85 (0.65-1.10). The RR per one unit increment of the MetS z-score was 1.35 (1.12-1.61). BMI, glucose and a composite MetS score were positively and cholesterol negatively associated with risk of liver cancer.

Antimicrobial peptides have been shown to exert cytotoxic activity towards cancer cells through their ability to interact with negatively charged cell membranes. In this study the cytotoxic effect of the antimicrobial peptide, LfcinB was tested in a panel of human neuroblastoma cell lines. LfcinB displayed a selective cytotoxic activity against both MYCN-amplified and non-MYCN-amplified cell lines. Non-transformed fibroblasts were not substantially affected by LfcinB. Treatment of neuroblastoma cells with LfcinB induced rapid destabilization of the cytoplasmic membrane and formation of membrane blebs. Depolarization of the mitochondria membranes and irreversible changes in the mitochondria morphology was also evident. Immuno- and fluorescence-labeled LfcinB revealed that the peptide co-localized with mitochondria. Furthermore, treatment of neuroblastoma cells with LfcinB induced cleavage of caspase-6, -7 and -9 followed by cell death. However, neither addition of the pan-caspase inhibitor, zVAD-fmk, or specific caspase inhibitors could reverse the cytotoxic effect induced by LfcinB. Treatment of established SH-SY-5Y neuroblastoma xenografts with repeated injections of LfcinB resulted in significant tumor growth inhibition. These results revealed a selective destabilizing effect of LfcinB on two important targets in the neuroblastoma cells, the cytoplasmic- and the mitochondria membrane.

The association between oral contraceptive (OC) use and benign breast changes in extra-tumoral breast tissue was studied histologically in 1,503 breast cancer patients from The WHO Collaborative Study of Neoplasia and Steroid Contraceptives. The occurrence of ductal hyperplasia, ductal atypia, sclerosing adenosis, cysts, apocrine metaplasia, apocrine hyperplasia, apocrine atypia, adenosis, lobular atypia, duct ectasia, calcifications, inflammatory reaction, lactational metaplasia and a high epithelial-stromal ratio was graded semi-quantitatively. Prevalence odds ratio (POR) for each histologic variable was calculated by logistic regression analyses. Patients who had ever used OC had lower occurrence of ductal hyperplasia than never users (POR 0.72 (95% CI 0.52-0.99)). Current use and more than 8 years of use was also associated with a lower prevalence of ductal hyperplasia (POR 0.40 (0.20-0.81) and POR 0.33 (0.17-0.64), respectively). Age > 35 years at first use was associated with increased prevalence of ductal carcinoma in situ (POR 2.15 (1.05-4.40)), but not of atypical ductal hyperplasia. Our results show that the effects of OC use on ductal hyperplasia in non-neoplastic breast tissue of breast cancer patients are similar to what others have found in patients with benign breast disease only. The increased prevalence of extra-tumoral ductal carcinoma in situ in breast cancer patients who started OC use at high age may possibly be explained by a longer preinvasive phase in these patients.

Histology-specific long-term trends in the incidence of ovarian cancer and borderline tumours in Norway were examined, based on data from the population-based Cancer Registry of Norway. A total of 14,352 cases of ovarian cancer were diagnosed between 1954-1993, of which 94% of the histologically verified ovarian cancers were epithelial tumours. The age-adjusted incidence rate rose from 10 per 100,000 person-years in 1954-1958 to a peak of 14 per 100,000 person-years in 1984-1988. In women older than 50 years, there was an increasing trend in incidence rates during the entire study period. From the cohort perspective, the largest increase was observed among women born between 1870-1899. A total of 2,343 borderline tumours was diagnosed between 1970-1993. The age-adjusted incidence rate has increased since 1970, reaching 4.8 per 100,000 person-years in 1989-1993.

The occurrence of multiple primary cancers is relatively rare, but may provide indications of common or opposite risk factors for different types of cancer. In the present study, the occurrence of multiple primary cancers was used to indicate possible associations between smoking and the incidence of cancers other than those generally accepted as smoking-associated. All cancer cases in persons above the age of 30, registered at the population-based Cancer Registry of Norway (1953-1993), were used in the analysis. For each type of cancer, the observed occurrence of smoking-associated cancers in the patients was compared with the expected occurrence if the patients had the same risk as the general population. Similar comparisons were made for the occurrence of other cancers in patients with a smoking-associated cancer. The results were presented as standardized incidence ratio (SIR), the ratio of the observed and the expected numbers of cases. The results indicated that uterine cervical cancer may share some important risk factor(s) with the cancers generally accepted as smoking-associated. This is in accordance with the literature, where an association between smoking and uterine cervical cancer has been found consistently. In addition, the results for liver cancer and leukemia indicated that these types of cancer also share some risk factor(s) with the smoking-associated cancers.

Multiple primary cancers in the same individual occur rarely. Consequently, a large number of cancer patients have to be followed for long periods to obtain adequate information about their risk of subsequent tumour development. Studies of multiple malignancies are of interest, since they may provide information on common or opposite risk factors. In the present study, the risk of second primary cancers following carcinoma in situ of the uterine cervix diagnosed in Norway in the period 1970-1992 was examined and quantified. Altogether, 37,001 patients with carcinoma in situ were followed from the date of diagnosis until 31 December 1992. The follow-up period was divided into 5-year intervals. The results were expressed as standardized incidence ratios (SIR = O/E), and their 95% confidence intervals were given. A total of 1,037 second primary cancers in 989 individuals were identified. There was no overall excess of second primary cancers. However, there were differences depending on the site: cancers of the oesophagus, nose, nasal cavities, trachea, bronchus, lung, vulva, vagina, bladder and other urinary organs, and other skin cancers, excluding basal-cell carcinoma, occurred more frequently. A lower risk than expected was noted for cancer of the cervix uteri and cancer of the corpus uteri. There was a rising trend with time in the observed/expected ratio for cancer of urinary organs. In the group of patients evaluated, the likelihood of subsequent tumour development was no greater than in the general female population. Nevertheless, cancer sites of higher and of lower risk than expected were identified among the carcinoma-in situ patients.