Pregnancy-associated cancer and the risk of second primary cancer.

PURPOSE: Hormonal changes related to pregnancy and lactation among women treated for cancer might influence the risk of second primary cancer. We investigated whether pregnancy near the time of breast cancer, Hodgkin lymphoma or other cancer diagnoses is associated with increased risk of developing a new primary cancer. METHODS: Women born after 1 April 1935 diagnosed with cancer at ages 15-44 years during 1968-2006 were identified in the Danish Cancer Registry. Information about pregnancies from various nationwide registers was used to identify women with a pregnancy-associated cancer defined as a cancer diagnosed 6 or fewer months before the pregnancy, during the pregnancy or up to 1 year after the pregnancy. Second primary cancers were ascertained through 2013, and hazard ratios (HRs) were calculated using Cox regression models adjusted for age, calendar-period and number of pregnancies with the reference defined as cancer not associated with a pregnancy. RESULTS: We identified 2,974 women with pregnancy-associated cancer and 31,970 women who were not pregnant near the time of their cancer diagnosis. There was no association between pregnancy-associated cancer and a second cancer (HR 0.91; 95% CI 0.79-1.05). Among 680 women with either breast cancer or Hodgkin lymphoma associated with pregnancy, a HR of 1.16 (95% CI 0.87-1.56) for second breast cancer was observed based on 48 cases. CONCLUSION: While hormonal changes might stimulate development of specific cancers, in particular breast cancer, it is reassuring that risk of breast and other second cancers was not related to pregnancy near the time of a first primary cancer diagnosis.

Tumors of the central nervous system among women treated with fertility drugs: a population-based cohort study.

PURPOSE: To investigate the association between fertility drugs and tumors of the central nervous system (CNS). METHODS: This cohort study was based on The Danish Infertility Cohort and included 148,016 infertile women living in Denmark (1995-2017). The study cohort was linked to national registers to obtain information on use of specific fertility drugs, cancer diagnoses, covariates, emigration, and vital status. Cox proportional hazard regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for all CNS tumors and separately for gliomas, meningiomas and diverse benign tumors of the brain and other parts of the CNS. RESULTS: During a median 11.3 years of follow-up, 328 women were diagnosed with CNS tumors. No marked associations were observed between use of the fertility drugs clomiphene citrate, gonadotropins, gonadotropin-releasing hormone receptor modulators and progesterone and CNS tumors. However, use of human chorionic gonadotropin was associated with a decreased rate of meningiomas (HR 0.49 95% CI 0.28-0.87). No clear associations with CNS tumors were observed according to time since first use or cumulative dose for any of the fertility drugs. CONCLUSION: No associations between use of most types of fertility drugs and CNS tumors were observed. However, our findings only apply to premenopausal women and additional studies with longer follow-up time are necessary.

Fertility drugs and incidence of thyroid cancer in a Danish nationwide cohort of 146 024 infertile women.

STUDY QUESTION: Do fertility drugs increase the risk of thyroid cancer among infertile women? SUMMARY ANSWER: The use of most types of fertility drugs was not associated with an increased risk of thyroid cancer. WHAT IS KNOWN ALREADY: The incidence of thyroid cancer is higher for women than men, especially during reproductive years, indicating that reproductive hormones may be involved in the development of thyroid cancer. Only a few previous studies have examined the association between the use of fertility drugs and incidence of thyroid cancer and the results are inconclusive. STUDY DESIGN, SIZE, DURATION: A retrospective, population-based cohort study including all 146 024 infertile women aged 20-45 years and living in Denmark in the period 1995-2017. The women were followed from the date of entry in the cohort (i.e. date of first infertility diagnosis) until the occurrence of thyroid cancer or any other cancer (except non-melanoma skin cancer), death, emigration, total thyroidectomy or the end of follow-up (31 December 2018), whichever occurred first. The median length of follow-up was 11.3 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 167 women were diagnosed with thyroid cancer during the follow-up period. Information on the use of specific fertility drugs (clomiphene citrate, gonadotropins, hCGs, GnRH receptor modulators and progesterone), thyroid cancer, covariates and vital status was obtained from the Danish Infertility Cohort and various Danish national registers. Cox proportional hazard regression models were used to calculate hazard ratios (HRs) and 95% CIs for thyroid cancer overall and for papillary thyroid cancer. MAIN RESULTS AND THE ROLE OF CHANCE: After adjustment for the calendar year of infertility diagnosis, the highest obtained level of education, parity status, obesity or thyroid disease and mutual adjustment for other registered fertility drugs, no marked associations were observed between the use of clomiphene citrate, hCG, gonadotropins or GnRH receptor modulators and risk of overall or papillary thyroid cancer. However, ever use of progesterone was associated with an increased rate of both overall (HR 1.63; 95% CI 1.07-2.48) and papillary (HR 1.66, 95% CI 1.04-2.65) thyroid cancer after mutual adjustment for other specific fertility drugs. For most specific fertility drugs, we observed a tendency toward higher associations with thyroid cancer within the first 5 years after the start of drug use than after 5 years from the start of use. No marked associations were detected according to the cumulative dose for any of the specific fertility drugs. LIMITATIONS, REASONS FOR CAUTION: Despite a large study population, the statistical precision in some subgroup analyses may be affected due to the low number of thyroid cancer cases. Although we were able to adjust for a number of potential confounders, residual and unmeasured confounding may potentially have affected the observed associations, as we could not adjust for some factors that may influence the association between fertility drugs and thyroid cancer, including age at menarche and BMI. WIDER IMPLICATIONS OF THE FINDINGS: Although this study, which is the largest to date, provides reassuring evidence that there is no strong link between the use of fertility drugs and thyroid cancer incidence, we observed a modest increased thyroid cancer incidence after the use of progesterone. However, we cannot rule out that this is a chance finding and the potential association between the use of progesterone and thyroid cancer should therefore be investigated further in large epidemiological studies. The results of the present study provide valuable knowledge for clinicians and other health care personnel involved in the diagnosis and treatment of infertility. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by research grants from the Jascha Foundation and the Aase and Ejner Danielsens Foundation. B.N. received honoraria and/or non-financial support by Gedeon Richter Nordics AB, IBSA Nordic APS and Merck KGAA. The remaining authors have no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Late mortality among survivors of childhood acute lymphoblastic leukemia diagnosed during 1971-2008 in Denmark, Finland, and Sweden: A population-based cohort study.

OBJECTIVE: Investigate all-cause and cause-specific late mortality after childhood acute lymphoblastic leukemia (ALL) in a population-based Nordic cohort. METHODS: From the cancer registries of Denmark, Finland, and Sweden, we identified 3765 five-year survivors of ALL, diagnosed before age 20 during 1971-2008. For each survivor, up to five matched comparison subjects were randomly selected from the general population (n = 18,323). Causes of death were classified as relapse related, health related, and external. Late mortality was evaluated by cumulative incidences of death from 5-year survival date. Mortality hazard ratios (HR) were evaluated with Cox proportional models. RESULTS: Among the survivors, 315 deaths occurred during a median follow-up of 16 years from 5-year survival date (range 0-42). The majority were attributable to relapse (n = 224), followed by second neoplasm (n = 45). Cumulative incidence of all-cause late mortality at 15 years from diagnosis decreased gradually over treatment decades, from 14.4% (95% confidence interval [CI]: 11.6-17.2) for survivors diagnosed during 1971-1981, to 2.5% (95% CI: 1.3-3.7) for those diagnosed during 2002-2008. This was mainly attributable to a reduction in relapse-related deaths decreasing from 13.4% (95% CI: 10.7-16.1) for survivors diagnosed during 1971-1981 to 1.9% (95% CI: 0.9-2.8) for those diagnosed during 2002-2008. Health-related late mortality was low and did not change substantially across treatment decades. Compared to comparison subjects, all-cause mortality HR was 40 (95% CI: 26-61) 5-9 years from diagnosis, and 4.4 (95% CI: 3.4-5.6) ≥10 years from diagnosis. CONCLUSIONS: Survivors of ALL have higher late mortality than population comparison subjects. Among the survivors, there was a temporal reduction in risk of death from relapse, without increments in health-related death.

Endometrial cancer risk after fertility treatment: a population-based cohort study.

PURPOSE: Using data from a large population-based cohort of women with fertility problems in Denmark, we examined the association between use of fertility drugs and endometrial cancer incidence. METHODS: Women aged 20-45 years living in Denmark during 1 January 1995-31 December 2017 and diagnosed with fertility problems (i.e., subfertile women) were identified from the Danish Infertility Cohort. Information on use of fertility drugs, endometrial cancer, covariates and vital status was obtained from various Danish national registers. Cox proportional hazard models were used adjusted for calendar year of study entry, highest level of education, parity status, hormonal contraceptive use, obesity and diabetes mellitus. RESULTS: Of the 146,104 subfertile women, 129,478 (88.6%) were treated with fertility drugs. During a median follow-up of 10.1 years, 119 women were diagnosed with endometrial cancer. Use of any fertility drugs was not associated with an increased rate of overall (HR 0.82; 95% CI 0.50-1.34) or type I endometrial cancer (HR 1.08; 95% CI 0.60-1.95). No associations between use of specific types of fertility drugs and endometrial cancer were observed. No marked associations were observed according to cumulative dose of specific fertility drugs, parity status, or with increasing follow-up time. CONCLUSIONS: No marked associations between use of fertility drugs and risk of endometrial cancer were observed. The relatively young age of the cohort at end of follow-up, however, highlights the need for longer follow-up of women after fertility drug use.

Disease-specific hospitalizations among 5-year survivors of Wilms tumor: A Nordic population-based cohort study.

BACKGROUND: With modern therapy, over 90% of Wilms tumor patients can expect to become long-term survivors, and focus on morbidity and late effects become increasingly important. We provide a novel evaluation and insight to subsequent hospitalizations in 5-year survivors of Wilms tumor. METHODS: As part of the Adult Life after Childhood Cancer in Scandinavia (ALiCCS) study, we identified 5-year survivors of Wilms tumor. Based on stratified random sampling, we constructed a population comparison cohort. Outcomes of interest were overall hospitalizations; hospitalizations for specific organ systems and disease-specific categories. Standardized hospitalization rate ratios (SHRR) and absolute excess risks (AER) were calculated. RESULTS: We included 913, 5-year survivors of Wilms tumor and 152 231 population comparisons. Survivors of Wilms tumor had an increased overall risk of being hospitalized (SHRR 1.8; 95% confidence interval (CI) 1.7-2.0). The hospitalization risk was increased within all major organ systems: urinary and genital organs (SHRR 2.5; 95% CI 2.1-3.0), endocrine (SHRR 2.5; 95% CI 1.9-3.3), cardiovascular (SHRR 2.2; 95% CI 1.7-2.9), and gastrointestinal (SHRR 1.5; 95% CI 1.3-1.8). Risks for specific diseases are reported in the study. CONCLUSIONS: Survivors of Wilms tumor had higher risks than population comparisons for a wide range of diseases, with the highest risks seen for urinary, endocrine, and cardiovascular disorders. Five to 20 years after the Wilms tumor diagnosis, 43% of survivors had been hospitalized at least once versus 29% of population comparisons. The overall AER was 2.3, which translates into 0.2 extra hospitalizations in 10 years for every Wilms tumor survivor.

Esophageal disease among childhood cancer survivors-A report from the Childhood Cancer Survivors Study.

There is limited information addressing the occurrence of esophageal strictures among the growing population of survivors of childhood cancer. Using the Childhood Cancer Survivor Study, we analyzed data from 17,121 5-year survivors and 3400 siblings to determine the prevalence and risk factors for esophageal strictures. Prevalence among survivors was 2.0% (95% confidence interval [CI]: 1.8-2.2%), representing a 7.6-fold increased risk compared to siblings. Factors significantly associated with risk of esophageal stricture included diagnosis of Hodgkin lymphoma, greater chest radiation dose, younger age at cancer diagnosis, platinum chemotherapy, and hematopoietic stem cell transplantation. While uncommon, survivors are at risk for therapy-related esophageal strictures.

Hospital admission for neurologic disorders among 5-year survivors of noncentral nervous system tumors in childhood: A cohort study within the Adult Life after Childhood Cancer in Scandinavia study.

Large, comprehensive studies of the risk for neurologic disorders among long-term survivors of noncentral nervous system (CNS) childhood cancers are lacking. Thus, the aim of our study was to assess the lifetime risk of Nordic non-CNS childhood cancer survivors for neurologic disorders. We identified 15,967 5-year survivors of non-CNS childhood cancer diagnosed in Denmark, Iceland, Finland and Sweden in 1943-2008, and 151,118 matched population comparison subjects. In-patient discharge diagnoses of neurologic disorders were used to calculate relative risks (RRs) and absolute excess risks (AERs). A neurologic disorder was diagnosed in 755 of the survivors while 370 were expected, yielding a RR of 2.0 (95% confidence interval (CI) 1.9-2.2). The highest risks were found among survivors of neuroblastoma (4.1; 95% CI 3.2-5.3) and leukemia (2.8; 95% CI 2.4-3.2). The AER decreased from 331 (278-383) excess neurologic disorders per 100,000 person-years 5-9 years after diagnosis to 82 (46-118) ≥ 20 years after diagnosis. Epilepsy was the most common diagnosis (n = 229, 1.4% of all survivors), and significantly increased risks were seen among survivors of eight out of 12 types of childhood cancer. Survivors of neuroblastoma had remarkably high risks (RR ≥ 10) for hospitalization for paralytic syndromes and hydrocephalus, while survivors of leukemia had additional high risks for dementia and encephalopathy. In conclusion, survivors of non-CNS childhood cancer are at high risk for neurologic disorders, especially within the first decade after diagnosis. Therefore, intensive follow-up to identify those who require close management is needed.

Prevalence of human papillomavirus DNA and p16INK4a in penile cancer and penile intraepithelial neoplasia: a systematic review and meta-analysis.

BACKGROUND: Although previous meta-analyses have examined human papillomavirus (HPV) DNA prevalence in penile cancer, none, to our knowledge, have assessed pooled HPV DNA prevalence in penile intraepithelial neoplasia or p16INK4a percent positivity in penile cancer and penile intraepithelial neoplasia. Therefore, we aimed to examine the prevalence of HPV DNA and p16INK4a positivity in penile cancer and penile intraepithelial neoplasia worldwide. METHODS: In this systematic review and meta-analysis, we searched PubMed, Embase, and the Cochrane Library until July 24, 2017, for English-language articles published from Jan 1, 1986, onwards reporting the prevalence of HPV DNA and p16INK4a positivity, either alone or in combination, in at least five cases of penile cancer or penile intraepithelial neoplasia. Only studies that used PCR or hybrid capture for the detection of HPV DNA and immunohistochemical staining or methylation for the detection of p16INK4a were included. Data were extracted and subsequently crosschecked, and inconsistencies were discussed to reach consensus. Using random-effects models, we estimated the pooled prevalence and 95% CI of HPV DNA and p16INK4a positivity in penile cancer and penile intraepithelial neoplasia, stratifying by histological subtype and HPV DNA or p16INK4a detection method. Type-specific prevalence of HPV6, HPV11, HPV16, HPV18, HPV31, HPV33, and HPV45 in penile cancer was estimated. FINDINGS: Our searches identified 1836 non-duplicate records, of which 73 relevant papers (71 studies) were found to be eligible. The pooled HPV DNA prevalence in penile cancer (52 studies; n=4199) was 50·8% (95% CI 44·8-56·7; I2=92·6%, pheterogeneity<0·0001). A high pooled HPV DNA prevalence was seen in basaloid squamous cell carcinomas (84·0%, 95% CI 71·0-93·6; I2=48·0%, pheterogeneity=0·0197) and in warty-basaloid carcinoma (75·7%, 70·1-81·0; I2=0%, pheterogeneity=0·52). The predominant oncogenic HPV type in penile cancer was HPV16 (68·3%, 95% CI 58·9-77·1), followed by HPV6 (8·1%, 4·0-13·7) and HPV18 (6·9%, 2·9-12·4). The pooled HPV DNA prevalence in penile intraepithelial neoplasia (19 studies; n=445) was 79·8% (95% CI 69·3-88·6; I2=83·2%, pheterogeneity<0·0001). The pooled p16INK4a percent positivity in penile cancer (24 studies; n=2295) was 41·6% (95% CI 36·2-47·0; I2=80·6%, pheterogeneity<0·0001), with a high pooled p16INK4a percent positivity in HPV-related squamous cell carcinoma (85·8%, 95% CI 72·1-95·4; I2=56·4%, pheterogeneity=0·0011) as compared with non-HPV-related squamous cell carcinoma (17·1%, 7·9-29·1; I2=78·3%, pheterogeneity<0·0001). Moreover, among HPV-positive cases of penile cancer, the p16INK4a percent positivity was 79·6% (95% CI 65·7-90·7; I2=89·9%, pheterogeneity<0·0001), compared with 18·5% (9·6-29·6; I2=89·3%, pheterogeneity<0·0001) in HPV-negative penile cancers. The pooled p16INK4a percent positivity in penile intraepithelial neoplasia (six studies; n=167) was 49·5% (95% CI 18·6-80·7). INTERPRETATION: A large proportion of penile cancers and penile intraepithelial neoplasias are associated with infection with HPV DNA (predominantly HPV16), emphasising the possible benefits of HPV vaccination in men and boys. FUNDING: None.

Human papillomavirus and p16 in squamous cell carcinoma and intraepithelial neoplasia of the vagina.

We estimated the overall and type-specific prevalence of human papillomavirus (HPV) and p16 overexpression in vaginal cancer and vaginal intraepithelial neoplasia (VaIN). We conducted a systematic search of PubMed, Embase and Cochrane Library to identify studies published between 1986 and 2017 using PCR-based or Hybrid Capture 2 tests to evaluate the presence of HPV DNA and/or using any method to detect p16 overexpression in VaIN, vaginal squamous cell carcinoma (VaSCC), or other types of vaginal cancer. Applying a random effects model, we estimated the pooled prevalence of HPV and p16 overexpression along with 95% confidence intervals (CIs). The I2 statistic was used to assess heterogeneity. We included 26 studies, reporting HPV prevalence and six studies evaluating p16 overexpression. The pooled HPV prevalences in VaSCC (n = 593) and VaIN (n = 1,374) were 66.7% (95% CI = 54.7-77.8) and 85.2% (95% CI = 78.2-91.0), respectively. Substantial inter-study heterogeneity was observed, and analyses stratified on geographic region, type of tissue, HPV detection method or PCR primer type did not fully explain the observed heterogeneity. The most predominant HPV type among the HPV positive VaSCC and VaIN cases was HPV16, followed by HPV33, and HPV45 (in VaIN) and HPV18, and HPV33 (in VaSCC). In pooled analyses, 89.9% (95% CI = 81.7-94.6) of HPV positive and 38.9% (95% CI = 0.9-90.0) of HPV negative vaginal cancers were positive for p16 overexpression. Our findings suggest that vaccination against HPV might prevent a substantial proportion of vaginal neoplasia and highlight the need for further studies of the possible clinical value of p16 testing in these patients.

Follow-up strategies following completion of primary cancer treatment in adult cancer survivors.

BACKGROUND: Most cancer survivors receive follow-up care after completion of treatment with the primary aim of detecting recurrence. Traditional follow-up consisting of fixed visits to a cancer specialist for examinations and tests are expensive and may be burdensome for the patient. Follow-up strategies involving non-specialist care providers, different intensity of procedures, or addition of survivorship care packages have been developed and tested, however their effectiveness remains unclear. OBJECTIVES: The objective of this review is to compare the effect of different follow-up strategies in adult cancer survivors, following completion of primary cancer treatment, on the primary outcomes of overall survival and time to detection of recurrence. Secondary outcomes are health-related quality of life, anxiety (including fear of recurrence), depression and cost. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, four other databases and two trials registries on 11 December 2018 together with reference checking, citation searching and contact with study authors to identify additional studies. SELECTION CRITERIA: We included all randomised trials comparing different follow-up strategies for adult cancer survivors following completion of curatively-intended primary cancer treatment, which included at least one of the outcomes listed above. We compared the effectiveness of: 1) non-specialist-led follow-up (i.e. general practitioner (GP)-led, nurse-led, patient-initiated or shared care) versus specialist-led follow-up; 2) less intensive versus more intensive follow-up (based on clinical visits, examinations and diagnostic procedures) and 3) follow-up integrating additional care components relevant for detection of recurrence (e.g. patient symptom education or monitoring, or survivorship care plans) versus usual care. DATA COLLECTION AND ANALYSIS: We used the standard methodological guidelines by Cochrane and Cochrane Effective Practice and Organisation of Care (EPOC). We assessed the certainty of the evidence using the GRADE approach. For each comparison, we present synthesised findings for overall survival and time to detection of recurrence as hazard ratios (HR) and for health-related quality of life, anxiety and depression as mean differences (MD), with 95% confidence intervals (CI). When meta-analysis was not possible, we reported the results from individual studies. For survival and recurrence, we used meta-regression analysis where possible to investigate whether the effects varied with regards to cancer site, publication year and study quality. MAIN RESULTS: We included 53 trials involving 20,832 participants across 12 cancer sites and 15 countries, mainly in Europe, North America and Australia. All the studies were carried out in either a hospital or general practice setting. Seventeen studies compared non-specialist-led follow-up with specialist-led follow-up, 24 studies compared intensity of follow-up and 12 studies compared patient symptom education or monitoring, or survivorship care plans with usual care. Risk of bias was generally low or unclear in most of the studies, with a higher risk of bias in the smaller trials. Non-specialist-led follow-up compared with specialist-led follow-up It is uncertain how this strategy affects overall survival (HR 1.21, 95% CI 0.68 to 2.15; 2 studies; 603 participants), time to detection of recurrence (4 studies, 1691 participants) or cost (8 studies, 1756 participants) because the certainty of the evidence is very low. Non-specialist- versus specialist-led follow up may make little or no difference to health-related quality of life at 12 months (MD 1.06, 95% CI -1.83 to 3.95; 4 studies; 605 participants; low-certainty evidence); and probably makes little or no difference to anxiety at 12 months (MD -0.03, 95% CI -0.73 to 0.67; 5 studies; 1266 participants; moderate-certainty evidence). We are more certain that it has little or no effect on depression at 12 months (MD 0.03, 95% CI -0.35 to 0.42; 5 studies; 1266 participants; high-certainty evidence). Less intensive follow-up compared with more intensive follow-up Less intensive versus more intensive follow-up may make little or no difference to overall survival (HR 1.05, 95% CI 0.96 to 1.14; 13 studies; 10,726 participants; low-certainty evidence) and probably increases time to detection of recurrence (HR 0.85, 95% CI 0.79 to 0.92; 12 studies; 11,276 participants; moderate-certainty evidence). Meta-regression analysis showed little or no difference in the intervention effects by cancer site, publication year or study quality. It is uncertain whether this strategy has an effect on health-related quality of life (3 studies, 2742 participants), anxiety (1 study, 180 participants) or cost (6 studies, 1412 participants) because the certainty of evidence is very low. None of the studies reported on depression. Follow-up strategies integrating additional patient symptom education or monitoring, or survivorship care plans compared with usual care: None of the studies reported on overall survival or time to detection of recurrence. It is uncertain whether this strategy makes a difference to health-related quality of life (12 studies, 2846 participants), anxiety (1 study, 470 participants), depression (8 studies, 2351 participants) or cost (1 studies, 408 participants), as the certainty of evidence is very low. AUTHORS' CONCLUSIONS: Evidence regarding the effectiveness of the different follow-up strategies varies substantially. Less intensive follow-up may make little or no difference to overall survival but probably delays detection of recurrence. However, as we did not analyse the two outcomes together, we cannot make direct conclusions about the effect of interventions on survival after detection of recurrence. The effects of non-specialist-led follow-up on survival and detection of recurrence, and how intensity of follow-up affects health-related quality of life, anxiety and depression, are uncertain. There was little evidence for the effects of follow-up integrating additional patient symptom education/monitoring and survivorship care plans.

Risk for use of antidepressants, anxiolytics, and hypnotics in partners of glioma patients-A nationwide study covering 19 years of prescriptions.

OBJECTIVE: Suffering from malignant brain tumor is a stressful condition, for patients and their partners. In a retrospective cohort study using nationwide registries, we examined partners' risk for first use of antidepressants, anxiolytics, or hypnotics. METHODS: We followed all 4373 partners of adults with glioma, diagnosed in 1998 to 2013 in Denmark and a cohort of 43 808 partners of glioma-free persons matched 1:10. In Cox proportional hazard models, we estimated hazard ratios (HRs) for a first prescription of psychotropic medications (antidepressants, anxiolytics, or hypnotics) according to the partner's glioma status. Among partners of glioma patients, we further estimated HRs for a first prescription of psychotropic medication according to disease characteristics, sociodemographic factors, and bereavement. RESULTS: Two years after diagnosis, 29% of female and 21% of male partners of glioma patients had had a first prescription of psychotropic medication compared with 10% in female and 8% in male partners of glioma-free persons. Partners of glioma patients had a significantly increased, 4-fold higher risk for a first prescription of psychotropic medications in the first year after diagnosis than partners of glioma-free persons (HR 4.10, 95% CI, 3.80:4.43). Among partners of glioma patients, the risk was significantly reduced in bereaved compared with non-bereaved partners. CONCLUSIONS: We have documented, for the first time, that the psychological impact of a diagnosis of glioma is such a severe stress exposure that it increases the risk for having medication prescribed to treat symptoms of anxiety, sleep problems, and depression.

Prevalence and type distribution of human papillomavirus in squamous cell carcinoma and intraepithelial neoplasia of the vulva.

In this updated systematic review and meta-analysis, we estimate the pooled prevalence of human papillomavirus (HPV) DNA and HPV type distribution in squamous cell carcinoma of the vulva (vulvar cancer) and vulvar intraepithelial neoplasia (VIN). PubMed, Embase and Cochrane Library databases were used to identify studies published between 1990 and 2015 and using a PCR-based or hybrid capture test to evaluate the presence of HPV DNA in vulvar cancer or VIN. Pooled estimates of the HPV prevalence with corresponding 95% confidence intervals (CI) were calculated based on a random effects model. The I2 statistic was used to describe the amount of heterogeneity. In meta-regression analyses, potential sources of heterogeneity were evaluated. We identified 92 eligible papers, comprising altogether 5,015 cases of vulvar cancer (64 papers) and 2,764 cases of VIN (48 papers). The pooled prevalence of HPV in vulvar cancer was 39.7% (95% CI: 35.1-44.4%). Overall, 76.3% (95% CI: 70.1-82.1%) of VIN lesions tested HPV-positive, while the HPV prevalence in new subcategories of VIN, uVIN and dVIN, was 86.2% (95% CI: 73.5-95.5%) and 2.0% (95% CI: 0-10.0%), respectively. Substantial between-study heterogeneity was observed (vulvar cancer: I2 = 88.4%; VIN: I2 = 90.7%) with the largest variation between geographical regions. Among HPV-positive cases, the predominant high-risk HPV type was HPV16, followed by HPV33 and HPV18. HPV6 was detected as a single infection in a small subset of VIN and vulvar cancer samples. Thus, HPV vaccination targeting these HPV types may prevent a substantial number of vulvar lesions.

Pelvic Inflammatory Disease and the Risk of Ovarian Cancer and Borderline Ovarian Tumors: A Pooled Analysis of 13 Case-Control Studies.

Inflammation has been implicated in ovarian carcinogenesis. However, studies investigating the association between pelvic inflammatory disease (PID) and ovarian cancer risk are few and inconsistent. We investigated the association between PID and the risk of epithelial ovarian cancer according to tumor behavior and histotype. We pooled data from 13 case-control studies, conducted between 1989 and 2009, from the Ovarian Cancer Association Consortium (OCAC), including 9,162 women with ovarian cancers, 2,354 women with borderline tumors, and 14,736 control participants. Study-specific odds ratios were estimated and subsequently combined into a pooled odds ratio using a random-effects model. A history of PID was associated with an increased risk of borderline tumors (pooled odds ratio (pOR) = 1.32, 95% confidence interval (CI): 1.10, 1.58). Women with at least 2 episodes of PID had a 2-fold increased risk of borderline tumors (pOR = 2.14, 95% CI: 1.08, 4.24). No association was observed between PID and ovarian cancer risk overall (pOR = 0.99, 95% CI: 0.83, 1.19); however, a statistically nonsignificantly increased risk of low-grade serous tumors (pOR = 1.48, 95% CI: 0.92, 2.38) was noted. In conclusion, PID was associated with an increased risk of borderline ovarian tumors, particularly among women who had had multiple episodes of PID. Although our results indicated a histotype-specific association with PID, the association of PID with ovarian cancer risk is still somewhat uncertain and requires further investigation.

The potential diagnostic value of serum microRNA signature in patients with pancreatic cancer.

Biomarkers for early diagnosis of patients with pancreatic cancer (PC) are needed. Our aim was to identify panels of miRNAs in serum in combination with CA 19-9 for use in the diagnosis of PC. Four hundred seventeen patients with PC were included prospectively from Denmark (n = 306) and Germany (n = 111). Controls included 59 patients with chronic pancreatitis (CP) and 248 healthy subjects (HS). MiRNAs were analyzed in pretreatment serum samples from 3 cohorts: discovery cohort (754 human miRNAs, TaqMan(®) Human MicroRNA assay, Applied Biosystem; PC n = 133, controls n = 72); training cohort (34 miRNAs, real-time qPCR using the Fluidigm BioMark™ System; PC n = 198, controls n = 184); validation cohort (13 miRNAs, real-time qPCR using the Fluidigm BioMark™ System; PC n = 86, controls n = 51). We found that 34 miRNAs in serum from PC patients in the discovery cohort were expressed differently than in controls. These miRNAs were tested in the training cohort, and four diagnostic panels were constructed that included 5 or 12 miRNAs (miR-16, -18a, -20a, -24, -25, -27a, -29c, -30a.5p, -191, -323.3p, -345 and -483.5p). Diagnostic accuracy of detecting PC in the training cohort was AUC (Index I 0.85; II 0.87; III 0.85; IV 0.95; CA 19-9 0.93); specificity (I 0.71; II 0.76; III 0.66; IV 0.90 (fixed sensitivity at 0.85); CA 19-9 0.93). Combining serum CA 19-9 and Index II best discriminated Stages I and II PC from HS [AUC 0.93 (0.90-0.96), sensitivity 0.77 (0.69-0.84), specificity 0.94 (0.90-0.96) and accuracy 0.88 (0.84-0.91)]. In conclusion, we identified four diagnostic panels based on 5 or 12 miRNAs in serum that could distinguish patients with PC from HS and CP.

Increased risk of borderline ovarian tumors in women with a history of pelvic inflammatory disease: A nationwide population-based cohort study.

OBJECTIVE: Some studies suggest that pelvic inflammatory disease (PID) is a potential risk factor for ovarian cancer. However, only few studies have investigated the association between PID and risk of borderline ovarian tumors. We conducted a population-based cohort study to investigate the association between PID and risk of borderline ovarian tumors. METHODS: Using various nationwide Danish registries we identified all women in Denmark during 1978-2012, who were born during 1940-1970 (n=1,318,925). Of these, 81,263 women were diagnosed with PID in the study period, and 2736 women had a borderline ovarian tumor (1290 serous and 1344 mucinous). Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between PID and risk of borderline tumors were estimated using Cox regression models with adjustment for potential confounders. RESULTS: A history of PID was associated with an increased risk of borderline ovarian tumors (HR=1.39; 95% CI: 1.19-1.61). However, histotype-specific analyses revealed significant variation in risk as PID was only associated with an increased risk of serous borderline tumors (HR=1.85; 95% CI: 1.52-2.24), but not with mucinous borderline tumors (HR=1.06; 95% CI: 0.83-1.35). CONCLUSIONS: PID is associated with an increased risk of serous borderline tumors. Further research on the potential underlying biological mechanisms and on the identification of the subset of women with PID who are at increased risk of serous borderline tumors is warranted.

Non-steroidal anti-inflammatory drug use and risk of endometrial cancer: A systematic review and meta-analysis of observational studies.

OBJECTIVE: Non-steroidal anti-inflammatory drug (NSAID) use has been linked to a reduction in the risk of several cancer types. For endometrial cancer, however, results have been inconsistent. To summarize the available evidence on the risk of endometrial cancer associated with use of aspirin or non-aspirin (NA-) NSAIDs, we performed a systematic review and meta-analysis of observational studies. METHODS: We conducted a bibliographic database search in PubMed, Embase and Cochrane Library. Relative risk estimates were extracted from eligible case-control and cohort studies and pooled using a random effects model. RESULTS: Six case-control and seven cohort studies were found eligible for our meta-analysis. We observed risk reductions in endometrial cancer associated with regular use of aspirin (case-control: 11%, cohort: 8%) and NA-NSAIDs (case-control: 9%, cohort: 6%), compared to non-use. However, the pooled risk ratios were not statistically significant. Higher risk reductions were seen with high frequency of notably aspirin use (case-control: 37%, cohort: 20%). The inverse association between regular aspirin use and endometrial cancer risk was strongest among women with a body mass index above 30 (case-control: 44%, cohort: 20%). CONCLUSIONS: Regular use of aspirin or NA-NSAIDs was associated with a marginally reduced risk of endometrial cancer. Larger risk reductions were linked with high frequency of NSAID use and high BMI.

Maternal smoking during pregnancy and risk of stillbirth: results from a nationwide Danish register-based cohort study.

INTRODUCTION: Maternal smoking during pregnancy has been associated with an increased risk of stillbirth. Only a few studies have been conducted to determine whether smoking affects the risk of antepartum and intrapartum stillbirth differently or whether smoking cessation in early pregnancy reduces the risk. Previous results are inconclusive. We addressed these questions in a large Danish population-based cohort study. MATERIAL AND METHODS: From the Danish Medical Birth Register, we identified 841 228 singleton births in Denmark between 1997 and 2010 and gathered detailed information on maternal smoking during pregnancy and the vital status of the infant. Associations (odds ratios with 95% confidence intervals) between maternal smoking and risk of stillbirth overall and separately for antepartum and intrapartum stillbirth were analyzed using logistic regression models (generalized estimating equations), adjusting for potential confounders. RESULTS: Any smoking during pregnancy increased the risk of stillbirth, both overall (odds ratio 1.42, 95% confidence interval 1.30-1.55) and for antepartum (odds ratio 1.38, 95% confidence interval 1.25-1.53) and intrapartum (odds ratio 1.52, 95% confidence interval 1.18-1.96) stillbirths. Women who quit smoking at the beginning of the second trimester at the latest had no increased risk of stillbirth overall (odds ratio 1.03, 95% confidence interval 0.80-1.32). CONCLUSIONS: Maternal smoking during pregnancy increases the risk of stillbirth, both overall and for antepartum and intrapartum stillbirth separately. Women who quit smoking in the beginning of their pregnancy reduce their risk compared with that of non-smokers.

Comparison of statistical methods for finding network motifs.

There has been much recent interest in systems biology for investigating the structure of gene regulatory systems. Such networks are often formed of specific patterns, or network motifs, that are interesting from a biological point of view. Our aim in the present paper is to compare statistical methods specifically with regard to the question of how well they can detect such motifs. One popular approach is by network analysis with Gaussian graphical models (GGMs), which are statistical models associated with undirected graphs, where vertices of the graph represent genes and edges indicate regulatory interactions. Gene expression microarray data allow us to observe the amount of mRNA simultaneously for a large number of genes p under different experimental conditions n, where p is usually much larger than n prohibiting the use of standard methods. We therefore compare the performance of a number of procedures that have been specifically designed to address this large p-small n issue: G-Lasso estimation, Neighbourhood selection, Shrinkage estimation using empirical Bayes for model selection, and PC-algorithm. We found that all approaches performed poorly on the benchmark E. coli network. Hence we systematically studied their ability to detect specific network motifs, pairs, hubs and cascades, in extensive simulations. We conclude that all methods have difficulty detecting hubs, but the PC-algorithm is most promising.

The combined impact of adherence to five lifestyle factors on all-cause, cancer and cardiovascular mortality: a prospective cohort study among Danish men and women.

Individual lifestyle factors have been associated with lifestyle diseases and premature mortality by an accumulating body of evidence. The impact of a combination of lifestyle factors on mortality has been investigated in several studies, but few have applied a simple index taking national guidelines into account. The objective of the present prospective cohort study was to investigate the combined impact of adherence to five lifestyle factors (smoking, alcohol intake, physical activity, waist circumference and diet) on all-cause, cancer and cardiovascular mortality based on international and national health recommendations. A Cox proportional hazards model was used to estimate hazard ratios (HR) with 95 % CI. During a median follow-up of 14 years, 3941 men and 2827 women died. Among men, adherence to one additional health recommendation was associated with an adjusted HR of 0·73 (95 % CI 0·71, 0·75) for all-cause mortality, 0·74 (95 % CI 0·71, 0·78) for cancer mortality and 0·70 (95 % CI 0·65, 0·75) for cardiovascular mortality. Among women, the corresponding HR was 0·72 (95 % CI 0·70, 0·75) for all-cause mortality, 0·76 (95 % CI 0·73, 0·80) for cancer mortality and 0·63 (95 % CI 0·57, 0·70) for cardiovascular mortality. In the present study, adherence to merely one additional health recommendation had a protective effect on mortality risk, indicating a huge potential in enhancing healthy lifestyle behaviours of the population.