Prescription rates for drugs used in treatment of benign prostatic hyperplasia and erectile dysfunction before and after prostate cancer diagnosis.

BACKGROUND: Symptoms and treatment of benign prostatic hyperplasia (BPH) or erectile dysfunction (ED) may lead to prostate cancer workup, and patterns of prescriptions before diagnosis may affect findings of pharmacoepidemiological studies. Usage of BPH and ED drugs after diagnosis may be related to prostate cancer treatment. We investigated differences in prescription rates of BPH and ED drugs among prostate cancer patients and cancer-free comparisons and between patients with localized and non-localized disease. MATERIAL AND METHODS: A nationwide register-based study, including all Danish men aged 50-85 years diagnosed with prostate cancer during 1998-2015 and an age-matched comparison cohort without cancer. We calculated rates of new and total prescriptions in 1-month intervals from 3 years before to 3 years after cancer diagnosis for drugs used to treat BPH and ED, overall and stratified by clinical stage. RESULTS: We identified 54,286 men with prostate cancer and a comparison cohort of 249,645 age-matched men. The new prescription rate for BPH drugs increased for men with prostate cancer in the year before diagnosis and peaked 1 month before diagnosis with an 18-fold higher rate. Men with prostate cancer had a higher total prescription rate of BPH drugs 3 years before diagnosis, notably among men with localized disease. Before diagnosis, the new prescription rates for ED drugs were similar among men with prostate cancer and comparisons. After diagnosis, men with prostate cancer had a 7-fold higher rate of new prescriptions for ED drugs. Among men with localized disease, the total prescription rate of ED drugs increased in the months following diagnosis. CONCLUSION: Differences in prescription rates suggest increased prostate cancer surveillance among men receiving BPH drugs, whereas the post-diagnostic increase in ED drugs among men with localized disease is compatible with the increased risk of ED following prostate cancer treatment.

Hormonal contraception use before and after breast cancer diagnosis: A nationwide drug utilization study.

PURPOSE: To describe the use of hormonal contraceptives in Danish breast cancer patients. METHODS: Nationwide drug utilization study in Danish women diagnosed with breast cancer at ages 13-50 years during 2000-2015. User proportions were estimated in 6-months intervals from 2 years before to 2 years after diagnosis. RESULTS: Use of hormonal contraceptives declined sharply after breast cancer diagnosis. Still, 7% of patients aged 13-39 years filled hormonal contraceptive prescriptions within 6 months after the diagnosis. CONCLUSIONS: The majority of premenopausal breast cancer patients discontinues hormonal contraception at diagnosis. All prescribers of hormonal contraceptives should acknowledge that hormonal contraception is contraindicated for breast cancer patients. PLAIN LANGUAGE SUMMARY: Use of hormonal contraception is contraindicated among women with breast cancer. In this nationwide study, we assessed the use of hormonal contraceptives among all Danish premenopausal women diagnosed with breast cancer during 2000-2015. Hormonal contraceptive use was assessed within 2 years before and 2 years after breast cancer diagnosis. The majority of patients discontinued hormonal contraception at breast cancer diagnosis. However, 7% of patients aged 13-39 years filled hormonal contraceptive prescriptions within 6 months after the diagnosis.

Prescription rates for commonly used drugs before and after a prostate cancer diagnosis.

PURPOSE: To investigate differences in prescription rates of commonly used drugs among prostate cancer patients and cancer-free comparisons and between patients diagnosed with localized and non-localized disease. METHODS: We conducted a register-based study including all men aged 50-85 years diagnosed with prostate cancer in Denmark from 1998 to 2015 and an age-matched cancer-free comparison cohort. We calculated the number of new and total prescriptions from three years before to three years after the date of diagnosis of the case for selected drug classes divided by the number of person-months and stratified by stage at diagnosis. RESULTS: We included 54,286 prostate cancer patients and 249,645 matched comparisons. 30,712 patients were diagnosed with localized disease and 12,884 with non-localized disease. The rates of new prescriptions increased considerably among patients within the year before the diagnosis. Hereafter the rates varied between drug classes. For most drug classes, total prescription rates for patients and comparisons increased similarly in the study period. Total prescription rates varied between men with localized and non-localized disease for all drug classes apart from statins. CONCLUSION: Our findings indicate that a large proportion of prostate cancer cases are likely diagnosed during medical work-up for other reasons than prostate cancer. Increased rates occur within the last year before diagnosis and future studies on the interaction between drug use and prostate cancer should at least include a one year pre-diagnostic lag-time. Post-diagnostic prescription rates demonstrated an increased use of drugs most likely associated with the consequences of the disease.

Bilateral oophorectomy and rate of colorectal cancer: A prospective cohort study.

Worldwide, colorectal cancer is the second most common cancer and third cause of cancer death in women. Estrogen exposure has been inversely associated with colorectal cancer. Oophorectomy reduces circulating estrogen, but the effect on colorectal cancer remains uncertain. The aim of this study was to examine the association between unilateral and bilateral oophorectomy and subsequent risk of colorectal cancer, and whether this association varied by menopausal status at time of oophorectomy, use of hormone replacement therapy (HRT) at baseline, hysterectomy and baseline body mass index (BMI). The study included 25 698 female nurses (aged ≥45 years) participating in the Danish Nurse Cohort. Nurses were followed from baseline until date of colorectal cancer, death, emigration or end of follow-up at December 31, 2018, whichever came first. We examined the association between oophorectomy and colorectal cancer (all ages and stratified by menopausal status). The potential modifying effects of hysterectomy, HRT use at baseline and BMI were investigated. During 542 140 person-years of follow-up, 863 (3.4%) nurses were diagnosed with colorectal cancer. Bilateral oophorectomy was associated with a 79% increased colorectal cancer rate, adjusted rate ratio (aRR) (95% confidence interval [CI]): 1.79 (1.33-2.42). Effect estimates following unilateral oophorectomy also showed higher rate of colorectal cancer, although less pronounced and nonstatistically significant (aRR) (95% CI): 1.25 (0.86-1.82). Similar results were seen when stratifying by menopausal status. The association was not modified by baseline HRT use, hysterectomy or BMI. Oophorectomy was associated with increased rate of colorectal cancer, with highest rates among women with bilateral oophorectomy.

Skeletal adverse events in childhood cancer survivors: An Adult Life after Childhood Cancer in Scandinavia cohort study.

The dynamic growth of the skeleton during childhood and adolescence renders it vulnerable to adverse effects of cancer treatment. The lifetime risk and patterns of skeletal morbidity have not been described in a population-based cohort of childhood cancer survivors. A cohort of 26 334 1-year cancer survivors diagnosed before 20 years of age was identified from the national cancer registries of Denmark, Finland, Iceland and Sweden as well as a cohort of 127 531 age- and sex-matched comparison subjects randomly selected from the national population registries in each country. The two cohorts were linked with data from the national hospital registries and the observed numbers of first-time hospital admissions for adverse skeletal outcomes among childhood cancer survivors were compared to the expected numbers derived from the comparison cohort. In total, 1987 childhood cancer survivors had at least one hospital admission with a skeletal adverse event as discharge diagnosis, yielding a rate ratio (RR) of 1.35 (95% confidence interval, 1.29-1.42). Among the survivors, we observed an increased risk for osteonecrosis with a RR of 25.9 (15.0-44.5), osteoporosis, RR 4.53 (3.28-6.27), fractures, RR 1.27 (1.20-1.34), osteochondropathies, RR 1.57 (1.28-1.92) and osteoarthrosis, RR 1.48 (1.28-1.72). The hospitalization risk for any skeletal adverse event was higher among survivors up to the age of 60 years, but the lifetime pattern was different for each type of skeletal adverse event. Understanding the different lifetime patterns and identification of high-risk groups is crucial for developing strategies to optimize skeletal health in childhood cancer survivors.

Psychiatric disorders in individuals with neurofibromatosis 1 in Denmark: A nationwide register-based cohort study.

The aim of this study was to assess the risks of psychiatric disorders in a large cohort of 905 individuals with NF1 and 7614 population comparisons matched on sex and year of birth. The cohort was linked to the Danish Psychiatric Central Research Register to ascertain information on hospital contacts for psychiatric disorders based on the International Classification of Diseases version 8 and 10. The hazard ratio (HR) for a first psychiatric hospital contact was higher in girls (4.19, 95% confidence interval [CI] 1.81-9.69) and boys with NF1 (5.02, 95% CI 3.27-7.69) <7 years of age than in the population comparisons. Both sexes had increased HRs for developmental disorders, including attention deficit/hyperactivity disorders, autism spectrum disorders, and intellectual disabilities in childhood. Females with NF1 had also increased HRs for unipolar depression, other emotional and behavioral disorders, and severe stress reaction and adjustment disorders in early adulthood. The HRs for psychoses, schizophrenia, bipolar disorders, and substance abuse were similar in individuals with NF1 and the population comparisons. Finally, the cumulative incidence of a first hospital contact due to any psychiatric disorder by age 30 years was 35% (95% CI 29-41) in females and 28% (95% CI 19-37) in males with NF1. Thus, screening for psychiatric disorders may be important for early diagnosis and facilitation of appropriate and effective treatment in individuals with NF1.

Breast cancer rate after oophorectomy: A Prospective Danish Cohort Study.

The association between oophorectomy and risk of breast cancer in the general population is uncertain. The aim of our study was to determine the breast cancer rate in women from the general population after oophorectomy (performed before/after menopause), and whether this varies by use of hormone replacement therapy (HRT), hysterectomy, body mass index (BMI) and shift work. The study included 24 409 female nurses (aged ≥45 years) participating in the Danish Nurse Cohort. Nurses were followed from cohort entry until date of breast cancer, death, emigration or end of follow-up at 31 December 2018, whichever came first. Poisson regression with log-transformed person-years as the offset examined the association between oophorectomy and breast cancer (all ages and stratified by menopausal status at time of oophorectomy). The potential modifying effect of HRT use, hysterectomy, BMI and shift work on the associations was estimated. During 502 463 person-years of follow-up, 1975 (8.1%) nurses were diagnosed with breast cancer. Bilateral oophorectomy was associated with a reduced breast cancer rate compared to nurses with preserved ovaries, adjusted rate ratio (95% confidence interval): 0.79 (0.64; 0.99). Similar associations (magnitude and direction) were detected for unilateral oophorectomy and when stratifying according to menopausal status at time of oophorectomy, but without statistical significance. Unilateral and bilateral oophorectomy is associated with a reduced breast cancer rate in women from the general population. This association is not modified by use of HRT, hysterectomy, BMI or shift work.

Somatostatin Receptor-Targeted Radiopeptide Therapy in Treatment-Refractory Meningioma: Individual Patient Data Meta-analysis.

Somatostatin receptor (SSTR)-targeted peptide receptor radionuclide therapy (PRRT) represents a promising approach for treatment-refractory meningiomas. Methods: We performed an individual patient data meta-analysis, including all published data on meningioma patients treated with SSTR-targeted PRRT. The main outcomes were toxicity, response to treatment, progression-free survival (PFS), and overall survival (OS). We applied the Kaplan-Meier method to estimate survival probabilities and report incidence rates per 100 person-years. We applied Cox proportional hazards models to determine the effect of covariates. Results: We screened 537 papers and identified 6 eligible cohort studies. We included a total of 111 patients who had treatment-refractory meningioma and received SSTR-targeted PRRT. Disease control was achieved in 63% of patients. The 6-mo PFS rates were 94%, 48%, and 0% for World Health Organization grades I, II, and III, respectively. The risk of disease progression decreased by 13% per 1,000-MBq increase in the total applied activity. The 1-y OS rates were 88%, 71%, and 52% for World Health Organization grades I, II, and III, respectively. The risk of death decreased by 17% per 1,000-MBq increase in the total applied activity. The main side effects comprised transient hematotoxicity, such as anemia in 22% of patients, leukopenia in 13%, lymphocytopenia in 24%, and thrombocytopenia in 17%. Conclusion: To our knowledge, this individual patient data meta-analysis represents the most comprehensive analysis of the benefits of and adverse events associated with SSTR-targeted PRRT for treatment-refractory meningioma. The treatment was well tolerated, achieved disease control in most cases, and showed promising results regarding PFS and OS.

Multisystem burden of neurofibromatosis 1 in Denmark: registry- and population-based rates of hospitalizations over the life span.

PURPOSE: The aim was to assess lifetime risk for hospitalization in individuals with neurofibromatosis 1 (NF1). METHODS: The 2467 individuals discharged with a diagnosis indicating NF1 or followed in a clinical center for NF1 were matched to 20,132 general population comparisons. Based on diagnoses in 12 main diagnostic groups and 146 subcategories, we calculated rate ratios (RRs), absolute excess risks (AERs), and hazard ratios for hospitalizations. RESULTS: The RR for any first hospitalization among individuals with NF1 was 2.3 (95% confidence interval 2.2-2.5). A high AER was seen for all 12 main diagnostic groups, dominated by disorders of the nervous system (14.5% of all AERs), benign (13.6%) and malignant neoplasms (13.4%), and disorders of the digestive (10.5%) and respiratory systems (10.3%). Neoplasms, nerve and peripheral ganglia disease, pneumonia, epilepsy, bone and joint disorders, and intestinal infections were major contributors to the excess disease burden caused by NF1. Individuals with NF1 had more hospitalizations and spent more days in hospital than the comparisons. The increased risk for any hospitalization was observed for both children and adults, with or without an associated cancer. CONCLUSION: NF1 causes an overall greater likelihood of hospitalization, with frequent and longer hospitalizations involving all organ systems throughout life.

Risk of febrile seizures among children conceived following fertility treatment: A cohort study.

BACKGROUND: Studies have shown that fertility treatment in mothers is associated with neurological problems in children. However, knowledge about any association between maternal use of fertility treatment and febrile seizures in children is lacking. OBJECTIVE: To determine whether maternal use of fertility treatment is associated with febrile seizures in children. METHODS: All liveborn children in Denmark during 1996-2012 (n = 1 065 901) were linked with the Danish Infertility Cohort and the Danish national registers and were followed from one year of age until the first episode of a febrile seizure, death, emigration, loss to follow-up, or end of follow-up (December 2015). Cox proportional hazard regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for potential confounders. RESULTS: Approximately 16% children (n = 172 140) were conceived by infertile women, and approximately 3% (n = 34 082) were diagnosed with febrile seizures during follow-up. Compared with children conceived by fertile women, children conceived following any fertility treatment (HR 1.11, 95% CI 1.06, 1.16), following specific fertility treatment, for example IVF (HR 1.15, 95% CI 1.05, 1.25), ICSI (HR 1.20, 95% CI 1.10, 1.32), and following fertility drugs (HR 1.06, 95% CI 1.00, 1.11) had slight increase in risk of febrile seizures, after adjusting for calendar year of birth, parental age, education, parity status, and maternal smoking during pregnancy. The associations were unchanged when children conceived naturally by infertile women were used as the reference group. CONCLUSIONS: Children conceived following fertility treatment had slightly increased relative risk for febrile seizures.

Poor prognosis associated with TERT gene alterations in meningioma is independent of the WHO classification: an individual patient data meta-analysis.

BACKGROUND: TERT gene alterations (TERT-alt) have been linked to increased risk of recurrence in meningiomas, whereas the association to mortality largely remain incompletely investigated. As incongruence between clinical course and WHO grade exists, reliable biomarkers have been sought. METHODS: We applied the Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data Statement. We compiled data from eight studies and allocated patients to TERT-alt (n=59) or TERT promoter wild-type (TERTp-wt; n=618). We compared the two groups stratified for WHO grades as: incidence rates, survival probabilities and cumulative recurrences. We estimated the effects of WHO grade, age at diagnosis and sex as HRs. RESULTS: TERT-alt occurred in 4.7%, 7.9% and 15.4% of WHO-I/WHO-II/WHO-III meningiomas, respectively. The median recurrence-free survival was 14 months for all TERT-alt patients versus 101 months for all TERTp-wt patients. The HR for TERT-alt was 3.74 in reference to TERTp-wt. For all TERT-alt patients versus all TERTp-wt patients, the median overall survival was 58 months and 160 months, respectively. The HR for TERT-alt was 2.77 compared with TERTp-wt. TERT-alt affected prognosis independent of WHO grades. Particularly, the recurrence rate was 4.8 times higher in WHO-I/-II TERT-alt patients compared with WHO-III TERTp-wt patients. The mortality rate was 2.7 times higher in the WHO-I and WHO-II TERT-alt patients compared with WHO-III TERTp-wt patients. CONCLUSIONS: TERT-alt is an important biomarker for significantly higher risk of recurrence and death in meningiomas. TERT-alt should be managed and surveilled aggressively. We propose that TERT-alt analysis should be implemented as a routine diagnostic test in meningioma and integrated into the WHO classification. TRIAL REGISTRATION NUMBER: PROSPERO: CRD42018110566.

Educational level and first-time PSA testing in general practice.

Introduction: Different patterns in the use of prostate-specific antigen (PSA) testing might explain socioeconomic differences in prostate cancer incidence and mortality. We examined the association between socioeconomic position, measured as education and first-time PSA testing in general practice.Material and Methods: A population-based cohort study of men aged 45-79 years without prior prostate cancer diagnosis living in the Capital Region of Denmark between 2000 and 2014. Information on socioeconomic indicators (education, income, cohabitation status and work market affiliation), prostate cancer diagnoses, and vital status were obtained from national registries. Date of first PSA test was obtained from the Copenhagen Primary Care Laboratory database. Temporal trends of PSA testing were calculated as annual age-standardised incidence rates and the association was examined by a multivariable Cox proportional hazards model.Results: The cohort consists of 431,997 men of which 105,476 (24%) had a first-time PSA test in the study period. Men with longer education, higher income, living with a partner, and employed had higher rates of PSA testing. For men with short education, the rate of PSA test was 28.3 tests per 1000 person-years compared to 31.2 tests among men with long education. The fully adjusted hazard ratio for a first PSA test among men with short education was 0.87 (95% CI, 0.85-0.89) compared to men with long education.Conclusion: The association between education and first-time PSA testing indicates socioeconomic disparities in health care utilisation, which could explain part of the observed socioeconomic difference in prostate cancer incidence and mortality.

Risk of cardiovascular events in men treated for prostate cancer compared with prostate cancer-free men.

BACKGROUND: The effect of lifestyle, anthropometry and cardiovascular risk factors on cardiovascular disease in men with prostate cancer (PCa) remains unclear. METHODS: Using a population-based cohort of 25,436 Danish, cancer-free men aged 50-64 years, we obtained information on self-reported pre-cancer lifestyle, objectively measured anthropometry and cardiovascular risk factors, and linked them to national health registers for information on major cardiovascular outcomes. We assessed hazard ratios (HRs) of incident acute myocardial infarction (MI), ischaemic stroke (IS) and heart failure (HF) among 1546 men diagnosed with PCa treated with first-line active surveillance, watchful waiting, intended curative or palliative treatment compared with PCa-free men during 18 years of follow-up. RESULTS: Men who received first-line palliative treatment had higher rates of IS and HF with adjusted HRs of 2.09 (95% CI 1.49-2.93) and 2.05 (95% CI 1.43-2.94), respectively, compared with PCa-free men. The risks were increased from start of treatment. We did not find the same relation for men in any other treatment group. No differences between men treated for PCa and cancer-free controls were observed for MI after adjustment for lifestyle, anthropometry, and cardiovascular risk factors. CONCLUSION: Pre-diagnosis lifestyle, anthropometry or cardiovascular risk factors did not explain the risk of IS and HF in PCa patients receiving palliative treatment. The results emphasise the need for balancing disease management and monitoring of cardiovascular health in this patient group.

Treatment intensity and survival in patients with relapsed or refractory diffuse large B-cell lymphoma in Denmark: a real-life population-based study.

PURPOSE: High-dose chemotherapy with autologous stem cell transplantation (ASCT) is considered to be the only curative treatment option for patients with refractory or relapsed diffuse large B-cell lymphoma (DLBCL). Due to toxicity, not all patients are eligible for this treatment leading to different treatment intensities. Here, we aim to analyze the impact of treatment intensity on survival in patients previously treated with rituximab and chemotherapy, and, furthermore, to analyze the association between socioeconomic position and treatment intensity, defined as palliation, non-salvage, and salvage regimens. MATERIALS AND METHODS: We identified patients with refractory or relapsed DLBCL diagnosed in 2000-2015 in the Danish National Lymphoma Registry (n=1,228). We analyzed the impact of treatment intensity on survival in patients previously treated with rituximab (n=277) using a Cox proportional hazards model. Multinomial regression analyses were performed to identify associations between socioeconomic factors and treatment intensity for the entire cohort. RESULTS: In the rituximab era, the 5-year overall survival (OS) was 31% for patients receiving salvage regimens (n=194), and 17% for patients receiving non-salvage regimens (n=83). In the adjusted analysis, HR was 1.88, 95% CI: 0.9-3.9 for patients receiving salvage regimens. Patients living alone were significantly less likely to receive salvage regimens, as were patients with two or more comorbidities. CONCLUSION: We observed a better OS in patients treated with salvage regimens compared with non-salvage regimens; however, the adjusted analysis contradicts this. Furthermore, our results indicate that there is a chance of remission for patients not eligible for ASCT.

Socioeconomic Differences in Referral to Phase I Cancer Clinical Trials: A Danish Matched Cancer Case-Control Study.

PURPOSE: In this nationwide registry study, we investigated socioeconomic and structural patterns in referral to phase I cancer trials in a case-control study design. METHODS: Personal identification numbers on all Danish patients referred to the Danish Phase I Unit at Rigshospitalet from 2005 to 2016, and a control group matched on age, sex, type of cancer, year of diagnosis, and time from diagnosis to referral ensured individual-level linkage between several registries. We examined the association between nonclinical factors-indicators of socioeconomic position and distance to the Phase I Unit-and referral using a conditional logistic regression analysis adjusted for several clinical factors. Association between nonclinical factors and enrollment once referred was examined with a Cox proportional hazards regression analysis in an historical cohort study design. RESULTS: Complete data were available for 1,026 (84%) of 1,220 referred patients. Significantly decreased odds for referral were identified for patients with long distance to the Phase I Unit compared with short distance (adjusted odds ratio [OR], 0.35; 95% CI, 0.30 to 0.41), for less education (less than 9 years) compared with more (more than 12 years; OR, 0.69; 95% CI, 0.56 to 0.91), and for belonging to the lowest income quintile compared with the highest (OR, 0.78; 95% CI, 0.62 to 0.97). Medium education (9 to 12 years) compared with more, being outside the workforce compared with being within, and living alone compared with living with a partner were also negatively associated with referral. Among patients referred, 252 enrolled in a trial. Nonclinical factors were not associated with enrollment. CONCLUSION: On the basis of individual long-term registry data from an unselected cohort, novel anticancer therapies seem to be tested on a socially selected group of patients with cancer.

The association between education and risk of major cardiovascular events among prostate cancer patients: a study from the Diet, Cancer and Health study.

Background: High socioeconomic position is associated with better prognosis in prostate cancer patients but it is unknown if part of this association may be explained by socioeconomic differences in severe late effects. We investigated the association between education as an indicator for socioeconomic position and cardiovascular events after prostate cancer and if such associations were mediated by differences in lifestyle, cardiovascular risk factors and prostate cancer treatment. Material and methods: We identified 1980 men diagnosed with prostate cancer from 1993 to 2014 among participants in the Danish Diet, Cancer and Health study. Individual level information on education, lifestyle, cardiovascular risk factors and prostate cancer clinical information were obtained from questionnaires, registries and medical records. The Cox proportional hazards models were used to evaluate the risk of incident acute myocardial infarction, ischemic stroke and heart failure during up to 18 years of follow-up for men with short (<9 years) or medium (9-12 years) compared with long education (>12 years). Results: Compared to men with long education, we found an increased risk of acute myocardial infarction in men with medium and short education (HR 3.14, 95% CI 1.53-6.47 and HR 2.14, 95% CI 0.82-5.58, respectively). Adjusting for stage, first-line treatment, lifestyle and cardiovascular risk factors did not change the HRs substantially (adjusted HRs 3.04, 95% CI 1.47-6.31 and 2.07, 95% CI 0.78-5.53, respectively). There were no educational differences in risk for ischemic stroke or heart failure. Conclusions: The risk of acute myocardial infarction was increased in prostate cancer patients with short or medium education compared with long education. Although the educational inequality did not seem to be explained by differences in treatment, lifestyle or cardiovascular risk factors, monitoring of cardiovascular health and health promotion should involve all prostate cancer patients regardless of social position to ensure best prognosis for all.

Adverse pregnancy outcomes and infant mortality after quadrivalent HPV vaccination during pregnancy.

BACKGROUND: Few studies have studied the association between unintended human papillomavirus (HPV) vaccination and adverse pregnancy outcomes. This study set out to determine the association between HPV vaccination during pregnancy and subsequent risk of spontaneous abortion, stillbirth, and one-year infant mortality. METHODS: Population-based study including all pregnancies in Denmark (October 2006-December 2014) among women born 1975-1992. From nationwide health registries using the personal identification numbers, we obtained information on HPV vaccination, pregnancy outcomes, and infant mortality. The exposure window went from four weeks before conception date until 22 weeks of gestation for the outcome spontaneous abortion, and until birth for stillbirth and infant mortality outcomes. In the analyses of spontaneous abortion, we used time to event models, for stillbirth logistic regression models, and for infant mortality Cox regression was applied. RESULTS: We included 522,705 pregnancies for the outcome spontaneous abortion (7487 exposed to at least one dose during pregnancy); 351,878 births (5262 exposed to at least one dose during pregnancy) for the stillbirth; and 350,739 live births (5245 exposed to at least one dose during pregnancy) for infant mortality. No significantly increased rate of spontaneous abortion among women vaccinated during pregnancy compared with unvaccinated women was found. In addition, we found no association between HPV vaccination during pregnancy and stillbirth (adjusted odds ratio = 0.96 [95% CI: 0.57-1.61]), or infant mortality (adjusted hazard ratio = 0.94 [95% CI: 0.53-1.67]). A secondary analysis showed no association between number of doses and timing of administration (i.e. vaccination before or during pregnancy) and an increased risk of spontaneous abortion. CONCLUSION: We found no increased risk of spontaneous abortion, stillbirth, or infant mortality following unintended HPV vaccination during pregnancy.

Prolonged hospitalization, primary refractory disease, performance status and age are prognostic factors for survival in patients with diffuse large B-cell lymphoma and transformed indolent lymphoma undergoing autologous stem cell transplantation.

In patients with relapsed diffuse large B-cell lymphoma (DLBCL), high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is standard treatment. Here, we aim to identify factors associated with survival in patients undergoing ASCT. A total of 369 patients with relapsed DLBCL undergoing ASCT from 2000 to 2012 were identified in the Danish National Lymphoma Registry. Information on clinical and socioeconomic factors was obtained from medical records and national registries. Factors associated with survival were assessed using a Cox's proportional hazards model. Median overall survival was 6.8 years, median progression-free survival was 2.6 years, and treatment-related mortality at Day 100 was 6%. Factors associated with a significant adverse impact on survival were age, primary refractory disease, prolonged hospitalization during salvage treatment, and performance status >0 prior to conditioning therapy. Reconsideration of ASCT for those patients may be required in order to select the right patients for this toxic procedure.

Williams syndrome transcription factor (WSTF) acts as an activator of estrogen receptor signaling in breast cancer cells and the effect can be abrogated by 1α,25-dihydroxyvitamin D3.

A majority of estrogen receptor positive (ER+) breast cancers are growth stimulated by estrogens. The ability to inhibit the ER signaling pathway is therefore of critical importance in the current treatment of ER+ breast cancers. It has been reported that 1α,25-dihydroxyvitamin D3 down-regulates the expression of the CYP19A1 gene, encoding the aromatase enzyme that catalyzes the synthesis of estradiol. Furthermore, 1α,25-dihydroxyvitamin D3 has also been reported to down-regulate the expression of estrogen receptor α (ERα), the main mediator of ER signaling. This study reports a novel transcription factor critical to 1α,25-dihydroxyvitamin D3-mediated regulation of estrogenic signaling in MCF-7 breast cancer cells. We have investigated the molecular mechanisms for the 1α,25-dihydroxyvitamin D3-mediated down-regulation of CYP19A1 and ERα gene expression in human MCF-7 breast cancer cells and found that Williams syndrome transcription factor (WSTF) plays a key role by binding to the promoters of CYP19A1 and ERα. Although sometimes reported as an inhibitor of gene expression, we found that WSTF acts as an activator of the promoter activity of both CYP19A1 and ERα. Silencing of WSTF by siRNA transfection resulted in decreased aromatase-dependent cell growth as well as decreased ER signaling in the cells. When cells were treated with 1α,25-dihydroxyvitamin D3, WSTF was dissociated from the promoters and the promoter activities of CYP19A1 and ERα were decreased. We have measured the expression of WSTF in ER-positive tumor-samples from breast cancer patients and found that WSTF is expressed in the majority of the investigated samples and that the expression is higher in cancer tissue than in normal tissue. However, we were not able to show any significant association between the WSTF expression in the tumor and the disease free and overall survival in this patient group who have received adjuvant tamoxifen treatment, nor between the WSTF expression and the expression of ERα, progesterone receptor or HER2. The major conclusions of this study are that WSTF acts as an activator of ER signaling in MCF-7 breast cancer cells, that this action can be inhibited by 1α,25-dihydroxyvitamin D3, and that the expression of WSTF is higher in breast cancer tissue than in normal tissue. WSTF may by a new target for treatment of estrogen-dependent breast cancer cell growth.

Return to work for patients with diffuse large B-cell lymphoma and transformed indolent lymphoma undergoing autologous stem cell transplantation.

BACKGROUND: Autologous stem cell transplantation (ASCT) is the standard treatment for patients with relapsed diffuse large B-cell lymphoma (DLBCL) or transformed indolent lymphoma (TIL). The treatment is mainly considered for younger patients still available for the work market. In this study, social outcomes after ASCT in terms of return to work (RTW) are described. PATIENTS AND METHODS: Information from national administrative registers was combined with clinical information on patients, who received ASCT for relapse of DLBCL or TIL between 2000 and 2012. A total of 164 patients were followed until RTW, disability or old-age pension, death, or December 31, 2015, whichever came first. A total of 205 patients were followed with disability pension as the event of interest. Cox models were used to determine cause-specific hazards. RESULTS: During follow-up, 82 (50%) patients returned to work. The rate of returning to work in the first year following ASCT was decreased for patients being on sick leave at the time of relapse (hazard ratio [HR] 0.3 [0.2;0.5]) and increased for patients aged ≥55 years (HR 1.9 [1.1;3.3]). In all, 56 (27%) patients were granted disability pension. Being on sick leave at the time of relapse was positively associated with receiving a disability pension in the first 2 years after ASCT (HR 3.7 [1.8;7.7]). CONCLUSION: Patients on sick leave at the time of relapse have a poorer prognosis regarding RTW and have a higher rate of disability pension. Furthermore, patients >55 are more likely to RTW compared to younger patients. These results indicate an unmet need for focused social rehabilitation.