Association between medical androgen deprivation therapy and long-term cardiovascular disease and all-cause mortality in nonmetastatic prostate cancer

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.publishedVersio

Preeclampsia in pregnancy and later use of antihypertensive drugs

We explored the association between preeclampsia and later use of antihypertensive drugs in a population-based study with data from the Medical Birth Registry of Norway and the Norwegian Prescription Database. The study cohort consisted of 980,000 women having 2.1 million pregnancies during 1967–2012. Hazard ratios (HRs) with 95 % confidence intervals (95 % CI) were estimated in multivariate time-dependent Cox proportional hazards regression models. Overall, the HR of later use of antihypertensive drugs was 2.0 (95 % CI 2.0–2.0) in women with one preeclamptic pregnancy compared to women without preeclamptic pregnancies. The HR increased by increasing number of preeclamptic pregnancies, both term and preterm pregnancies. In women with two or more preeclamptic pregnancies, the HR was 2.8 (2.7–3.0). The overall HR after 40 years of follow-up for women with one preeclamptic pregnancy was 1.3 (1.2–1.4) and for two or more preeclamptic pregnancies the HR was 1.6 (1.1–2.1). The first 5 years after the first birth, the HR of being dispensed antihypertensive drugs was higher in preterm [8.4 (7.7–9.1)] than term preeclamptic pregnancies [4.3(4.0–4.6)]. However, after 10 years, this difference was no longer present. The HR of later use of antihypertensive drugs increased with the number of preeclamptic pregnancies, and in the first 10 years the HR was higher after a preterm than a term preeclamptic pregnancy. Although the HR decreased with time since first birth, the risk was still elevated after 40 years. Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited

Cervical cancer in women under 30 years of age in Norway: a population-based cohort study

Background We compared women with incident cervical cancer under the age of 30 with older women with regard to stage, morphology, screening history and cervical cancer mortality in a population-based cohort study. Methods We included data from the Cancer Registry of Norway. Incidence rates (per 100,000 women-years) were calculated and joinpoint regression was used to analyse trends. The Nelson-Aalen cumulative hazard function for risk of cervical cancer death during a 15-year follow-up was displayed. The hazard ratios (HRs) of cervical cancer mortality with 95% confidence intervals (CIs) were derived from Cox regression models. Results The incidence of cervical cancer in women under the age of 30 has almost tripled since the 1950s, with the steepest increase during 1955–80 (with an annual percentage change (APC) of 7.1% (95%CI 4.4–9.8)) and also an increase after 2004 (3.8% (95%CI -1.3–9.2)). Out of 21,160 women with cervical cancer (1953–2013), 5.3% were younger than 30 years. A lower proportion of younger women were diagnosed at more advanced stages and a slightly higher proportion were diagnosed with adenocarcinoma and adenosquamous carcinoma comparing women above 30 years. The cumulative risk of cervical cancer death was lower for patients under the age of 30. However, the difference between the age groups decreased over time. The overall adjusted HR of cervical cancer mortality was 0.69 (95% CI 0.58–0.82) in women diagnosed under the age of 30 compared to older women. Conclusion There has been an increase in cervical cancer incidence in women under the age of 30. Cervical cancer in younger women was not more advanced at diagnosis compared to older women, and the cervical cancer mortality was lower.publishedVersio

Risk of diabetes after gestational diabetes and preeclampsia. A registry-based study of 230,000 women in Norway

This study aimed to use a population-based Prescription Database to explore later development of diabetes in women registered with gestational diabetes mellitus (GDM) and/or preeclampsia in the Medical Birth Registry of Norway (MBRN) during 2004–8. We used two nationwide Norwegian registries, the Norwegian Prescription Database and the MBRN, to explore the onset of later diabetes after pregnancy complications, indicated by receiving prescriptions of drugs used to treat diabetes, in 230,000 women giving birth in 2004–8. The mean follow-up of the study cohort was 3.7 years. Five years after pregnancy, about 19 and 2% of women with GDM and preeclampsia, respectively, received drugs used to treat diabetes, compared to 0.5% of those without these complications. The risk of being dispensed drugs used to treat diabetes within the first years after pregnancy was estimated to be 41 times (95% CI: 35–47) and 3.0 times (95% CI: 2.4–3.6) higher in women with GDM and preeclampsia, respectively, compared to women without these pregnancy complications. Women with pregnancies complicated with preeclampsia or GDM had an increased risk of later diabetes, especially those having GDM. If the increase in frequency of GDM observed in MBRN in recent years is real, a further increase in diabetic women can be expected

Real-world data on cervical cancer risk stratification by cytology and HPV genotype to inform the management of HPV-positive women in routine cervical screening

Background HPV16/18 detection may improve cervical cancer risk stratification and better guide which HPV-positive women warrant immediate colposcopy/biopsy. We estimated risks of cervical precancer and cancer by HPV genotype and cytology during the implementation phase of primary HPV testing in Norway. Methods A total of 3111 women, aged 34–69 years, testing HPV-positive at baseline and undergoing cytology testing from February 2015 to April 2018 had data available for analysis. Risk estimates with 95% confidence intervals (95%CIs) of cervical intraepithelial neoplasia grade 3 or more severe (CIN3+) were estimated for cytology results and HPV genotypes (HPV16, HPV18, and other high-risk HPV). Results CIN3+ risks were higher for HPV16/18 than other high-risk HPV genotypes. Among women with any cytologic abnormality [atypical squamous cells of undetermined significance or worse], immediate risks were 57.8% (95%CI = 53.0–62.6%) for HPV16, 40.2% (95%CI = 32.3–49.2%) for HPV18, and 31.4% (95%CI = 28.7–34.3%) for other high-risk HPV. Among those with normal cytology, CIN3+ risks were 19.9% (95%CI = 15.0–26.1%) for HPV16 positives, 10.8% (95%CI = 5.6–20.5%) for HPV18 positives, and 5.5% (95%CI = 4.2–7.1%) for other high-risk HPV. Conclusions The benefits and harms of managing women based on HPV positivity and cytology results can be better balanced by inclusion of HPV genotyping in screening and choosing more conservative management for other high-risk HPV compared to HPV16/18.publishedVersio

Cardiovascular outcomes after curative prostate cancer treatment: A population-based cohort study

Objective: To investigate differences in cardiovascular disease (CVD) morbidity and mortality after radical prostatectomy or definitive radiotherapy with or without androgen deprivation therapy (ADT). Materials and methods: We used population-based data from the Cancer Registry of Norway, the Norwegian Patient Registry and the Norwegian Cause of Death Registry including 19 289 men ≤80 years diagnosed with non-metastatic prostate cancer during 2010-2019. Patients were treated with radical prostatectomy or definitive radiotherapy. We used competing risk models to compare morbidity from overall CVD, acute myocardial infarction (AMI), cerebral infarction, thromboembolism, and CVD-specific mortality for the overall cohort and stratified by prognostic risk groups. Results: After a median follow-up time of 5.4 years (IQR 4.6 years), there were no differences in adjusted rates of AMI, cerebral infarction, and CVD-specific death between radical prostatectomy and definitive radiotherapy in any of the prognostic risk groups. Rates of overall CVD (0.82; 95% CI 0.76-0.89) and thromboembolism (0.30; 95% CI 0.20-0.44) were lower for definitive radiotherapy than radical prostatectomy during the first year of follow-up. After this overall CVD rates (1.19; 95% CI 1.11-1.28) were consistently higher across all risk groups in patients treated with definitive radiotherapy, but there were no differences regarding thromboembolism. Conclusions: During the first years after treatment, no differences were found in rates of AMI, cerebral infarction, and CVD-specific death between radiotherapy and radical prostatectomy in any of the prognostic risk groups. This suggests that ADT use in combination with radiotherapy may not increase the risks of these outcomes in a curative setting. The increased overall CVD rate for definitive radiotherapy after the first year indicates a possible relationship between definitive radiotherapy and other CVDs than AMI and cerebral infarction.publishedVersio

Metabolomics identifies placental dysfunction and confirms Flt-1 (FMS-like tyrosine kinase receptor 1) biomarker specificity

Clinical end-stage parameters define the pregnancy disorders preeclampsia and fetal growth restriction while classification of the underlying placental dysfunction is missing and urgently needed. Flt-1 (FMS-like tyrosine kinase receptor 1) is the most promising placenta-derived predictive biomarker for preeclampsia. We aimed to classify placental dysfunction in preeclampsia and fetal growth restriction at delivery by metabolic profiling and authenticate the biomarker Flt-1 for placental dysfunction. We studied 143 pregnancies with or without preeclampsia and/or fetal growth restriction delivered by cesarean section. Metabolic placenta profiles were created by high-resolution magic angle spinning nuclear magnetic resonance spectroscopy and the resulting placental phenotypes obtained by hierarchical clustering. Placental Flt-1 expression (membrane-bound and soluble isoforms combined) and maternal serum Flt-1 expression (soluble isoforms) were analyzed by immunohistochemistry and ELISA, respectively. We identified 3 distinct placenta groups by 21 metabolites and diagnostic outcome parameters; normal placentas, moderate placental dysfunction, and severe placental dysfunction. Increased placental Flt-1 was associated with severe placental dysfunction, and increased serum Flt-1 was associated with moderate and severe placental dysfunction. The preeclamptic pregnancies with and without placental dysfunction could be distinguished by 5 metabolites and placental Flt-1. Placental Flt-1 alone could separate normal pregnancies with and without placental dysfunction. In conclusion, metabolomics could classify placental dysfunction and provide information not identified by traditional diagnostics and metabolites with biomarker potential were identified. Flt-1 was confirmed as precision biomarker for placental dysfunction, substantiating its usefulness for identification of high-risk pregnancies for preeclampsia and fetal growth restriction with placental involvement.acceptedVersio

Treatment and 30-day mortality after myocardial infarction in prostate cancer patients: A population-based study from Norway

Introduction: There is limited knowledge about the use of invasive treatment and mortality after acute myocardial infarction (AMI) in prostate cancer (PCa) patients. We therefore wanted to compare rates of invasive treatment and 30-day mortality between AMIs in patients with PCa and AMIs in the general Norwegian male population. Methods: Norwegian population-based registry data from 2013 to 2019 were used in this cohort study to identify AMIs in patients with a preceding PCa diagnosis. We compared invasive treatment rates and 30-day mortality in AMI patients with PCa to the same outcomes in all male AMI patients in Norway. Invasive treatment was defined as performed angiography with or without percutaneous coronary intervention or coronary artery bypass graft surgery. Standardized mortality (SMR) and incidence ratios, and logistic regression were used to evaluate the association between PCa risk groups and invasive treatment. Results: In 1,018 patients with PCa of all risk groups, the total rates of invasive treatment for AMIs were similar to the rates in the general AMI population. In patients with ST-segment elevation AMIs, rates were lower in metastatic PCa compared to localized PCa (OR 0.15, 95% CI: 0.04–0.49). For non-ST-segment elevation AMIs, there were no differences between PCa risk groups. The 30-day mortality after AMI was lower in PCa patients than in the total population of similarly aged AMI patients (SMR 0.77, 95% CI: 0.61–0.97). Conclusion: Except for patients with metastatic PCa experiencing an ST-segment elevation AMI, PCa patients were treated as frequent with invasive treatment for their AMI as the general AMI population. 30-day all-cause mortality was lower after AMI in PCa patients compared to the general AMI population.publishedVersio

Metabolic profiles of placenta in preeclampsia using HR-MAS MRS metabolomics

Introduction Preeclampsia is a heterogeneous gestational disease characterized by maternal hypertension and proteinuria, affecting 2–7% of pregnancies. The disorder is initiated by insufficient placental development, but studies characterizing the placental disease components are lacking. Methods Our aim was to phenotype the preeclamptic placenta using high-resolution magic angle spinning nuclear magnetic resonance spectroscopy (HR-MAS MRS). Placental samples collected after delivery from women with preeclampsia (n = 19) and normotensive pregnancies (n = 15) were analyzed for metabolic biomarkers including amino acids, osmolytes, and components of the energy and phospholipid metabolism. The metabolic biomarkers were correlated to clinical characteristics and inflammatory biomarkers in the maternal sera. Results Principal component analysis showed inherent differences in placental metabolic profiles between preeclamptic and normotensive pregnancies. Significant differences in metabolic profiles were found between placentas from severe and non-severe preeclampsia, but not between preeclamptic pregnancies with fetal growth restricted versus normal weight neonates. The placental metabolites correlated with the placental stress marker sFlt-1 and triglycerides in maternal serum, suggesting variation in placental stress signaling between different placental phenotypes. Discussion HR-MAS MRS is a sensitive method for defining the placental disease component of preeclampsia, identifying several altered metabolic pathways. Placental HR-MAS MRS analysis may improve insight into processes affected in the preeclamptic placenta, and represents a novel long-required tool for a sensitive placental phenotyping of this heterogeneous disease.acceptedVersio

Metabolically (un)healthy obesity and risk of obesity-related cancers: a pooled study

Background Studies of obesity with or without metabolic aberrations, commonly termed metabolically unhealthy or healthy obesity, in relation to cancer risk are scarce. Methods We investigated body mass index (normal weight, overweight, obesity) jointly and in interaction with metabolic health status in relation to obesity-related cancer risk (n = 23 630) among 797 193 European individuals. A metabolic score comprising mid-blood pressure, plasma glucose, and triglycerides was used to define metabolically healthy and unhealthy status. Hazard ratios (HRs) and multiplicative interactions were assessed using Cox regression, and additive interactions were assessed using the relative excess risk for interaction. All statistical tests were 2-sided. Results Metabolically unhealthy obesity, with a baseline prevalence of 7%, was, compared with metabolically healthy normal weight, associated with an increased relative risk of any obesity-related cancer and of colon, rectal, pancreas, endometrial, liver, gallbladder, and renal cell cancer (P < .05), with the highest risk estimates for endometrial, liver, and renal cell cancer (HR = 2.55-3.00). Metabolically healthy obesity showed a higher relative risk for any obesity-related cancer and colon (in men), endometrial, renal cell, liver, and gallbladder cancer, though the risk relationships were weaker. There were no multiplicative interactions, but there were additive, positive interactions between body mass index and metabolic health status on obesity-related and rectal cancer among men and on endometrial cancer (P < .05). Conclusions This study highlights that the type of metabolic obesity phenotype is important when assessing obesity-related cancer risk. In general, metabolic aberrations further increased the obesity-induced cancer risk, suggesting that obesity and metabolic aberrations are useful targets for prevention.publishedVersio