Microvascular proliferation in luminal Aand basal-like breast cancer subtypes

Aims: The aims of this study were to examine microvessel density (MVD), proliferating MVD (pMVD) and Vascular Proliferation Index (VPI) in basal-like phenotype (BP) and luminal A subtypes of breast cancer and to study their prognostic value. Methods: Dual-colour immunohistochemistry for von Willebrand factor and Ki67 was done on sections from 62 luminal A and 62 BP tumours matched for grade and selected from 909 breast cancers previously reclassified into molecular subtypes. Associations between MVD, pMVD and VPI, molecular subtypes and breast cancer prognosis were estimated using linear regression and survival analyses. Results: Both pMVD (difference 1.9 microvessels/mm2 (p=0.002)) and VPI (difference 1.7 percentage points (p=0.014)) were higher in BP tumours compared with luminal A. No clear difference between subtypes was found for MVD. However, only MVD was associated with prognosis. HR for breast cancer death for all cases was 1.10 (95% CI 1.02 to 1.18) per 10 vessels increase. Among luminal A tumours, HR was 1.22 per 10 vessels increase (p<0.001) and in BP it was 1.04 (p=0.37). Conclusions: High MVD was associated with poor prognosis in luminal A, but not in BP cancers. Vascular proliferation was higher in BP, indicating a more active angiogenesis than in luminal A tumours. The luminal A subgroup comprised mostly histopathological grade 3 cancers in this selected series, and further studies are needed to clarify whether MVD provides additional prognostic information for luminal A tumours irrespective of grade. This may contribute to stratification of this large group of patients and may aid in identifying tumours with a particularly good prognosis.acceptedVersio

Puberty disorders among ART-conceived singletons : a Nordic register study from the CoNARTaS group

STUDY QUESTION Do ART-conceived children have an increased risk for puberty disorders? SUMMARY ANSWER Both ART-conceived boys and girls had a higher risk of puberty disorders; early puberty was more common among girls and late puberty among boys. WHAT IS KNOWN ALREADY Some physiological differences in growth and metabolism have been reported for ART-conceived children compared to non-ART-conceived children. Knowledge on pubertal development and disorders in ART-conceived children is limited. STUDY DESIGN, SIZE, DURATION A register-based cohort study was carried out including data from 1985 to 2015. The Committee of Nordic Assisted Reproductive Technology and Safety (CoNARTaS) study population consists of all live and stillborn children, as well as their mothers, registered in the Medical Birth Registers during the study period in Denmark, Sweden, Finland and Norway. PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 122 321 ART-conceived singletons and 6 576 410 non-ART singletons born in Denmark (1994-2014), Finland (1990-2014), Norway (2002-2015) and Sweden (1985-2015) were included. Puberty disorders were defined using International Classification of Diseases and Related Health Problems (ICD)-9/ICD-10 codes and classified in the following groups: late puberty (6268/E30.0), early puberty (2591 and 2958/E30.1 and E30.8) and unspecified disorders (V212 and V579/E30.9 and Z00.3 as well as Z51.80 for Finland). The results in Cox regression were adjusted for maternal age, parity, smoking, gestational diabetes, chronic hypertension, hypertensive disorders during pregnancy and country, and further for either gestational age, birthweight, small for gestational age or large for gestational age. MAIN RESULTS AND THE ROLE OF CHANCE There were 37 869 children with diagnoses related to puberty disorders, and 603 of them were born after ART. ART-conceived children had higher risks for early (adjusted hazard ratio (aHR) 1.45, 95% CI: 1.29-1.64) and late puberty (aHR 1.47, 95% CI: 1.21-1.77). Girls had more diagnoses related to early puberty (aHR 1.46, 95% CI: 1.29-1.66) and boys with late puberty (aHR 1.55, 95% CI: 1.24-1.95). LIMITATIONS, REASONS FOR CAUTION Using reported puberty disorders with ICD codes in health care registers might vary, which may affect the numbers of cases found in the registers. Register data may give an underestimation both among ART and non-ART-conceived children, especially among non-ART children, who may not be as carefully followed as ART-conceived children. Adjustment for causes and duration of infertility, mothers' own puberty characteristics and BMI, as well as children's BMI, was not possible because data were not available or data were missing for the early years. It was also not possible to compare ART to non-ART siblings or to study the pubertal disorders by cause of subfertility owing to a small number of discordant sibling pairs and a large proportion of missing data on cause of subfertility. WIDER IMPLICATIONS OF THE FINDINGS This large, register-based study suggests that ART-conceived children have a higher risk for puberty disorders. However, the mechanisms of infertility and pubertal onset are complex, and ART is a rapidly advancing field with various treatment options. Studying the pubertal disorders of ART-conceived offspring is a continuing challenge. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the Nordic Trial Alliance: a pilot project jointly funded by the Nordic Council of Ministers and NordForsk (71450), the Central Norway Regional Health Authorities (46045000), the Nordic Federation of Obstetrics and Gynaecology (NF13041, NF15058, NF16026 and NF17043), the Interreg oresund-Kattegat-Skagerrak European Regional Development Fund (ReproUnion project), the Research Council of Norway's Centre of Excellence funding scheme (262700), the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-70940) and FLUX Consortium 'Family Formation in Flux-Causes, Consequences and Possible Futures', funded by the Strategic Research Council, Academy of Finland (DEMOGRAPHY 345130). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors have no conflicts of interest to disclose.Peer reviewe

Molecular subtypes, histopathological grade and survival in a historic cohort of breast cancer patients

Molecular subtyping of breast cancer may provide additional prognostic information regarding patient outcome. However, its clinical significance remains to be established. In this study, the main aims were to discover whether reclassification of breast cancer into molecular subtypes provides more precise information regarding outcome compared to conventional histopathological grading and to study breast cancer-specific survival in the different molecular subtypes. Cases of breast cancer occurring in a cohort of women born between 1886 and 1928 with long-term follow-up were included in the study. Tissue microarrays were constructed from archival formalin-fixed, paraffin-embedded tissue from 909 cases. Using immunohistochemistry and in situ hybridisation as surrogates for gene expression analyses, all cases were reclassified into the following molecular subtypes: Luminal A; Luminal B (HER2−); Luminal B (HER2+); HER2 subtype; Basal phenotype; and five negative phenotype. Kaplan–Meier survival curves and Cox proportional hazards models were used in the analyses. During the first 5 years after diagnosis, there were significant differences in prognosis according to molecular subtypes with the best survival for the Luminal A subtype and the worst for HER2 and five negative phenotype. In this historic cohort of women with breast cancer, differences in breast cancer-specific survival according to subtype occur almost exclusively amongst the histopathological grade 2 tumours. From 5 years after time of diagnosis until the end of follow-up, there appears to be no difference in survival according to molecular subtype or histopathological grade.publishedVersio

A Semiotic Approach for Guiding the Visualizing of Time and Space in Enterprise Models

Part 2: Organizational Semiotics and ApplicationsInternational audienceEven if geographical aspects such as location are included already in the Zachman framework (as the where-perspective), it is not common to have detailed geographical aspects included in enterprise models. Cartography is the science of visualizing geographical information in maps. Traditionally the field has not included conceptual relationships that you find in enterprise models. Both cartography and enterprise modelling have developed guidelines for obtaining high quality visualizations. SEQUAL is a quality framework developed for understanding quality of models and modelling languages based on semiotic theory. In cartography such frameworks are not common. An adaptation of SEQUAL in the context of cartographic maps called MAPQUAL has been presented earlier. Differences between quality of maps and quality of conceptual models, pointing to guidelines for combined representations have been performed, and we try in this paper to investigate the utility of these guidelines in a simple trial. The result of the trial is presented, indicating that it is possible to represent conceptual, temporal, and spatial aspects in the same models in many ways, but that the choice of main perspective should depend on participant appropriateness

Separating parental and treatment contributions to perinatal health after fresh and frozen embryo transfer in assisted reproduction : A cohort study with within-sibship analysis

Background Compared to naturally conceived children, adverse perinatal outcomes are more common among children born after assisted reproductive technology with fresh embryo transfer (fresh-ET) or frozen embryo transfer (frozen-ET). However, most previous studies could not adequately control for family confounding factors such as subfertility. We compared birth size and duration of pregnancy among infants born after fresh-ET or frozen-ET versus natural conception, using a within-sibship design to account for confounding by maternal factors. Methods and findings This registry-based cohort study with nationwide data from Denmark (1994-2014), Norway (1988-2015), and Sweden (1988-2015) consisted of 4,510,790 live-born singletons, 4,414,703 from natural conception, 78,095 from fresh-ET, and 17,990 from frozen-ET. We identified 33,056 offspring sibling groups with the same mother, conceived by at least 2 different conception methods. Outcomes were mean birthweight, small and large for gestational age, mean gestational age, preterm (= 37), and very preterm birth (= 32). Singletons born after fresh-ET had lower mean birthweight (- 51 g, 95% CI - 58 to - 45, p < 0.001) and increased odds of small for gestational age (odds ratio [OR] 1.20, 95% CI 1.08 to 1.34, p < 0.001), while those born after frozen-ET had higher mean birthweight (82 g, 95% CI 70 to 94, p < 0.001) and increased odds of large for gestational age (OR 1.84, 95% CI 1.56 to 2.17, p < 0.001), compared to naturally conceived siblings. Conventional population analyses gave similar results. Compared to naturally conceived siblings, mean gestational age was lower after fresh-ET (-1.0 days, 95% CI - 1.2 to -0.8AU : Here; andinTable2; in 1:0days; 95%CI 1:2to 0:84; Ichanged 0:84to, p < 0.001), but not after frozen-ET (0.3 days, 95% CI 0.0 to 0.6, p = 0.028). There: were; so that related values are all given to the same decimal place: were increased odds of preterm birth after fresh-ET (OR 1.27, 95% CI 1.17 to 1.37, p < 0.001), and in most models after frozen-ET, versus naturally conceived siblings, with somewhat stronger associations in population analyses. For very preterm birth, population analyses showed increased odds for both fresh-ET (OR 2.03, 95% CI 1.90 to 2.12, p < 0.001) and frozen-ET (OR 1.66, 95% CI 1.42 to 1.94, p < 0.001) compared with natural conception, but results were notably attenuated within siblings (OR 1.18, 95% CI 1.0 to 1.41, p = 0.059, and OR 0.92, 95% CI 0.67 to 1.27, p = 0.6, for fresh-ET and frozen-ET, respectively). Sensitivity analyses in full siblings, in siblings born within 3-year interval, by birth order, and restricting to single embryo transfers and blastocyst transfers were consistent with the main analyses. Main limitations were high proportions of missing data on maternal body mass index and smoking. Conclusions We found that infants conceived by fresh-ET had lower birthweight and increased odds of small for gestational age, and those conceived by frozen-ET had higher birthweight and increased odds of large for gestational age. Conception by either fresh-ET or frozen-ET was associated with increased odds of preterm birth. That these findings were observed within siblings, as well as in conventional multivariable population analyses, reduces the likelihood that they are explained by confounding or selection bias.Peer reviewe

Molecular Subtypes of Breast Cancer: Long-term Incidence Trends and Prognostic Differences

Background: Secular trends in incidence and prognosis of molecular breast cancer subtypes are poorly described. We studied long-term trends in a population of Norwegian women born 1886–1977. Methods: A total of 52,949 women were followed for breast cancer incidence, and 1,423 tumors were reclassified into molecular subtypes using IHC and in situ hybridization. We compared incidence rates among women born 1886–1928 and 1929–1977, estimated age-specific incidence rate ratios (IRR), and performed multiple imputations to account for unknown subtype. Prognosis was compared for women diagnosed before 1995 and in 1995 or later, estimating cumulative risk of death and HRs. Results: Between 50 and 69 years of age, incidence rates of Luminal A and Luminal B (HER2−) were higher among women born in 1929 or later, compared with before 1929 [IRRs 50–54 years; after imputations: 3.5; 95% confidence interval (CI), 1.8–6.9 and 2.5; 95% CI, 1.2–5.2, respectively], with no clear differences for other subtypes. Rates of death were lower in women diagnosed in 1995 or later, compared to before 1995, for Luminal A (HR 0.4; 95% CI, 0.3–0.5), Luminal B (HER2−; HR 0.5; 95% CI, 0.3–0.7), and Basal phenotype (HR 0.4; 95% CI, 0.2–0.9). Conclusions: We found a strong secular incidence increase restricted to Luminal A and Luminal B (HER2−) subtypes, combined with a markedly improved prognosis for these subtypes and for the Basal phenotype.acceptedVersio

Time trends in placenta-mediated pregnancy complications after assisted reproductive technology in the Nordic countries

Background The use of assisted reproductive technology (ART) is increasing worldwide and conception after assisted reproduction currently comprises 3-6% of birth cohorts in the Nordic countries. The risk of placenta-mediated pregnancy complications is higher after ART compared to spontaneously conceived pregnancies. Whether the excess risk of placenta-mediated pregnancy complications in pregnancies following assisted reproduction has changed over time, is unknown. Objectives To investigate whether time trends in risk of pregnancy complications (hypertensive disorders in pregnancy, placental abruption and placenta previa) differ for pregnancies after ART compared to spontaneously conceived pregnancies during three decades of assisted reproduction treatment in the Nordic countries. Study Design In a population-based cohort study, with data from national health registries in Denmark (1994-2014), Finland (1990-2014), Norway (1988-2015) and Sweden (1988-2015), we included 6,830,578 pregnancies resulting in delivery. Among these, 146,998 (2.2%) were pregnancies after assisted reproduction (125,708 singleton pregnancies, 20,668 twin pregnancies and 622 of higher order plurality) and 6,683,132 (97.8%) pregnancies were conceived spontaneously (6,595,185 singleton pregnancies, 87,106 twin pregnancies and 1,289 of higher order plurality). We used logistic regression with post-estimation to estimate absolute risks and risk differences for each complication. We repeated analyses for singleton and twin pregnancies, separately. In sub-samples with available information, we also adjusted for maternal body mass index, smoking during pregnancy, previous cesarean section, culture duration and cryopreservation. Results The risk of each placental complication was consistently higher in pregnancies following ART compared to spontaneously conceived pregnancies across the study period, except for hypertensive disorders in twin pregnancies, where risks were similar. Risk of hypertensive disorders increased over time in twin pregnancies for both conception methods, but more strongly for pregnancies following ART (risk difference 1.73 percentage points per 5 years, 95% confidence interval 1.35 to 2.11) than for spontaneously conceived twins (risk difference 0.75 percentage points, 95% confidence interval 0.61 to 0.89). No clear time trends were found for hypertensive disorders in singleton pregnancies. Risk of placental abruption decreased over time in all groups (risk difference -0.16 percentage points, 95% confidence interval -0.19 to -0.12 and -0.06 percentage points, 95% confidence interval -0.06 to -0.05 for pregnancies after assisted reproduction and spontaneously conceived pregnancies, respectively, for singletons and multiple pregnancies combined). Over time, the risk of placenta previa increased in pregnancies after assisted reproduction among both singletons (risk difference 0.21 percentage points, 95% confidence interval 0.14 to 0.27) and twins (risk difference 0.30 percentage points, 95% confidence interval 0.16 to 0.43), but remained stable in spontaneously conceived pregnancies. When adjusting for culture duration, the temporal increase in placenta previa became weaker in all groups of ART pregnancies, whereas adjustment for cryopreservation moderately attenuated trends in ART twin pregnancies. Conclusions The risk of placenta-mediated pregnancy complications following ART remains higher compared to spontaneously conceived pregnancies, despite declining rates of multiple pregnancies. For hypertensive disorders in pregnancy and placental abruption, pregnancies after assisted reproduction follow the same time trends as the background population, whereas for placenta previa, risk has increased over time in pregnancies after ART.Peer reviewe

Trends over time in congenital malformations in live-born children conceived after assisted reproductive technology

IntroductionChildren born after assisted reproductive technology, particularly singletons, have been shown to have an increased risk of congenital malformations compared with children born after spontaneous conception. We wished to study whether there has been a change in the past 20 years in the risk of major congenital malformations in children conceived after assisted reproductive technology compared with children spontaneously conceived. Material and methodsPopulation-based cohort study including 90 201 assisted reproductive technology children and 482 552 children spontaneously conceived, born in Denmark, Finland, Norway and Sweden. Both singletons and twins born after in vitro fertilization, intracytoplasmatic sperm injection and frozen embryo transfer were included. Data on children were taken from when the national Nordic assisted reproductive technology registries were established until 2007. Multiple logistic regression analyses were used to estimate the risks and adjusted odds ratios for congenital malformations in four time periods: 1988-1992, 1993-1997, 1998-2002 and 2003-2007. Only major malformations were included. ResultsThe absolute risk for singletons of being born with a major malformation was 3.4% among assisted reproductive technology children vs. 2.9% among children spontaneously conceived during the study period. The relative risk of being born with a major congenital malformation between all assisted reproductive technology children and children spontaneously conceived remained similar through all four time periods (p = 0.39). However, we found that over time the number of children diagnosed with a major malformation increased in both groups across all four time periods. ConclusionWhen comparing children conceived after assisted reproductive technology and spontaneously conceived, the relative risk of being born with a major congenital malformation did not change during the study period.Peer reviewe

Resting Heart Rate as Predictor for Left Ventricular Dysfunction and Heart Failure MESA (Multi-Ethnic Study of Atherosclerosis)

ObjectivesThe objective of this study was to investigate the relationship between baseline resting heart rate and incidence of heart failure (HF) and global and regional left ventricular (LV) dysfunction.BackgroundThe association of resting heart rate to HF and LV function has not been well described in an asymptomatic multi-ethnic population.MethodsResting heart rate was measured in participants in the MESA (Multi-Ethnic Study of Atherosclerosis) trial at inclusion. Incident HF was registered (n = 176) during follow-up (median 7 years) in those who underwent cardiac magnetic resonance imaging (n = 5,000). Changes in ejection fraction (ΔEF) and peak circumferential strain (Δεcc) were measured as markers of developing global and regional LV dysfunction in 1,056 participants imaged at baseline and 5 years later. Time to HF (Cox model) and Δεcc and ΔEF (multiple linear regression models) were adjusted for demographics, traditional cardiovascular risk factors, calcium score, LV end-diastolic volume, and mass in addition to resting heart rate.ResultsCox analysis demonstrated that for 1 beat/min increase in resting heart rate, there was a 4% greater adjusted relative risk for incident HF (hazard ratio: 1.04; 95% CI: 1.02 to 1.06; p < 0.001). Adjusted multiple regression models demonstrated that resting heart rate was positively associated with deteriorating εcc and decrease in EF, even when all coronary heart disease events were excluded from the model.ConclusionsElevated resting heart rate was associated with increased risk for incident HF in asymptomatic participants in the MESA trial. Higher heart rate was related to development of regional and global LV dysfunction independent of subclinical atherosclerosis and coronary heart disease. (Multi-Ethnic Study of Atherosclerosis [MESA]; NCT00005487