Effects of tamoxifen on normal breast tissue histological composition: Results from a randomised six-arm placebo-controlled trial in healthy women

Tamoxifen prevents recurrence of breast cancer and is suggested for preventive risk-reducing therapy. Tamoxifen reduces mammographic density, a proxy for therapy response, but little is known about its effects in remodelling normal breast tissue. Our study, a substudy within the double-blinded dose-determination trial KARISMA, investigated tamoxifen-specific changes in breast tissue composition and histological markers in healthy women. We included 83 healthy women randomised to 6 months daily intake of 20, 10, 5, 2.5, 1 mg of tamoxifen or placebo. The groups were combined to “no dose” (0-1 mg), “low-dose” (2.5-5 mg) or “high-dose” (10-20 mg) of tamoxifen. Ultrasound-guided biopsies were collected before and after tamoxifen exposure. In each biopsy, epithelial, stromal and adipose tissues was quantified, and expression of epithelial and stromal Ki67, oestrogen receptor (ER) and progesterone receptor (PR) analysed. Mammographic density using STRATUS was measured at baseline and end-of-tamoxifen-exposure. We found that different doses of tamoxifen reduced mammographic density and glandular-epithelial area in premenopausal women and associated with reduced epithelium and increased adipose tissue. High-dose tamoxifen also decreased epithelial ER and PR expressions in premenopausal women. Premenopausal women with the greatest reduction in proliferation also had the greatest epithelial reduction. In postmenopausal women, high-dose tamoxifen decreased the epithelial area with no measurable density decrease. Tamoxifen at both low and high doses influences breast tissue composition and expression of histological markers in the normal breast. Our findings connect epithelial proliferation with tissue remodelling in premenopausal women and provide novel insights to understanding biological mechanisms of primary prevention with tamoxifen.     

Real-World Effectiveness of Anti-Resorptive Treatment in Patients With Incident Fragility Fractures—The STORM Cohort—A Swedish Retrospective Observational Study

Results from real-world evidence (RWE) from the largest healthcare region in Sweden show low uptake of antiresorptive (AR) treatment, but beneficial effect in those receiving treatment, especially for the composite outcome of hip fracture or death. For RWE studies, Sweden is unique, with virtually complete coverage of electronic medical records (EMRs) and both regional and national registries, in a universal publicly funded healthcare system. To our knowledge, there is no previous RWE study evaluating the efficacy of AR treatment compared to no AR treatment after fragility fracture, including data on parenteral treatments administered in hospital settings. The Stockholm Real World Management (STORM) study cohort was established in the healthcare region of Stockholm to retrospectively assess the effectiveness of AR treatment after first fragility fracture using the regional EMR system for both hospital and primary care. Between 2012 and 2018, we identified 69,577 fragility fracture episodes among 59,078 patients, men and women, 50 years and older. Of those, 21,141 patients met inclusion and exclusion criteria (eligible cohort). From these, the final matched study cohort comprised 9840 fragility fractures (cases receiving AR treatment [n = 1640] and controls not receiving AR treatment [n = 8200]). Propensity scores were estimated using logistic regression models with AR treatment as outcome and confounders as independent variables followed by analysis using Cox proportional hazard models. Real world evidence from Sweden's largest healthcare region, comprising a quarter of the Swedish population, show that only 10% of patients receive AR treatment within 1 year after a fragility fracture. Factors associated with not receiving treatment include having a diagnosis of cardiovascular disease. In those treated, AR have positive effects particularly on the composite of fracture and death (any fracture/death and hip fracture/death) in individuals matched for all major confounders. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Five-year change scores in old age for six neuropsychological tests and normative data for the Useful Field of View (UFOV) test: The influence of physical health

Introduction: Neuropsychological assessment of cognitive change over time is often conducted in clinical settings, but whether neuropsychological change scores are influenced by physical health has, as far as we know, not been examined previously.

Method: In a sample of 153 older Swedish adults (age range, 72–86 years), we evaluated the influence of common age-related diseases, terminal decline pathology, age, education, and gender, to provide (a) preliminary test-specific regression weights and 90% confidence intervals to assess significant change in performance after five years on tests of visual scanning, mental shifting, visual spatial ability, memory, reaction time, and selective attention, and (b) normative data for the Useful Field of View test (UFOV) from a single testing occasion.

Results: Multiple regression analyses showed that test–retest changes were affected by physical health for mental shifting, visual spatial ability, memory, and reaction time, by age for mental shifting and visual reaction time, by education for visual spatial ability, and by Age × Education for auditory reaction time. Gender did not affect any of the change scores. The overall average of variance explained was 2.5%: up to 8.1% for physical health, 4.4% for age, and 3.6% for education. The UFOV scores were mostly influenced by age, but also by physical health and education.

Conclusions: The findings indicate that considering the influence of health on normative change scores in old age in addition to demographic factors leads to more accurate predictions of whether true change has occurred.     

Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models

Microglia, the innate immune cells of the CNS, perform critical inflammatory and noninflammatory functions that maintain normal neural function. For example, microglia clear misfolded proteins, elaborate trophic factors, and regulate and terminate toxic inflammation. In Alzheimer’s disease (AD), however, beneficial microglial functions become impaired, accelerating synaptic and neuronal loss. Better understanding of the molecular mechanisms that contribute to microglial dysfunction is an important objective for identifying potential strategies to delay progression to AD. The inflammatory cyclooxygenase/prostaglandin E2 (COX/PGE₂) pathway has been implicated in preclinical AD development, both in human epidemiology studies and in transgenic rodent models of AD. Here, we evaluated murine models that recapitulate microglial responses to Aβ peptides and determined that microglia-specific deletion of the gene encoding the PGE₂ receptor EP2 restores microglial chemotaxis and Aβ clearance, suppresses toxic inflammation, increases cytoprotective insulin-like growth factor 1 (IGF1) signaling, and prevents synaptic injury and memory deficits. Our findings indicate that EP2 signaling suppresses beneficial microglia functions that falter during AD development and suggest that inhibition of the COX/PGE₂/EP2 immune pathway has potential as a strategy to restore healthy microglial function and prevent progression to AD.     

Apomorphine formulation may influence subcutaneous complications from continuous subcutaneous apomorphine infusion in Parkinson’s disease

Journal of Neurology - Continuous subcutaneous (s.c.) apomorphine infusion is an effective therapy for Parkinson’s disease (PD), but a limitation is the formation of troublesome s.c. nodules....