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.     

Video-assisted thoracoscopic surgery for thoracic empyema in patients on maintenance hemodialysis

Thoracic empyema in uremic patients on maintenance hemodialysis is a challenging situation. The clinical characteristics are rarely reported, and the surgical outcomes remain unclear. We report our experience with video-assisted thoracoscopic surgery in these patients during 10-year period of time. Between 2005 and 2015, we retrospectively reviewed the clinical characteristics, bacteriological studies, and thoracoscopic surgical results of 23 empyema patients undergoing maintenance hemodialysis. The mean patient age was 67.1 ± 12.9 years. All patients had additional preexisting systemic diseases. The mean duration of hemodialysis was 34.7 ± 25.8 months. The infections causing empyema were pneumonia in 11 (47.8%), blood stream infection in 8 (34.8%), and uremic pleuritis in 4 (17.4%). Among the 22 identified microorganisms, the most common pathogen was methicillin-resistant Staphylococcus aureus (31.8%). After thoracoscopic surgery, 8 patients (34.8%) required additional procedures for complications, including 2 patients who required repeated thoracoscopy for hemothorax and 6 (26.1%) patients who required open drainage for residual empyema. The mean hospital stay was 62.4 days, and 6 patients (26.1%) died in the hospital. Univariate and multivariate analyses revealed that maintenance hemodialysis longer than 5 years was a significant factor associated with in-hospital mortality (odds ratio: 14.8, 95% confidence interval 1.5–151.6; p < 0.0001). While surgical management of thoracic empyema in uremic patients undergoing maintenance hemodialysis is associated with high rates of complication and mortality, thoracoscopic surgery is feasible, especially for patients undergoing hemodialysis for less than 5 years.     

An analysis of gender differences in treatment and outcome of periampullary tumours in Sweden – A national cohort study

BackgroundLittle is known of possible gender differences in treatment of periampullary tumours and outcome after pancreatoduodenectomy (PD), and the aim of this study was therefore to investigate any variances from national multicentre perspective.MethodsData from the Swedish National Registry for Pancreatic and Periampullary Cancer for all patients diagnosed with a periampullary tumour from 2012 throughout 2017 was collected. The material was analysed in two groups, men and women, for palliative treatment and curative intended resection.ResultsA total of 5677 patients were included, 2906 (51%) men and 2771 (49%) women. Women were older than men, 72 (65–78) years vs. 70 (64–76), p < 0.001. A lesser proportion of women were planned for resection (1131 (41%) vs. 1288 (44%), p = 0.008), but after adjusting for age and tumour location no difference was seen. Postoperative morbidity was equal, but women had significantly better long-term survival than men. The survival was equal for palliative men and women.ConclusionNo gender bias could be established when analysing treatment for periampullary tumours in Sweden, even though less women were offered surgery. Data suggest that even though women were older they tolerate surgery well and hence offering PD at a higher age for women could be suggested.     

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.     

Intravenous Thrombolysis Is Safe and Effective for the Cryptogenic Stroke in China: Data From the Thrombolysis Implementation and Monitor of Acute Ischemic Stroke in China (TIMS-China)

Background

The intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (rt-PA) therapy is safe and efficient during the treatment of acute ischemic stroke. Nonetheless, the different outcomes among various stroke subgroups have limited data with regard to the safety and efficacy of cryptogenic stroke (CS). The present study compared the safety and efficacy when IVT with rt-PA was used for the treatment of CS and the other stroke subtypes.