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.     

Efficacy,effectiveness and side effects of medications used to prevent fractures

There is an increasing number of effective therapies for fracture prevention in adults at risk of osteoporosis. However, shortcomings in the evidence underpinning our management of osteoporosis still exist. Evidence of antifracture efficacy in the groups of patients who most commonly use calcium and vitamin D supplements is lacking, the safety of calcium supplements is in doubt, and the safety and efficacy of high doses of vitamin D give cause for concern. Alendronate, risedronate, zoledronate and denosumab have been shown to prevent spine, nonspine and hip fractures; in addition, teriparatide and strontium ranelate prevent both spine and nonspine fractures, and raloxifene and ibandronate prevent spine fractures. However, most trials provide little information regarding long‐term efficacy or safety. A particular concern at present is the possibility that oral bisphosphonates might cause atypical femoral fractures. Observational data suggest that the incidence of this type of fracture increases steeply with duration of bisphosphonate use, resulting in concern that the benefit–risk balance may become negative in the long term, particularly in patients in whom the osteoporotic fracture risk is not high. Therefore, reappraisal of ongoing use of bisphosphonates after about 5 years is endorsed by expert consensus, and ‘drug holidays’ should be considered at this time. Further studies are needed to guide clinical practice in this area.     

Electronic health records and support for primary care teamwork

Objective Consensus that enhanced teamwork is necessary for efficient and effective primary care delivery is growing. We sought to identify how electronic health records (EHRs) facilitate and pose challenges to primary care teams as well as how practices are overcoming these challenges.Methods Practices in this qualitative study were selected from those recognized as patient-centered medical homes via the National Committee for Quality Assurance 2011 tool, which included a section on practice teamwork. We interviewed 63 respondents, ranging from physicians to front-desk staff, from 27 primary care practices ranging in size, type, geography, and population size.Results EHRs were found to facilitate communication and task delegation in primary care teams through instant messaging, task management software, and the ability to create evidence-based templates for symptom-specific data collection from patients by medical assistants and nurses (which can offload work from physicians). Areas where respondents felt that electronic medical record EHR functionalities were weakest and posed challenges to teamwork included the lack of integrated care manager software and care plans in EHRs, poor practice registry functionality and interoperability, and inadequate ease of tracking patient data in the EHR over time.Discussion Practices developed solutions for some of the challenges they faced when attempting to use EHRs to support teamwork but wanted more permanent vendor and policy solutions for other challenges.Conclusions EHR vendors in the United States need to work alongside practicing primary care teams to create more clinically useful EHRs that support dynamic care plans, integrated care management software, more functional and interoperable practice registries, and greater ease of data tracking over time.     

How does measurement of platelet P-selectin compare with other methods of measuring platelet function as a means of determining the effectiveness of antiplatelet therapy?

Measurement of P-selectin on activated platelets as a means of measuring platelet function utilizing the technology described here has the advantage of not requiring immediate access to specialist equipment and expertise. Blood samples are activated, fixed, stored, and transported to a central laboratory for flow cytometric analysis. Here we have compared P-selectin with other more traditional approaches to measuring platelet function in blood and/or platelet-rich plasma (PRP) from patients with acute coronary syndromes on treatment for at least 1 month with either aspirin and clopidogrel or aspirin with prasugrel. The comparators were light transmission aggregometry (LTA), VerifyNow and Multiplate aggregometry (for determining the effects of aspirin) and LTA, VerifyNow and Multiplate together with the BioCytex VASP phosphorylation assay (for the P2Y₁₂ antagonists). The P-selectin Aspirin Test revealed substantial inhibition of platelet function in all but three of 96 patients receiving aspirin with clopidogrel and in none of 51 patients receiving aspirin and prasugrel. The results were very similar to those obtained using LTA. There was only one patient with high residual platelet aggregation and low P-selectin expression. The same patients identified as “non-responders” to aspirin also presented with the highest residual platelet activity as measured using the VerifyNow system, although not quite as well separated from the other values. With the Multiplate test only one of these patients clearly stood out from the others. The results obtained using the P-selectin P2Y₁₂ Test in 102 patients taking aspirin and clopidogrel were similar to the more traditional approaches in that a wide scatter of results was obtained. Generally, high values seen with the P-selectin P2Y₁₂ Test were also high with the LTA, VerifyNow, Multiplate, and BioCytex VASP P2Y₁₂ Tests. Similarly, low residual platelet function using the P2Y₁₂ test was seen irrespective of the testing procedure used. However, there were differences in some patients. Prasugrel was always more effective than clopidogrel in inhibiting platelet function with none of 56 patients (P-selectin and VerifyNow), only 2 of 56 patients (Multiplate) and only 3 of 56 patients (Biocytex VASP) demonstrating high on-treatment residual platelet reactivity (HRPR) defined using previously published cut-off values. The exception was LTA where there were 11 of 56 patients with HRPR. It remains to be seen which experimental approach provides the most useful information regarding outcomes after adjusting therapies in treated patients.