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.     

Is routine extubation overnight safe in cardiac surgery patients?

Objectives

Expedient extubation after cardiac surgery has been associated with improved outcomes, leading to postoperative extubation frequently during overnight hours. However, recent evidence in a mixed medical-surgical intensive care unit population demonstrated worse outcomes with overnight extubation. This study investigated the impact of overnight extubation in a statewide, multicenter Society of Thoracic Surgeons database.

Two cases of Klebsiella pneumoniae liver abscess necessitating liver resection for effective treatment

We report two British cases of liver abscess, due to Klebsiella pneumoniae and associated with synchronous infection elsewhere, which required liver resection for definitive treatment. They illustrate the geographic spread of aggressive K pneumoniae liver infection and demonstrate the importance of early aggressive treatment.     

Hepatic effects of repeated oral administration of diclofenac to hepatic cytochrome P450 reductase null (HRN™) and wild-type mice

Hepatic NADPH-cytochrome P450 oxidoreductase null (HRN?) mice exhibit normal hepatic and extrahepatic biotransformation enzyme activities when compared to wild-type (WT) mice, but express no functional hepatic cytochrome P450 activities. When incubated in vitro with [¹⁴C]-diclofenac, liver microsomes from WT mice exhibited extensive biotransformation to oxidative and glucuronide metabolites and covalent binding to proteins was also observed. In contrast, whereas glucuronide conjugates and a quinone-imine metabolite were formed when [¹⁴C]-diclofenac was incubated with HRN? mouse liver, only small quantities of P450-derived oxidative metabolites were produced in these samples and covalent binding to proteins was not observed. Livers from vehicle-treated HRN? mice exhibited enhanced lipid accumulation, bile duct proliferation, hepatocellular degeneration and necrosis and inflammatory cell infiltration, which were not present in livers from WT mice. Elevated liver-derived alanine aminotransferase, glutamate dehydrogenase and alkaline phosphatase activities were also observed in plasma from HRN? mice. When treated orally with diclofenac for 7 days, at 30 mg/kg/day, the severities of the abnormal liver histopathology and plasma liver enzyme findings in HRN? mice were reduced markedly. Oral diclofenac administration did not alter the liver histopathology or elevate plasma enzyme activities of WT mice. These findings indicate that HRN? mice are valuable for exploration of the role played by hepatic P450s in drug biotransformation, but poorly suited to investigations of drug-induced liver toxicity. Nevertheless, studies in HRN? mice could provide novel insights into the role played by inflammation in liver injury and may aid the evaluation of new strategies for its treatment.