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.     

Impact of modified-release opioid use on clinical outcomes following total hip and knee arthroplasty: a propensity score-matched cohort study

Modified-release opioids are often prescribed for the management of moderate to severe acute pain following total hip and knee arthroplasty, despite recommendations against their use due to increasing concerns regarding harm. The primary objective of this multicentre study was to examine the impact of modified-release opioid use on the incidence of opioid-related adverse events compared with immediate-release opioid use, among adult inpatients following total hip or knee arthroplasty. Data for total hip and knee arthroplasty inpatients receiving an opioid analgesic for postoperative analgesia during hospitalisation were collected from electronic medical records of three tertiary metropolitan hospitals in Australia. The primary outcome was the incidence of opioid-related adverse events during hospital admission. Patients who received modified with or without immediate-release opioids were matched to those receiving immediate-release opioids only (1:1) using nearest neighbour propensity score matching with patient and clinical characteristics as covariates. This included total opioid dose received. In the matched cohorts, patients given modified-release opioids (n = 347) experienced a higher incidence of opioid-related adverse events overall, compared with those given immediate-release opioids only (20.5%, 71/347 vs. 12.7%, 44/347; difference in proportions 7.8% [95%CI 2.3–13.3%]). Modified-release opioid use was associated with an increased risk of harm when used for acute pain during hospitalisation after total hip or knee arthroplasty.     

Oral cancer prediction by noninvasive genetic screening

Oral squamous cell carcinomas (OSCCs) develop in genetically altered epithelium in the mucosal lining, also coined as fields, which are mostly not visible but occasionally present as white oral leukoplakia (OL) lesions. We developed a noninvasive genetic assay using next-generation sequencing (NGS) on brushed cells to detect the presence of genetically altered fields, including those that are not macroscopically visible. The assay demonstrated high accuracy in OL patients when brush samples were compared with biopsies as gold standard. In a cohort of Fanconi anemia patients, detection of mutations in prospectively collected oral brushes predicted oral cancer also when visible abnormalities were absent. We further provide insight in the molecular landscape of OL with frequent changes of TP53, FAT1 and NOTCH1. NGS analysis of noninvasively collected samples offers a highly accurate method to detect genetically altered fields in the oral cavity, and predicts development of OSCC in high-risk individuals. Noninvasive genetic screening can be employed to screen high-risk populations for cancer and precancer, map the extension of OL lesions beyond what is visible, map the oral cavity for precancerous changes even when visible abnormalities are absent, test accuracy of promising imaging modalities, monitor interventions and determine genetic progression as well as the natural history of the disease in the human patient.     

L-glutamic acid-g-poly hydroxyethyl methacrylate nanoparticles: acute and sub-acute toxicity and biodistribution potential in mice

The aim of this safety study in mice was to determine in vivo toxicity and biodistribution potential of a single and multiple doses of L-glutamic acid-g-p(HEMA) polymeric nanoparticles as a drug delivery system. The single dose did not cause any lethal effect, and its acute oral LD₅₀ was >2.000 mg/kg body weight (bw). Multiple doses (25, 50, or 100 mg/kg bw) given over 28 days resulted in no significant differences in body and relative organ weights compared to control. These results are supported by biochemical and histological findings. Moreover, nanoparticle exposure did not result in statistically significant differences in micronucleus counts in bone marrow cells compared to control. Nanoparticle distribution was time-dependent, and they reached the organs and even bone marrow by hour 6, as established by ex vivo imaging with the IVIS^® spectrum imaging system. In conclusion, L-glutamic acid-g-p(HEMA) polymeric nanoparticles appear biocompatible and have a potential use as a drug delivery system.KEY WORDS: biocompatibility, blood biochemistry, genotoxicity, histology, in vivo toxicity, micronucleus test, polymers     

Measuring Psychological Inflexibility of Suicidal Thoughts: The Acceptance and Action Questionnaire for Suicidal Ideation (AAQ-SI)

Cognitive Therapy and Research - Despite interest in psychological inflexibility as a marker of suicide risk, no measure of psychological inflexibility specific to SI exists. The present study...     

Comparison study of patient demographics and patient-related risk factors for peri-prosthetic joint infections following primary total shoulder arthroplasty

BackgroundWhile studies have demonstrated favorable outcomes in utilization of primary total shoulder arthroplasty (TSA) for the treatment of glenohumeral osteoarthritis (OA), adverse events such as infections can still occur. Periprosthetic joint infections (PJIs) are associated with worse outcomes and patient morbidity. The purpose of this study was to: (1) compare patient demographics amongst TSA patients with and without PJIs following primary TSA; and (2) identify patient-related risk factors for PJIs following primary TSA.MethodsPatients undergoing primary TSA for the treatment of glenohumeral OA were identified using the Mariner administrative claims database by CPT code 23,472. Laterality modifiers were utilized to ensure PJIs were developing in the correct laterality as those patients undergoing primary TSA. Inclusion for the study group consisted of patients who developed PJIs within 2-years after the index procedure, whereas patients who did not develop PJIs served as the comparison cohort. Primary outcomes analyzed included patient demographics and patient-related risk factors for PJIs following primary TSA. A stepwise backwards elimination multivariate binomial logistic regression analyses was performed to determine the odds (OR) of PJIs in patients undergoing primary TSA. A P value less than .05 was considered statistically significant.ResultsThe query yielded 15,396 patients who underwent primary TSA for glenohumeral OA, of which 191 patients developed PJIs and 15,205 did not develop PJIs. The study found statistically significant differences amongst patients who did and did not develop PJIs following primary TSA with respect to age, sex, and presence of comorbid conditions. Risk factors associated with developing PJIs following primary TSA included: pathologic weight loss (OR: 2.06, P < .0001), obesity (OR: 1.56, P = .0001), male sex (OR: 1.52, P = .007), and peripheral vascular disease (OR: 1.46, P = .022).ConclusionAs the number of primary TSAs for the treatment of glenohumeral OA increase worldwide, identifying modifiable risk-factors to reduce the incidence of infection is critical. The study found various modifiable and non-modifiable risk factors associated with developing PJIs following primary TSA. This study is valuable to orthopedists in order to identify and risk-stratify patients with regard to PJI in the setting of primary TSA for OA.Level of EvidenceLevel III; Case-Control Study