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.     

Renal Neoplasia in Tuberous Sclerosis: A Study of 41 Patients

ObjectiveTo study the clinical features and identify unique renal neoplasia subtypes and their prognostic implications in individuals with tuberous sclerosis complex (TSC).Patients and MethodsThe Mayo Clinic nephrectomy registry included 37 patients with TSC diagnosed between 1970 and 2018. Four additional patients were identified from the pathology consultation and autopsy files. All available renal tumors were further characterized using immunohistochemistry and fluorescence in situ hybridization. Clinicopathologic features and follow-up were obtained from the medical record. The American Association for Cancer Research Project GENIE registry was accessed using cBioPortal for molecular profiling of angiomyolipoma (AML).ResultsA total of 276 renal tumors from 41 patients were analyzed. Renal tumors were classified into 9 distinct morphological subtypes, with AML predominating (238 [86%]). Interestingly, all these tumors acted in a benign fashion except one renal cell carcinoma with clear cells and fibromyomatous stroma and one epithelioid AML that metastasized. Molecular profiling studies revealed that epithelioid AMLs were enriched for alterations of TP53, RB1, and ATRX. Eight patients died of direct complications of TSC, including 3 of end-stage renal disease. To date, none have died of a renal epithelial neoplasm.ConclusionThe identification of unique renal neoplasia subtypes may provide important clues to establish a diagnosis of TSC, and in the somatic setting, this finding has important implications for accurate prognostication. These tumors tend to be indolent, and only 2 of 276 tumors in our study exhibited metastatic behavior. Our results support multidisciplinary management with a focus on preservation of renal function.     

Association Between Abnormal Fetal Head Growth and Autism Spectrum Disorder

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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.     

Validation of a test meal paradigm to experimentally manipulate meal-related fears: A registered report

Fear is central to conceptualizations of weight and shape-focused eating disorders. The current study will examine the reliability and validity of a test meal paradigm that varies perceptions of fat content to manipulate fear. Undergraduate women with elevated eating pathology (N = 96) will be randomized to one of three test meal conditions: two “low” fat yogurts, two “high” fat yogurts, or one “high” fat and one “low” fat yogurt. In actuality, all yogurts will have the same fat content. Supporting reliability, we hypothesize that self-reported fear and electrodermal activity (psychophysiological index of fear-related arousal) will exhibit good test–retest reliability over a 48-hr period in the “high” fat/“high” fat and “low” fat/“low” fat conditions. Supporting construct validity, self-reported fear and electrodermal activity will be elevated during the “high” versus “low” fat condition and responses to the “high" fat condition will correlate with fear of food, eating, and weight gain. Supporting discriminant validity, self-reported disgust and anger will be comparable in the “high” and “low” fat conditions and will exhibit weak correlations with trait measures of disgust and anger. This experimental paradigm will allow researchers to manipulate fear in order understand the mechanisms by which fear maintains eating pathology.     

High-flow via a tracheostomy tube and speaking valve during weaning from mechanical ventilation and tracheostomy

Background

Weaning from mechanical ventilation and tracheostomy after prolonged intensive care consume enormous resources with optimal management not currently well described. Restoration of respiratory flow via the upper airway is essential and early cuff-deflation using a one-way valve (OWV) is recommended. However, extended OWV use may cause dry airways and thickened secretions which challenge the weaning process. High-flow therapy via the tracheostomy tube (HFT-T) humidifies inspired air and may be connected via an in-line OWV (HFT-T-OWV) alleviating these problems. We aim to provide clinical and experimental data on the safety of HFT-T-OWV along with a practical guide to facilitate clinical use during weaning from mechanical ventilation and tracheostomy.

Methods

Data on adverse events of HFT-T-OWV were retrieved from a quality register for patients treated at an intensive care rehabilitation center between 2019 and 2022. Benchtop experiments were performed to measure maximum pressures and pressure support generated by HFT-T-OWV at 25–60 L/min flow using two different HFT-T adapters (interfaces). In simulated airway obstruction using a standard OWV (not in-line) maximum pressures were measured with oxygen delivered via the side port at 1–3 L/min.

Results

Of 128 tracheostomized patients who underwent weaning attempts, 124 were treated with HFT-T-OWV. The therapy was well tolerated, and no adverse events related to the practice were detected. The main reason for not using HFT-T-OWV was partial upper airway obstruction using a OWV. Benchtop experiments demonstrated HFT-T-OWV maximum pressures <4 cmH₂O and pressure support 0–0.6 cmH₂O. In contrast, 1–3 L/min supplemental oxygen via a standard OWV caused pressures between 84 and 148 cmH₂O during simulated airway obstruction.

Conclusions

Current study clinical data and benchtop experiments indicate that HFT-T-OWV was well tolerated and appeared safe. Pressure support was low, but humidification may enable extended use of a OWV without dry airway mucosa and thickened secretions. Results suggest the treatment could offer advantages to standard OWV use, with or without supplementary oxygen, as well as to HFT-T without a OWV, for weaning from mechanical ventilation and tracheostomy. However, for definitive treatment recommendations, randomized clinical trials are needed.     

Collaborating toward equity in Pennsylvania: The Age-Friendly Care,PA project

Objective

To collaboratively implement the age-friendly health systems framework, known as the 4Ms: What Matters, Medication, Mentation, and Mobility, at The Primary Health Network (PHN), a federally qualified health center.

Data Sources

Data were collected from PHN electronic medical records (EMRs) for individuals over age 65 from December 30, 2019 to December 24, 2021 and from Project ECHO© attendance and evaluation surveys.

Study Design

The telementoring educational program, Project ECHO©, was used to engage PHN health care professionals working in rural areas of Pennsylvania to incorporate the 4Ms into their practice starting with the annual wellness visit (AWV). Project ECHO© was launched at three primary care sites. After 18 months, it was then disseminated to an additional 18 sites creating pilot and comparison groups. Outcomes included codesigned patient process metrics using EMR data and project ECHO© participant data.

Data Collection Methods

EMR data were generated by system reports created by PHN's quality assurance program manager. Project ECHO© data were collected and managed using REDCap electronic data capture tools. Outcomes were aggregated, analyzed for trends over time, and compared between groups.

Principal Findings

All nine process outcomes increased from baseline to follow-up at the three initial sites, ranging from 4% to 43% g. At year two, the three initial sites had higher rates on AWVs (pilot 24%, comparison 12%; p < 0.0001), Advance Care Planning (New on file, pilot 8%, comparison 2%; Discussed with patient, pilot 18%, comparison 13%; Patient declined, pilot 0%, comparison 0%; p = 0.0001), Dementia Screening (pilot 24%, comparison 12%; p < 0.0001), Fall Risk Management (pilot 43%, comparison 10%; p < 0.0001), and Mobility Goal (pilot 19%, comparison 9%; p < 0.0001); and lower rates on High-Risk Medication Elimination (pilot 54%, comparison, 63%, p < 0.02).

Conclusions

Access to high-quality geriatric care for rural older adults can be improved by increasing health care professionals' knowledge of the 4Ms, beginning with its incorporation into the AWV.