Co-designed weight management intervention for women recovering from oestrogen-receptor positive breast cancer.

BACKGROUND: Weight gain is commonly observed during and after breast cancer treatment and is associated with poorer survival outcomes, particularly in women with oestrogen receptor-positive (ER +) disease. The aim of this study was to co-design (with patients) a programme of tailored, personalised support (intervention), including high-quality support materials, to help female breast cancer patients (BCPs) with ER + disease to develop the skills and confidence needed for sustainable weight loss.  METHODS: ER + BCPs were recruited from two UK National Health Service (NHS) Trusts. The selection criteria included (i) recent experience of breast cancer treatment (within 36 months of completing primary treatment); (ii) participation in a recent focus group study investigating weight management perceptions and experiences; (iii) willingness to share experiences and contribute to discussions on the support structures needed for sustainable dietary and physical activity behaviour change. Co-design workshops included presentations and interactive activities and were facilitated by an experienced co-design researcher (HH), assisted by other members of the research team (KP, SW and JS). RESULTS: Two groups of BCPs from the North of England (N = 4) and South Yorkshire (N = 5) participated in a two-stage co-design process. The stage 1 and stage 2 co-design workshops were held two weeks apart and took place between Jan-March 2019, with each workshop being approximately 2 h in duration. Guided by the Behaviour Change Wheel, a theoretically-informed weight management intervention was developed on the basis of co-designed strategies to overcome physical and emotional barriers to dietary and physical activity behaviour change. BCPs were instrumental in designing all key features of the intervention, in terms of Capability (e.g., evidence-based information, peer-support and shared experiences), Opportunity (e.g., flexible approach to weight management based on core principles) and Motivation (e.g., appropriate use of goal-setting and high-quality resources, including motivational factsheets) for behaviour change. CONCLUSION: This co-design approach enabled the development of a theoretically-informed intervention with a content, structure and delivery model that has the potential to address the weight management challenges faced by BCPs diagnosed with ER + disease. Future research is required to evaluate the effectiveness of the intervention for eliciting clinically-important and sustainable weight loss in this population.

The introduction of radioactive seed localisation improves the oncological outcome of image guided breast conservation surgery.

INTRODUCTION: Radioactive seed localisation (RSL) has become increasingly popular for localisation of non-palpable breast tumours. This is largely due to advantages it offers in terms of practicality and convenience when compared to guide wire localisation (WL). This institute switched from using WL to RSL in September 2014. The primary aim was to assess whether this change improved the accuracy of excision with regards to inadequate margin rates and weight of excision specimens. The secondary aim was to establish whether there is a "learning curve" associated with RSL technique. METHODS: Retrospective data collection was performed for 333 consecutive cases of unifocal non-palpable invasive breast cancers undergoing excision with WL or RSL. An inadequate margin was defined as tumour <1 mm from an inked radial margin. Patient demographics, tumour characteristics and clinical outcomes were compared between WL and RSL cases. RESULTS: 100 WL and 233 RSL cases were included. Patient demographics and tumour characteristics were similar for both groups. Inadequate margin rates were 18% with WL and 8.6% with RSL (p = 0.013). Median specimen weights were 33.3 g with WL and 28.7 g with RSL (p = 0.014). Subdividing the RSL group into the first 100 cases performed (RSL1) and the subsequent 133 cases (RSL2), inadequate margin rates were 13.0% and 5.3% respectively (p = 0.037). Mean specimen weights were similar. CONCLUSION: Switching from WL to RSL results in a significant reduction in both inadequate margin rates and specimen weights. A procedure-specific learning curve is present on first implementation of RSL and following this, inadequate margin rates are further reduced.

A systematic review of generic and breast cancer specific life expectancy models in the elderly.

INTRODUCTION: The use of primary endocrine therapy (PET) in managing breast cancer in the elderly has become common practice. Whilst there appears to be no difference in overall survival in comparison with surgery, PET has been found to be inferior in local disease control with a limited duration of efficacy (2-3 years). The International Society of Geriatric Oncology (SIOG) state that PET may be considered in patients with a short life expectancy (<2 years) or considered unfit for surgery. Frequently, decision making for PET allocation is a subjective process by the clinician. METHOD: A systematic literature review was performed to establish what prediction models are available for all-cause mortality in the elderly, and what breast-specific models have been produced. RESULTS: 18 prognostic models were deemed eligible from 15 papers. 1 breast-specific model was found, 2 nursing home related and 15 for community-dwelling elders. Accuracy (as defined by discrimination; c-statistic or AUROC) ranged from 0.69 (moderate) to 0.86 (very good). CONCLUSIONS: This review highlighted a variety of validated prognostic indexes. Several models with very good accuracy were identified but most were validated in US-populations and relied on information from administrative datasets. One breast specific model by Stotter et al. was identified, specifically to aid treatment planning for frail elderly patients but had limited accuracy. The strength of an index will ultimately be on its clinical impact and influence on treatment decisions rather than its accuracy and as of yet no trials exploring this have been carried out.

Neoadjuvant Therapy in Early Breast Cancer: Treatment Considerations and Common Debates in Practice.

Neoadjuvant treatment offers a number of benefits for patients with early breast cancer, and is an important option for consideration by multidisciplinary teams. Despite literature showing its efficacy, the use of neoadjuvant therapy varies widely. Here we discuss the clinical evidence supporting the use of neoadjuvant therapy in early stage breast cancer, including patient selection, monitoring response, surgery and radiotherapy considerations, with the aim of assisting multidisciplinary teams to determine patient suitability for neoadjuvant treatment.

The N-terminal regulatory domain of cyclin A contains redundant ubiquitination targeting sequences and acceptor sites.

Cyclin A is destroyed during mitosis by the ubiquitin-proteasome system. Like cyclin B, a destruction box (D-box) motif is required for the destruction of cyclin A. However, cyclin A degradation is more complicated than cyclin B because cyclin A's D-box motif is more extensive and proteolysis involves complex signaling in some organisms. In this study, we found that in addition to the D-box, the region between residues 123-157 also contributed to the ubiquitination and degradation of human cyclin A. Indeed, removal of the bulk of the N-terminal regulatory domain was needed to completely stabilize cyclin A and eliminate ubiquitination. A putative second RxxL motif around residue 138 played only a minor role in cyclin A degradation. To distinguish between sequences recognized by the ubiquitination machinery and the ubiquitin acceptor sites per se, we utilized a novel approach involving in vitro cleavage of cyclin A after ubiquitination. We found that several lysine residues proximal to the D-box (Lys37, Lys54, and Lys68) were ubiquitin acceptor sites. Cyclin A lacking the three lysine residues was degraded slower than the wild-type protein. Although these lysines were normally used, ubiquitination could shift to other cryptic sites when the preferred sites were unavailable, suggesting the exact positions of the ubiquitin chains also contributed to degradation. Together, these data revealed that ubiquitination does not occur randomly on cyclin A and open up questions on the precise function of the D-box.

Cyclin F is degraded during G2-M by mechanisms fundamentally different from other cyclins.

Cyclin F, a cyclin that can form SCF complexes and bind to cyclin B, oscillates in the cell cycle with a pattern similar to cyclin A and cyclin B. Ectopic expression of cyclin F arrests the cell cycle in G(2)/M. How the level of cyclin F is regulated during the cell cycle is completely obscure. Here we show that, similar to cyclin A, cyclin F is degraded when the spindle assembly checkpoint is activated and accumulates when the DNA damage checkpoint is activated. Cyclin F is a very unstable protein throughout much of the cell cycle. Unlike other cyclins, degradation of cyclin F is independent of ubiquitination and proteasome-mediated pathways. Interestingly, proteolysis of cyclin F is likely to involve metalloproteases. Rapid destruction of cyclin F does not require the N-terminal F-box motif but requires the COOH-terminal PEST sequences. The PEST region alone is sufficient to interfere with the degradation of cyclin F and confer instability when fused to cyclin A. These data show that although cyclin F is degraded at similar time as the mitotic cyclins, the underlying mechanisms are entirely distinct.

Human gamma/delta T-cell lines derived from airway biopsies.

gamma/delta T cells have been postulated to play an important role in the immune response at epithelial boundaries, but have not been well described in human lung tissue. We have identified and characterized gamma/delta T-cell lines from human airway biopsies and compared them with T-cell lines from paired peripheral blood samples. Airway-derived T-cell lines stimulated with tetanus toxoid (TT) contained a greater proportion of gamma/delta T cells compared with T-cell lines stimulated with mitogens, other antigens, or without antigen. TT-stimulated airway T cells expressed different T-cell receptors (TCRs) than did blood- derived T cells, and used predominantly variable region (V)gamma I family genes rather than V gamma II family genes. Airway-derived gamma/delta T cells produced high levels of interferon-gamma and were associated with T helper 1--like cytokine profiles. This study describes the presence and antigen-dependent proliferation of gamma/delta T cells from human airway tissue, and demonstrates differences in lung-derived gamma/delta TCRs compared with gamma/delta T cells derived from peripheral blood. The data suggest that gamma/delta T cells may be functionally enriched in human airways relative to peripheral blood.

Bronchoprovocation testing.

Bronchoprovocation testing has been performed for more than 50 years. Challenge testing with nonselective agents has been used widely for the assessment of airflow limitation in patients, and has been used in the research setting to better characterize the pathophysiology of bronchial responsiveness. Based on this large body of literature, detailed guidelines are now available to allow for standardization of testing methodology. Such standardization is critical to achieve safe, accurate, and reproducible test results that may be interpreted meaningfully. Currently, bronchoprovocation testing with direct-acting stimuli such as methacholine is used most frequently in the clinical arena, but, in recent years, considerable interest has been developing in the use of indirect stimuli. (57) It now is recognized that bronchial hyperresponsiveness to indirect stimuli (e.g., exercise, cold air, and AMP) is highly specific for asthma and may have greater clinical relevance than does responsiveness to direct stimuli. (8) As a result, testing with indirect agents may become employed more widely in the future.

Identification of human lung and skin proteins conjugated with hexamethylene diisocyanate in vitro and in vivo.

Diisocyanates are asthma-causing chemicals used in the commercial production of polyurethane. We have previously shown that human lung epithelial cell proteins can become conjugated with hexamethylene diisocyanate (HDI) and may be biologically important in diisocyanate-induced asthma. The objective of this study was to identify specific human lung and skin proteins that become conjugated with diisocyanate after in vitro and in vivo exposure. Following in vitro exposure of human airway epithelial cells (A549), keratin 18, the 78-kD glucose-regulated protein, trans-1, 2-dihyrobenzene-1,2-diol dehydrogenase, and actin were identified as prominent diisocyanate-conjugated proteins through use of a combination of immunocytochemical and mass spectrometric techniques. Following in vivo inhalation of an HDI aerosol, keratin 18 was also identified as the predominant diisocyanate-conjugated protein in human endobronchial biopsy samples, whereas albumin was the predominant diisocyanate-conjugated protein in bronchoalveolar lavage fluid. Keratin was also identified as a predominant diisocyanate-conjugated protein in human skin biopsy samples after epicutaneous exposure to liquid-phase HDI, although the major skin diisocyanate-conjugated protein (56-kD) differed from the predominant lung diisocyanate-conjugated keratin (47-kD). The data from this study identify keratin and other proteins as potential "carriers" for diisocyanates in vivo, and suggest that HDI conjugation of these proteins may play a role in the pathogenesis of diisocyanate-induced asthma.

Moving Medicare to the FEHBP model, or how to make an elephant fly.

Transforming Medicare into a Federal Employees Health Benefits Program (FEHBP)-type program holds the promise of more choice, lower costs (in the long term), and higher quality--a fine concept that will collapse in its implementation unless at least three conditions are met. (1) Congress gets the regulatory structure right and then refrains from annual tinkering, (2) Congress does not set unrealistic expectations regarding "cost savings," especially if a prescription drug benefit is added, and (3) administrative agency staff have the requisite training and a "privatizing" orientation. Given Medicare's history and the "Medicare-industrial complex," none of those conditions is likely to be met.

Pulmonary manifestations of Sjögren's syndrome.

Sjögren's syndrome is one of the most common systemic rheumatic diseases. Pulmonary disease is prevalent in Sjögren's syndrome; respiratory manifestations include chronic cough, obstructive airways disease, pulmonary lymphoma, and interstitial lung disease that may progress to severe pulmonary fibrosis.

Effect of orally administered beclomethasone dipropionate on calcium absorption from the gut in normal subjects.

BACKGROUND: There is evidence that patients with chronic obstructive airways disease and asthma who take inhaled steroids have a low bone density. As most of a drug given from a metered dose inhaler is actually swallowed, the possibility that swallowed beclomethasone dipropionate acts topically in the gut to impair calcium absorption was investigated. Such an effect, if sustained, may be a causative factor of long term bone loss. METHODS: A two week randomised, double blind, placebo controlled, crossover trial was performed in 12 normal volunteers. Subjects were randomly allocated to swallow beclomethasone dipropionate capsules (500 micrograms twice a day) or placebo for one week. The alternate capsule was given throughout the second week. At the end of each week, calcium absorption was assessed by a strontium absorption test. Serum parathyroid hormone, plasma calcium, and plasma phosphate concentrations were determined on the last two days of each week. Twenty four hour urinary calcium, hydroxyproline, and cortisol concentrations were measured for four successive days in each week. RESULTS: All subjects completed the study. There was a 12% reduction in strontium absorption during the beclomethasone dipropionate ingestion week. There was also a 23% reduction in 24 hour urinary cortisol excretion during the same week. CONCLUSIONS: Calcium absorption (measured by a strontium absorption test) was reduced by oral administration of beclomethasone dipropionate for one week. Decreased calcium absorption due to swallowed corticosteroid may contribute to side effects of inhaled steroids and further long term studies are needed.

Choriogonadotropin-mediated thyrotoxicosis in a man.

A 38-year-old man with a metastatic gonadotropin-secreting tumor of unknown primary origin presented with both clinical and biochemical findings of hyperthyroidism in association with markedly increased concentrations of human choriogonadotropin (hCG) in plasma. After chemotherapy, the concentrations of both hCG and free thyroxin decreased and the patient became euthyroid. We discuss the rare occurrence of this presumably hCG-driven hyperthyroidism in men and compare it with the relatively more common eumetabolic hyperthyroidism associated with choriocarcinoma in women.