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.

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 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.

Preoperative pulmonary function and complications after cardiovascular surgery.

Results of preoperative pulmonary function tests were evaluated in 106 patients who had major thoracic or upper abdominal cardiovascular surgery. These results were related to the occurrence of postoperative complications by comparison of pulmonary function data in patients with an ICU stay of less than 5 days versus patients with an ICU stay of greater than 5 days. However, quantitative analysis of several specific parameters of pulmonary function tests failed to reveal any difference in the incidence of postoperative complications between patients with modest versus severe preoperative dysfunction. The occurrence of atelectasis was related to type of cardiovascular surgical procedure, but not to preoperative pulmonary function tests. Abnormalities on pulmonary function tests were not the major determinants of use of preoperative respiratory therapy, and its use was unrelated to the length of stay postoperatively in the ICU. We conclude that prior to cardiovascular surgery, routine quantitation of clinically apparent pulmonary dysfunction may be of little value in predicting postoperative morbidity and much less important than careful clinical evaluation. When pulmonary function tests are performed in such patients, simple spirometric tests and arterial blood gas levels are adequate.

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.

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.

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.

Is there a carcinoma in situ of gastric mucosa?

Carcinoma in situ, a precancerous lesion in the strict sense, was first recognized in stratified squamous epithelia. It is characterized by markedly atypical cells replacing the autochthonous epithelial cells without stromal invasion, the basement membrane being well preserved. Notwithstanding gradual transitions between carcinoma in situ on the one hand and dysplasias and invasive cancer on the other hand, its histological separation from the latter is feasible in the uterine portio. Its recognition has decisive therapeutic and prognostic implications, particularly in view of the frequently observed latent period between purely superficial spread and early invasive growth. In contrast difficulties are encountered in applying the concept of Carcinoma in situ to mucosal lesions of the stomach, though an analogous replacement stage has to be postulated, because the gastric and cervical mucous membranes differ fundamentally in their structural characteristics. The epithelial cells of the surface, pits and tubular glands do exhibit progressive atypia during cancerization. However, the single-layered epithelium offers far less distinctive criteria than the stratified squamous epithelium. Newly formed glandular complexes cannot be accepted as evidence for in situ growth. The latent period between purely superficial replacement by atypical cells and invasion appears to be considerably shorter in the stomach than in the portio, probably because the mechanical resistance of the loosely textured gastric lamina propria is small. In addition, stromal invasion may originate from any one epithelial cell in the gastric mucosa, whilst it is just the basal layer from which invasively growing cells may emanate in the uterine portio. The occurrence of dysplasia in the mucosa of the stomach does not justify a gastrectomy, according to our current experience, there being no intervention in gastric surgery equivalent to that of conization.

Cellular aspects of granulomas.

We investigated granulomas of sarcoidosis and de Quervain's thyroiditis of man as well as experimental granulomas of the rat-peritoneum. Though differing in their cellular composition, they show common features in their organisation. A central zone consisting predominantly of epithelioid cells, epithelioid cell equivalents and macrophages without phagosomes in contact with lymphocytes. An outer zone mainly consisting of large macrophages, rich in phagosomes, dark epithelioid cells, necrotic elements and newly immigrated cells. The outer zone is considered to be a functional transitional area. Many of the newly immigrated monocytes are often binucleate, which we consider to be due to disturbances in the spindle cleavage of mitosis following injury. Ordered multinucleate giant cells (Langhans type) are centrally organised under the influence of centrioles and cytoskeleton. They have one phagocytic pole, one large pluricorpuscular cytocentre and a nuclear pole. The ordered internal structure of these lightly stained giant cells indicates their functional activity. In contrast we consider the darkly stained giant cells to be exhausted elements possibly progressing to coagulative necrosis. Intercellular contacts in granulomas e.g. between macrophages are seen as interdigitations of microvilli with the formation of desmosome-similar junctions. We suppose them to be in part for exchange of information and fixation. Epithelioid cells are characterised by their prominent secretory apparatus as well as by a large centrosphere with radially diverging numerous Golgi dictyosomes. Microtubules, together with microfilaments, are significantly involved in transporting secretory granules towards the periphery of the cell. Degranulation also occurs in co-operation with the various components of the cytoskeleton. Disintegration of the membranes of epithelioid cells leading to necrosis may result from massive degranulation. We suppose the various subtypes of epithelioid cells described by other authors to be various stages of the same but not different types of epithelioid cells.

The cytoskeleton in activated and in functionally disordered cells of the macrophage system.

In animal experiments, and for various granulomatous diseases of humans, components of the so-called cytoskeleton in cells of the macrophage system were investigated in the electron microscope and with the aid of indirect immunofluorescence microscopy using monospecific antibodies. In young monocytes and in non-activated or only slightly activated mononuclear phagocytes, predilection areas and characteristic patterns of arrangement were found: F-actin is observable, densely arranged, in particular, around the nucleus and below the cytomembrane; intermediate filaments of the vimentin type form a broad, intensely fluorescent wreath around the cell nucleus; microtubules radiate from the perinuclear centriole in all directions into the neighbouring cytoplasm, taking the form of a microaster. Modifications of this pattern of distribution begin in the pre-mitotic phase, and become highly evident in karyokinesis and cytokinesis. Increases in the cell function are associated with changes in the arrangement of the cytoskeleton of quite a different nature, in particular in the regions of the cytomembrane, the cytocentre, including the Golgi dictyosomes and neighbouring portions of the rough endoplasmic reticulum, at sites of endocytosis and exocytosis and polarization and orientation, and in conjunction with intracytoplasmic translocations after the fusion of macrophages to form multinucleate giant cells. We do not consider the findings described here to be a sort of more or less static compartimentalization phenomenon, but, rather, believe them to bear a causal relationship to the functional dynamism of highly activated and specially differentiated macrophages, epithelioid cell equivalents, epithelioid cells and giant cells. Moreover, they are suggestive of function-dependent, intimate interactions of the individual cytoskeletal components. The experimental, reversible disturbance by the use of colchicine leads in macrophages to a transient loss of structural and functional identity with drastic alterations of microtubules and vimentin filaments.

Evidence for a cerebral cholinergic system and suggested pharmacological patterns of neural organization in the prostomium of the polychaete Nereis virens (SARS).

The histological visualization of choline acetyltransferase (CAT) and acetylcholinesterase (AChE) on frozen sections of prostomia of Nereis virens indicate a concentration of cholinergic activity in the anterior brain. Components are probably sensory epithelial cells with cholinergic axons entering the brain in cephalic nerves and efferent cholinergic axons to prostomial muscle leaving the brain in the same nerves. There are also subepidermal cholinergic cells that may be second order motor neurons serving epidermal mucous cells. The smaller, second lobe of the corpora pedunculata and its associated vertical fibre tract are CAT(+) and appear continuous, on each side of the cerebral ganglion, with a dorsal and ventral longitudinal bundle of AChE(+) fibers. This system tapers to nothing at the level of the posterior eyes. There is a small AChE(+) component to each optic nerve and AChE is present in the nuchal epithelium. These observations are discussed in relation to earlier studies on aminergic and neurosecretory activity in the same ganglion.

Uptake of tritium-labelled biogenic amines by the prostomium of the polychaete Nereis virens (Sars) (Annelida).

The uptake of tritium-labelled 5-HT, noradrenaline, 5-hydroxytrytophan, DOPA and dopamine by the cerebral ganglion and prostomial nervous system of the polychaete Nereis virens has been examined using radioautography at the level of the light microscope. Pronounced uptake of (3)H-5HT occurred in the antennal, palpal, tegumentary and nuchal nerves as well as in ganglionic nuclei 13, 14, 15, 16, 17, 20, 24 and 25, the mid-brain neuropile, the neurosecretory neuropil and the infracerebral organ; (3)H-NA uptake was observed in small cells in the prostomial epidermis, and the infracerebral organ; (3)H-dopamine only in one of two common types of epidermal mucus cells. Prostomial muscles labelled generally with (3)H-NA and at specific sites with (3)H-5HT. These observations support the concept of an efferent serotonergic system originating in several cerebral ganglionic nuclei and serving prostomial muscle and epidermis. Evidence for an afferent adrenergic system is less substantial. The role of dopamine remains obscure.

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.

Issues in the implementation of P.L. 93-641.

This article is aimed at an audience of health planners and any others who are already well versed in recent developments on the U.S. health planning scene. It assumes that the reader knows most of the details of Public Law 93-641 and its current status of implementation. The author discusses a few of the issues most central to the future of the program, provides a point of view on those issues, and invites response from the planning community to these and other issues. Attention is focused on four subjects (1) Inter-HSA Coordination; (2) State Agency Performance Standards; (3) Statewide Health Coordinating Councils; and, (4) Health Planning and the Goal of Cost Containment.