The role of bisphosphonates in breast cancer: The present and future role of bisphosphonates in the management of patients with breast cancer

At least 25% of patients with breast cancer develop skeletal metastases, with bone the site of disease producing the greatest morbidity. It is apparent that the bisphosphonates present an important component of the treatment strategy. They are now the treatment of choice in tumour-induced hypercalcaemia, and they can reduce bone pain and skeletal complications such as pathological fractures. In addition, bisphosphonates are being increasingly evaluated in the prevention of bone metastases and to prevent and treat cancer therapy-induced osteoporosis. Ongoing research is aimed at trying to define the optimum route, dose, schedule and type of bisphosphonate

The 'top 100' drugs and classes in England An updated 'starter formulary' for trainee prescribers.

AIMS: Prescribing is a complex skill required of doctors and, increasingly, other healthcare professionals. Use of a personal formulary can help to develop this skill. In 2006-9, we developed a core list of the 100 most commonly prescribed drugs. Our aim in the present study was to update this 'starter formulary' to ensure its continued relevance for prescriber training. METHODS: We analysed large contemporary primary and secondary care datasets to identify the most frequently prescribed medicinal products. Items were classified into natural groups, broadly following their British National Formulary classification. The resulting drug groups were included in the core list if they comprised ≥0.1% prescriptions in both settings or ≥0.2-0.3% prescriptions in one setting. Drugs from emergency guidelines that did not qualify by prescribing frequency completed the list. RESULTS: Over 1 billion primary care items and approximately 1.8 million secondary care prescriptions were analysed. The updated list comprises 81 drug groups commonly prescribed in both settings; 6 from primary care; 7 from secondary care; and 6 from emergency guidelines. 88% of the formulary was unchanged. Notable changes include entry of newer anti-epileptics and dipeptidyl peptidase-4 inhibitors and exit of phenytoin and thiazolidinediones. CONCLUSIONS: The relative stability of the core drug list over 9 years and the current update ensure that learning based on this list remains relevant to practice. Trainee prescribers may be encouraged to use this 'starter formulary' to develop a sound basis of prescribing knowledge and skills that they can subsequently apply more widely

Lorentz-Violating Supergravity

The standard forms of supersymmetry and supergravity are inextricably wedded to Lorentz invariance. Here a Lorentz-violating form of supergravity is proposed. The superpartners have exotic properties that are not possible in a theory with exact Lorentz symmetry and microcausality. For example, the bosonic sfermions have spin 1/2 and the fermionic gauginos have spin 1. The theory is based on a phenomenological action that is shown to follow from a simple microscopic and statistical picture.Comment: 15 pages; to be published in Proceedings of Beyond the Desert 2003 (Castle Ringberg, Tegernsee, Germany, 9-14 June 2003), edited by H. V. Klapdor-Kleingrothau

Flux Discharge Cascades in Various Dimensions

We study the dynamics of electric flux discharge by charged particle pair or spherical string or membrane production in various dimensions. When electric flux wraps at least one compact cycle, we find that a single "pair" production event can initiate a cascading decay in real time that "shorts out" the flux and discharges many units of it. This process arises from local dynamics in the compact space, and so is invisible in the dimensionally-reduced truncation. It occurs in theories as simple as the Schwinger model on a circle, and has implications for any theory with compact dimensions and electric flux, including string theories and the string landscape.Comment: 19+8 pages, 3 figures, 3 appendice

Electroweak Symmetry Breaking in the DSSM

We study the theoretical and phenomenological consequences of modifying the Kahler potential of the MSSM two Higgs doublet sector. Such modifications naturally arise when the Higgs sector mixes with a quasi-hidden conformal sector, as in some F-theory GUT models. In the Delta-deformed Supersymmetric Standard Model (DSSM), the Higgs fields are operators with non-trivial scaling dimension 1 < Delta < 2. The Kahler metric is singular at the origin of field space due to the presence of quasi-hidden sector states which get their mass from the Higgs vevs. The presence of these extra states leads to the fact that even as Delta approaches 1, the DSSM does not reduce to the MSSM. In particular, the Higgs can naturally be heavier than the W- and Z-bosons. Perturbative gauge coupling unification, a large top quark Yukawa, and consistency with precision electroweak can all be maintained for Delta close to unity. Moreover, such values of Delta can naturally be obtained in string-motivated constructions. The quasi-hidden sector generically contains states charged under SU(5)_GUT as well as gauge singlets, leading to a rich, albeit model-dependent, collider phenomenology.Comment: v3: 40 pages, 3 figures, references added, typos correcte

Pain outcomes in patients with bone metastases from advanced cancer: assessment and management with bone-targeting agents

Bone metastases in advanced cancer frequently cause painful complications that impair patient physical activity and negatively affect quality of life. Pain is often underreported and poorly managed in these patients. The most commonly used pain assessment instruments are visual analogue scales, a single-item measure, and the Brief Pain Inventory Questionnaire-Short Form. The World Health Organization analgesic ladder and the Analgesic Quantification Algorithm are used to evaluate analgesic use. Bone-targeting agents, such as denosumab or bisphosphonates, prevent skeletal complications (i.e., radiation to bone, pathologic fractures, surgery to bone, and spinal cord compression) and can also improve pain outcomes in patients with metastatic bone disease. We have reviewed pain outcomes and analgesic use and reported pain data from an integrated analysis of randomized controlled studies of denosumab versus the bisphosphonate zoledronic acid (ZA) in patients with bone metastases from advanced solid tumors. Intravenous bisphosphonates improved pain outcomes in patients with bone metastases from solid tumors. Compared with ZA, denosumab further prevented pain worsening and delayed the need for treatment with strong opioids. In patients with no or mild pain at baseline, denosumab reduced the risk of increasing pain severity and delayed pain worsening along with the time to increased pain interference compared with ZA, suggesting that use of denosumab (with appropriate calcium and vitamin D supplementation) before patients develop bone pain may improve outcomes. These data also support the use of validated pain assessments to optimize treatment and reduce the burden of pain associated with metastatic bone disease

Off-trial evaluation of bisphosphonates in patients with metastatic breast cancer

BACKGROUND: Bisphosphonate therapy has been readily accepted as standard of care for individuals with bone metastases from breast cancer. In this study we determined whether the proportion of patients experiencing a skeletal related event (SRE) in a clinical practice population was similar to that observed in phase III randomized controlled studies. METHODS: A retrospective chart review was conducted of 110 patients receiving intravenous bisphosphonates for advanced breast cancer. The proportion of patients experiencing at least one SRE after 12 months of therapy was determined. SRE included vertebral or non-vertebral fracture, cord compression, surgery and/or radiotherapy to bone. RESULTS: The proportion of patients who had an SRE was 30% (28 individuals) and the median time to first event was greater than 350 days. Non-vertebral events and radiotherapy were the most frequent type of SRE, while cord compression and hypercalcaemia were rare (1%). Most patients in the study had bone-only disease (58.2%) and most had multiple bone lesions. In the first 12 months the mean duration of exposure to intravenous bisphosphonates was 261 days and most patients remained on treatment until just before death (median 27 days). CONCLUSION: This study suggests that the rate of clinically relevant SREs is substantially lower than the event rate observed in phase III clinical trials. We attribute this lower rate to observational bias. In the clinical trial setting it is possible that over-detection of skeletal events occurs due to the utilisation of regular skeletal survey or radionucleotide bone scan, whereas these procedures are not routine in clinical practice. Phase IV observational studies need to be conducted to determine the true benefits of bisphosphonate therapy in order to implement rationale use of bisphosphonates

Winner-take-all selection in a neural system with delayed feedback

We consider the effects of temporal delay in a neural feedback system with excitation and inhibition. The topology of our model system reflects the anatomy of the avian isthmic circuitry, a feedback structure found in all classes of vertebrates. We show that the system is capable of performing a `winner-take-all' selection rule for certain combinations of excitatory and inhibitory feedback. In particular, we show that when the time delays are sufficiently large a system with local inhibition and global excitation can function as a `winner-take-all' network and exhibit oscillatory dynamics. We demonstrate how the origin of the oscillations can be attributed to the finite delays through a linear stability analysis.Comment: 8 pages, 6 figure