Brachytherapy for Organ and Function Preservation in Soft-Tissue Sarcomas in Adult and Paediatric Patients.

Adjuvant radiotherapy is an integral component in the management of soft-tissue sarcomas. Brachytherapy is a very convenient and conformal way of delivering adjuvant radiotherapy in such tumours, which spares the surrounding normal tissue. Randomised studies have established the efficacy of brachytherapy in the adjuvant setting, with a 5-year local control of 80-85%. High dose rate, low dose rate and pulsed dose rate have shown equivalent local control, but high dose rate has gained popularity owing to patient convenience, radiation safety and flexibility in dose optimisation. Freehand insertion perioperative brachytherapy (intraoperative placement and postoperative treatment) is the most commonly used technique in soft-tissue sarcomas, with intraoperative radiotherapy and radioactive seed placement being the less commonly used techniques. Brachytherapy can be used as monotherapy or in combination with external beam radiotherapy, such as in cases of close/positive margins for safe dose escalation. Although the quantum of side-effects with external beam radiotherapy has considerably reduced with the evolution of technology and the introduction of intensity modulation (intensity-modulated radiotherapy), brachytherapy still scores better in terms of dose conformality, especially in recurrent tumours (previously irradiated) and when used to treat paediatric and geriatric patients.

Thoughtflow: Standards and Tools for Provenance Capture and Workflow Definition to Support Model-Informed Drug Discovery and Development.

Pharmacometric analyses are complex and multifactorial. It is essential to check, track, and document the vast amounts of data and metadata that are generated during these analyses (and the relationships between them) in order to comply with regulations, support quality control, auditing, and reporting. It is, however, challenging, tedious, error-prone, and time-consuming, and diverts pharmacometricians from the more useful business of doing science. Automating this process would save time, reduce transcriptional errors, support the retention and transfer of knowledge, encourage good practice, and help ensure that pharmacometric analyses appropriately impact decisions. The ability to document, communicate, and reconstruct a complete pharmacometric analysis using an open standard would have considerable benefits. In this article, the Innovative Medicines Initiative (IMI) Drug Disease Model Resources (DDMoRe) consortium proposes a set of standards to facilitate the capture, storage, and reporting of knowledge (including assumptions and decisions) in the context of model-informed drug discovery and development (MID3), as well as to support reproducibility: "Thoughtflow." A prototype software implementation is provided.

Pharmacometrics Markup Language (PharmML): Opening New Perspectives for Model Exchange in Drug Development.

The lack of a common exchange format for mathematical models in pharmacometrics has been a long-standing problem. Such a format has the potential to increase productivity and analysis quality, simplify the handling of complex workflows, ensure reproducibility of research, and facilitate the reuse of existing model resources. Pharmacometrics Markup Language (PharmML), currently under development by the Drug Disease Model Resources (DDMoRe) consortium, is intended to become an exchange standard in pharmacometrics by providing means to encode models, trial designs, and modeling steps.

Drug and disease model resources: a consortium to create standards and tools to enhance model-based drug development.

Model-based drug development (MBDD) is accepted as a vital approach in understanding patients' drug-related benefit and risk by integrating quantitative information integration from diverse sources collected throughout drug development.(1) This perspective introduces the activities of the Drug and Disease Model Resources (DDMoRe) consortium, founded in 2011 through the Innovative Medicines Initiative Joint Undertaking (IMI-JU)(2) as a European public-private partnership to address a lack of common tools, languages, and standards for modeling and simulation (M&S) to improve model-based knowledge integration.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e34; doi:10.1038/psp.2013.10; advance online publication 20 March 2013.

Outcomes of elective surgery undertaken in independent sector treatment centres and NHS providers in England: audit of patient outcomes in surgery.

OBJECTIVE: To compare characteristics of patients and outcomes after elective surgery in independent sector treatment centres (ISTCs) and NHS providers. DESIGN: Follow-up study with outcomes reported by patients three to six months after surgery. SETTING: 25 ISTCs and 72 NHS providers in England. Population Consecutive patients undergoing hip or knee replacement (5671 in ISTCs and 14,292 in NHS), inguinal hernia repair (640 and 2023, respectively), or surgery for varicose veins (248 and 1336, respectively). MAIN OUTCOMES: Symptoms and disability reported by patients (Oxford hip and knee scores on a 48 point scale; Aberdeen varicose vein questionnaire) and quality of life (EuroQol EQ-5D score). RESULTS: Patients in ISTCs were healthier than those in NHS providers, had less severe preoperative symptoms, and were more affluent, though the differences were small. With adjustment, patients undergoing joint replacements in NHS providers had poorer outcomes: difference of -1.7 (95% confidence interval -2.5 to -0.9) on the Oxford hip score and -0.9 (-1.6 to -0.2) on the Oxford knee score. They more often reported complications: odds ratio 1.3 (95% confidence interval 1.1 to 1.5) for hip and 1.4 (1.2 to 1.6) for knee. There were no significant differences in outcomes after surgery for hernia or varicose veins, except that NHS patients more often reported poor results after hernia repair (1.4, 1.0 to 1.9) and additional surgery after varicose vein surgery (2.8, 1.2 to 6.8). CONCLUSION: Patients undergoing surgery in ISTCs were slightly healthier and had less severe conditions than those undergoing surgery in NHS providers. Some outcomes were better in ISTCs, but differences were small compared with the impact ISTCs could have on the provision of elective services.

Who should have priority for a knee joint replacement?

OBJECTIVES: To explore patients' views on who should have priority for total knee replacement (TKR). METHODS: In-depth, semistructured interviews were conducted with 25 patients on the waiting list for a TKR. RESULTS: All participants were willing to comment on waiting lists and prioritization for TKR. Two major themes emerged: what they thought should happen, and what they thought did happen. They thought that priority should be based on length and degree of suffering, pain severity, immobility, paid employment, payment of National Insurance contributions, and caring for dependants. In contrast, they thought that what actually happened depended on age and weight, excessive complaining and access to private practice. CONCLUSIONS: The participants agreed with health professionals that pain and disability should be key criteria on which to prioritize people for a TKR. However, they also argued for a fair decision-making process that also included additional factors specific to the patient's circumstances. Criteria to aid prioritization for joint surgery need to accommodate the views of patients as well as professionals.

The case for nonpharmacologic therapy of osteoarthritis.

This paper reviews the most commonly used nonpharmaceutical treatments for osteoarthritis, summarizing the available evidence. Four general areas are reviewed: aids and appliances, exercise and physiotherapy, education and behavioral change, and alternative and complementary therapies. The results of this review indicate that the use of nonpharmaceutical interventions in osteoarthritis is essential for good management of the disease. However, further research is required to improve the evidence base of the use of nonpharmacologic interventions in and the overall management of osteoarthritis.

Relation between agendas of the research community and the research consumer.

BACKGROUND: Previous studies have suggested that research agendas can be biased. To determine whether there is a mismatch between available research evidence and the research preferences of consumers we examined research on interventions for the treatment of osteoarthritis of the knee joint. METHODS: We searched published and unpublished studies on interventions in this condition to assess the structure of the evidence base. Focus groups and a postal survey of research consumers were then undertaken to examine their views and research priorities. FINDINGS: Review of published and unpublished reports showed that the evidence base was dominated by studies of pharmaceutical (550, 59%) and surgical (238, 26%) interventions. 24 (36%) of 67 survey respondents ranked knee replacement as the highest priority for research, whereas 14 (21%) chose education and advice as their first choice. INTERPRETATION: There is a mismatch between the amount of published work on different interventions, and the degree of interest of consumers. We suggest that broadening of the research agenda would be more in line with current treatment patterns and consumer views. If this mismatch is not addressed, then evidence-based medicine will not be representative of consumer needs.

Epidemiology of research into interventions for the treatment of osteoarthritis of the knee joint.

OBJECTIVE: To assess the published research base for interventions for osteoarthritis of the knee, and to identify areas in need of further research. METHODS: Literature searches were conducted on electronic databases (Medline, Embase, ISI, and Cochrane library), bibliographies of existing review articles were hand searched, and a postal questionnaire was sent to members of the Osteoarthritis Research Society International. All relevant articles were copied and searched for treatment type, study methodology, statistical results, conclusions, funding source, researcher affiliations, and year of publication, using a predetermined data extraction form. RESULTS: There have been marked changes in the literature over the period studied (1950-98), with a recent rise in trials of physical therapy, educational interventions, and complementary treatments. However, overall, most research was either drug (59.1%) or surgically (25.6%) related. Most of the studies reported positive results (94%). Research on oral drugs was significantly more likely to provide a positive result than research on any other intervention (p<0.001 by chi(2) test). Commercially funded studies were significantly more likely to produce a positive result than non-commercially funded research (p=0.0027 by chi(2) test). CONCLUSIONS: Analysis of time trends indicates that the research agenda does shadow changes in consumer demands. However, there are significant gaps in the research base that need to be considered.

Exploring the priorities of patients with osteoarthritis of the knee.

OBJECTIVE: To explore the perceived importance of symptoms, treatment preferences, and research priorities of people with osteoarthritis (OA) of the knee. METHODS: Results of a focus group were used to facilitate the design of a questionnaire, distributed to 112 people with knee OA. RESULTS: Pain, disability, and instability in the joint were the most important symptoms, and anxiety about knee OA caused distress to many people. Oral drugs (90%), physical therapy (62%), and aids and adaptations (56%) were the most commonly used treatments. Surgery, oral drugs, and intra-articular injections were perceived as the most efficacious interventions. Patients' highest priorities for research were surgery and educational interventions, despite the fact that few had had surgery and education was not perceived as very effective. CONCLUSIONS: The lack of a patient-centered approach to care leads professionals to ignore key symptoms and issues for individuals, and to a preoccupation with pharmaceutical interventions, rather than the treatment options that their patients prefer.

Commissioning health services research: an iterative method.

The standard linear method of commissioning research involves many stages, some lengthy. While assessment criteria are usually explicit, their weighting and interaction are not. Output is assessed on completion. This method is suitable where the research question is clear-cut. However, it has drawbacks when the research question and the form and scope of the research are not clear at the outset, as is often the case with research on the delivery and organisation of services. Also, it does not encourage potential users of the research to develop a sense of ownership. An alternative method is proposed by which the scope, form and content of research are not specified in advance but are developed iteratively. A programme director, advised by a group of potential users and research commissioners, has devolved authority to commit funding for the stages of the work as it unfolds, predicated on evolving need. There are foreseeable but avoidable risks of the group over-identifying with the researchers, of research management becoming cumbersome, and of unproductive friction between research groups when they are required to work together. The iterative method, being new and untried, is itself an organisational change requiring evaluation. However, from our local experience, it provides for productive dialogue between research commissioners, researchers and potential users.

The use of equipoise in clinical trials.

Randomised control trials (RCTs) are the standard method for treatment evaluation. Unfortunately RCTs are inherently difficult to recruit for, precisely because of the randomisation element that makes them so statistically attractive. Problems of low recruitment are now beginning to impact on trials, with many either not being started or being forced to stop, due to lack of participation. This paper examines one issue that bears on the recruitment problem: equipoise. Equipoise is defined as the point where a rational, informed person has no preference between two (or more) available treatments (Lilford and Jackson, 1995). The use of equipoise as the fundamental criterion for eligibility for a trial seems to impose a hurdle to recruitment. Here we examine the various arguments surrounding its use and measurement. We conclude that effective equipoise based upon constructed "zones of indifference" offers the best chance for bridging the gap between the individual's right to decide and the need for clinical trials to benefit society.