Radiotherapy Trial Set-up in the UK: Identifying Inefficiencies and Potential Solutions.

AIMS: Radiotherapy clinical trials are integral to the development of new treatments to improve the outcomes of patients with cancer. A collaborative study by the National Cancer Research Institute Clinical and Translational Radiotherapy Research Working Group and the National Institute for Health Research was carried out to understand better if and why inefficiencies occur in the set-up of radiotherapy trials in the UK. MATERIALS AND METHODS: Two online surveys collected information on the time taken for UK radiotherapy trials to reach key milestones during set-up and the research support currently being provided to radiotherapy centres to enable efficient clinical trial set-up. Semi-structured interviews with project managers and chief investigators identified better ways of working to improve trial set-up in the future. RESULTS: The timelines for the set-up of 39 UK radiotherapy trials were captured in an online survey showing that the median time from grant approval to trial opening was 600 days (range 169-1172). There were 38 responses from radiotherapy centres to a survey asking about the current support provided for radiotherapy research. Most of these centres have more than one type of staff member dedicated to supporting radiotherapy research. The most frequent barrier to radiotherapy trial set-up identified was lack of physicists' time and lack of time for clinical oncologists to carry out research activities. Four main themes around trial set-up were identified from semi-structured interviews: the importance of communication and building relationships, the previous experience of the chief investigator and clinical trials units, a lack of resources and having the time and personnel required to produce trial documentation and to process trial approval requests. CONCLUSIONS: This unique, collaborative project has provided up to date information about the current landscape of trial set-up and research support in the UK and identified several avenues on which to focus future efforts in order to support the excellent radiotherapy trial work carried out across the UK.

Report of a Royal College of Physicians and National Institute for Health Research workshop - developing research capacity to ensure successful study development and delivery.

The landscape and opportunities for clinical research have changed significantly following the creation of the National Institute for Health Research (NIHR) in 2006. This article describes the scale and impact of the NIHR network infrastructure for clinical research and identifies areas for future development in partnership with the National Health Service (NHS), clinicians and research funders.

Extending the clinical research network approach to all of healthcare.

The development of Clinical Research Networks (CRN) has been central to the work conducted by Health Departments and research funders to promote and support clinical research within the NHS in the UK. In England, the National Institute for Health Research has supported the delivery of clinical research within the NHS primarily through CRN. CRN provide the essential infrastructure within the NHS for the set up and delivery of clinical research within a high-quality peer-reviewed portfolio of studies. The success of the National Cancer Research Network is summarized in Chapter 5. In this chapter progress in five other topics, and more recently in primary care and comprehensively across the NHS, is summarized. In each of the 'topic-specific' networks (Dementias and Neurodegenerative Diseases, Diabetes, Medicines for Children, Mental Health, Stroke) there has been a rapid and substantial increase in portfolios and in the recruitment of patients into studies in these portfolios. The processes and the key success factors are described. The CRN have worked to support research supported by pharmaceutical, biotechnology and medical device companies and there has been substantial progress in improving the speed, cost and delivery of these 'industry' studies. In particular, work to support the increased speed of set up and delivery of industry studies, and to embed this firmly in the NHS, was explored in the North West of England in an Exemplar Programme which showed substantial reductions in study set-up times and improved recruitment into studies and showed how healthcare (NHS) organizations can overcome delays in set up times when they actively manage the process. Seven out of 20 international studies reported that the first patient to be entered anywhere in the world was from the UK. In addition, the CRN have supported research management and governance, workforce development and clinical trials unit collaboration and coordination. International peer reviews of all of the CRN have been positive and resulted in the continuation of the system for a further 5 years in all cases.

Tibial tuberosity avulsion fracture in dogs: a review of 59 dogs.

OBJECTIVES: To evaluate the high incidence of tibial tuberosity avulsion fracture diagnosed in skeletally immature Staffordshire bull terriers presenting to a UK animal welfare charity hospital. METHODS: A retrospective review of tibial tuberosity avulsion fractures treated by the hospital between 2002 and 2007. RESULTS: Sixty-five tibial tuberosity avulsion fractures were recorded in 59 dogs. Fifty-one tibial tuberosity avulsion fracture-affected dogs (86 per cent) were Staffordshire bull terriers. Dogs sustaining tibial tuberosity avulsion fractures had median and mean ages of five and 4.9 months, respectively (range three to 10 months). Where recorded, injury was associated with a short fall or jump (typically 3 to 4 feet) in 29 of 50 dogs. Three fracture patterns were recorded: 37 stifles sustained isolated tibial tuberosity avulsion fracture; 15 stifles sustained tibial tuberosity avulsion fracture accompanied by separation of the proximal tibial epiphysis; in 13 stifles epiphyseal separation extended to produce Salter-Harris type II fracture of the caudal tibial metaphysis. On analysis of the hospital database, tibial tuberosity avulsion fracture was a reason for presentation in 51 (3.3 per cent) of 1536 Staffordshire bull terriers, but only five (0.18 per cent) of 2815 other breed dogs, registered under the age of 12 months during the study period (P<0.001). CLINICAL SIGNIFICANCE: Staffordshire bull terriers commonly present with tibial tuberosity avulsion fracture, with or without concurrent separation of the proximal tibial epiphysis, to this urban charity hospital.

Issues for academic health centers to consider before implementing a balanced-scorecard effort.

Because of changes in the health care environment, it is likely that strategic planning and management will become much more important to academic health centers (AHCs) than in the past. One approach to strategic planning and management that is gaining the considerable interest of health care organizations is the balanced scorecard. Based on a year's experience in examining this management tool, and on early implementation efforts, the authors critically evaluate the applicability of the balanced-scorecard approach at AHCs in relation to two fundamental questions: Does the decentralized nature of most AHCs mitigate the potential usefulness of the balanced-scorecard approach? Are the balanced scorecard's four perspectives (learning and growth, internal; customer; and financial) appropriate for AHCs, which are neither for-profit nor manufacturing organizations? The authors conclude that (1) the unique characteristics of AHCs may mitigate the full benefit of the balanced-scorecard approach, and (2) in cases where it is used, some key modifications must be made in the balanced-scorecard approach to account for those unique characteristics. For example, in a corporation, the key question from the financial perspective is "To succeed financially, how should we appear to our stockholders?" But in an AHC, this question must be revised to "What financial condition must we achieve to allow us to accomplish our mission?"

Reported sexual abuse and subsequent psychopathology among women attending psychology clinics: the mediating role of dissociation.

OBJECTIVE: While there is now a good clinical research base that outlines the links between reported sexual abuse and psychological symptoms and disorders, there is less of an understanding of the psychological processes mediating that relationship. This study assessed the role of dissociation as a mediator between reported sexual abuse and a range of psychopathological characteristics. DESIGN: A patient-series design was used. METHOD: Participants were an unselected sample of 45 women attending clinical psychology services. Each woman was interviewed regarding a reported history of sexual abuse, and completed standardized measures of general psychopathology, borderline personality disorder characteristics and dissociation. RESULTS: Sexual abuse per se was associated with the extent of depression, somatization, compulsive behaviour, phobic symptoms and borderline personality disorder characteristics. In each case, dissociation served as a complete mediator in that link. However, the same mediating relationship was not found when attempting to explain the greater psychopathological impact of more 'severe' forms of abuse (childhood experiences; intra-familial abuse). CONCLUSION: These findings suggest that the effective of clinical work with these psychopathological features would be enhanced if dissociation symptoms were addressed in women with a reported history of sexual abuse. However, the importance of that therapeutic target may be unrelated to the severity of the psychological disturbance.

The role of constraints in determining optimal scores.

This paper is about Guttman's method for assigning optimal numerical scores to categorical variables, and related methods, which underlie Healy's TW1 and TW2 bone-age standards. In giving the methodological underpinning, Healy and Goldstein noted that the scores they obtained could depend critically on how essential constraints were specified, thus questioning the whole of optimal score theory. This paper is concerned with resolving this difficulty; the resolution is surprisingly intricate, involving: (i) the relationship between those optimality criteria expressed as ratios and those not; (ii) the distinction between weak constraints (identification constraints) and strong constraints; (iii) the relationship between working in terms of deviations from the mean scores and so-called 'uninteresting solutions'; (iv) the use of short-cut algorithms that yield admissible solutions only when the correct strong constraints are applied; (v) generalizations that lead to reformulations of classical multivariate methods with algorithmic as well as statistical consequences.

The effect of a synthetic hexadentate iron chelator (CP130) and desferrioxamine on rabbit kidneys exposed to cold and warm ischaemia.

The effect of CP130 (a synthetic hexadentate pyridinone iron chelator) on the formation of two markers of lipid peroxidation (TBA-reactive material and Schiff's bases) in rabbit kidneys following a 72 h period of cold (0-4 degrees C) ischaemia was investigated by either adding CP130 to the flush/storage solution (hypertonic citrate solution) or by administering the agent intravenously 15 min before removal of the organs. In both cases, CP130 blocked the adverse rises in lipid peroxidation caused by ischaemia and subsequent reoxygenation of the homogenates in vitro. Both CP130 and desferrioxamine (DFX) (administered intravenously 15 min before ischaemia and 5 min before reperfusion) were also found to significantly reduce post-ischaemic rates of in vitro lipid peroxidation in kidneys rendered warm ischaemic for 90 min followed by reperfusion for 5 or 60 min in situ. Kidneys exposed to warm ischaemia and reperfusion developed interstitial and intracellular oedema, congestion and haemorrhage. DFX administration had little effect on the histological outcome, whereas CP130 significantly reduced interstitial oedema (at 5 min reperfusion compared to the DFX-treated group), intracellular oedema (at 60 min reperfusion compared to the DFX-treated group) and congestion (at 5 min reperfusion compared with a control group not given any agent). It is concluded that while CP130 and DFX exhibited similar antioxidant properties, CP130 provided better protection from ischaemia/reperfusion injury at the histological level. Synthetic iron chelators may therefore be of benefit in clinical organ transplantation by protecting against tissue damage caused by prolonged ischaemia.

Reoxygenation following hypoxia stimulates lipid peroxidation and phosphatidylinositol breakdown in kidney cortical slices.

Reoxygenation of hypoxic (120 min at 37 degrees) rabbit kidney cortical slices in vitro resulted in a rapid increase in lipid peroxidation and phosphatidylinositol hydrolysis. No changes in phosphatidylinositol breakdown occurred during hypoxia or upon reoxygenation in the absence of calcium. Incubation of renal slices with carbon tetrachloride resulted in increased lipid peroxidation but had no effect on phosphatidylinositol breakdown. It is concluded that altered intracellular calcium homeostasis during reoxygenation is involved in mediating increased phosphatidylinositol hydrolysis through activation of a specific phospholipase C, but that oxidative stress per se does not have a significant effect on the inositol phosphate secondary messenger response in this model system.

Ultrastructural changes and lipid peroxidation in rat adipomusculocutaneous flap isotransplants after normothermic storage and reperfusion.

Parallel in vivo, histological, and ultrastructural studies were carried out and markers of lipid peroxidation (Schiff's bases [SB] and thiobarbituric-acid-reactive material [TBAR]) were measured in rat adipomusculocutaneous flap isotransplants that had been stored for 0, 2, 4, 6, and 8 hr under normothermic (37 degrees C) conditions and reperfused for specific periods. Flaps stored for 4 hr and treated with intravenous desferrioxamine (DFX) or hypertonic citrate flush (HCA) were also evaluated. In vivo assessment was made after 7 days of reperfusion. Flaps stored for 4 hr eventually exhibited partial necrosis in vivo, and neither DFX or HCA flush increased the area of surviving skin. Electron microscopy revealed extensive storage damage in epidermal, follicle, fat, and smooth muscle cells and in endothelium. HCA significantly preserved fat cells (P = 0.0035) and DFX diminished smooth muscle damage. Reperfusion injury was seen in endothelial cells in the form of swelling that was not prevented by HCA or DFX. Ultrastructural alterations correlated with changes in susceptibility to lipid peroxidation in fat but not in skin. The results of these parallel studies indicate that both free radical-dependent and independent mechanisms operate in ischemia and reperfusion injury in flap tissue and that fat has a greater predisposition to free radical damage than skin.

Ebselen. Antioxidant capacity in renal preservation.

Ebselen (PZ51) was tested for its ability to inhibit oxidative membrane damage and improve outcome of rabbit kidneys rendered cold ischaemic for 72 hr. In view of the rapid metabolism of ebselen, the antioxidant capacities of its two principal metabolites were first compared with that of the parent drug in an in vitro hepatic microsomal lipid peroxidation system initiated by NADPH/Fe(3+)-ADP. The potent antioxidant activity of ebselen was confirmed but metabolite I (2-glucuronylselenobenzanilide) exhibited no antioxidant potential up to a concentration of 50 microM; metabolite II (4-hydroxy-2-methyl-selenobenzanilide) did inhibit lipid peroxidation but was about 80 times less effective than the parent compound. The storage of rabbit kidneys in hypertonic citrate solution at 0 degrees for 72 hr of cold ischaemia resulted in greatly increased susceptibility to oxidative membrane damage in both the cortex and medulla as determined by the subsequent in vitro formation of two markers of lipid peroxidation (Schiff's bases and thiobarbituric acid-reactive material). Inclusion of ebselen (50 microM) in the flush and storage solution led to a highly significant reduction in these oxidative markers in both regions of the kidney. Intracellular and interstitial oedema was noted in organs subjected to 72 hr cold ischaemia and was reduced by ebselen (50 microM in the flush/storage solution). The rate of post-ischaemic lipid peroxidation was found to correlate well with the extent of oedema in the renal medulla (r = 0.84, P less than 0.001) but no such correlation was found in the cortex. Administration of ebselen (5.5 mg/kg i.v. and 100 microM in the flush/storage solution) did not improve the long-term survival of rabbits following autotransplantation of a single kidney stored for 48 or 72 hr. No protective effect of ebselen could be demonstrated either in terms of graded physiological function or histological outcome.

A chelator is required for microsomal lipid peroxidation following reductive ferritin-iron mobilisation.

In the past, antioxidant and chelator studies have implicated a role for iron-dependent oxidative damage in tissues subjected to ischaemia followed by reperfusion. As ferritin is a major source of iron in non-muscular organs and therefore a potential source of the iron required for oxygen radical chemistry, we have determined conditions under which ferritin iron reduction leads to the formation of a pool of iron which is capable of catalysing lipid peroxidation. Under anaerobic conditions and in the presence of rat liver microsomes, flavin mononucleotide (FMN) catalysed the reduction of ferritin iron as shown by both continuous spectrophotometric measurements of tris ferrozine-Fe(II) complex formation and post-reaction Fe(II) determination. The presence of either ferrozine or citrate was not found to alter the time course or extent of ferritin reduction. In contrast, the addition of air to the reactants after a 20 min period of anaerobic reduction resulted in peroxidation of the microsome suspension (as determined with the 2-thiobarbituric acid test) only in the presence of a chelator such as citrate, ADP or nitrilotriacetic acid. These results support the concept that reduced ferritin iron can mediate oxidative damage during reperfusion of previously ischaemic tissues, provided that chelating agents such as citrate or ADP are present.

Function of single rat lung isografts after 48-hour cold storage. The effect of treatment with free radical antagonists and prostacyclin PGI2.

Single orthotopic rat lung isografts were carried out in adult male AS rats after 48-hour cold storage (0 degrees C). Grafts were preserved by simple organ flush followed by low-temperature immersion. Hypertonic citrate (HCA) without additives was evaluated as the basic flush solution. In other groups desferrioxamine (an iron chelator), verapamil (a calcium channel blocker) and prostacyclin (PGI2) were added separately to HCA and given intravenously to donor and recipient animals in an attempt to improve the preservation. Baseline controls were fresh HCA-flushed lungs grafted immediately after harvest. Negative controls to the HCA assessment were lungs flushed with isotonic saline (NaCl) stored for 48 hr at 0 degrees C. Functional studies were carried out at weekly intervals until sacrifice (in the fifth postoperative week) and included assessment of blood flow, aeration and gas transfer by perfusion scintigraphy, chest roentgenograms, and blood gas analysis. Of the baseline control animals, 10/10 survived to the end of the study period; all grafts appeared macroscopically normal and blood gas analysis showed good function. Of the animals grafted with HCA-flushed, 48-hr-stored lungs 2/10 died postoperatively; 7/10 grafts appeared macroscopically normal at the end of the study, and one was slightly reduced in size. Blood gas analysis of HCA-flushed, 48-hr-stored lungs showed function similar to that of baseline control grafts. NaCl-flushed lungs (negative controls) survived surprisingly well: 3/10 animals died postoperatively, 6/10 lungs appeared normal, and one was reduced in size. Assessment of graft function showed no significant benefit of HCA flush compared with NaCl. Treatment with desferrioxamine, verapamil or prostacyclin (PGI2) failed to improve the outcome after HCA flush; in fact desferrioxamine gave significantly poorer results. The study has shown that successful 48-hr preservation of rat lung isografts can be achieved by simple organ flush with HCA and storage at 0 degrees C. Contrary to expectation and experience with preservation of other organs, rat lungs were remarkably well preserved after flush with NaCl.

Lipid peroxidation and ultrastructural changes in rat lung isografts after single-passage organ flush and 48-hour cold storage with and without one-hour reperfusion in vivo.

Rat lung isografts were preserved for 48 hr at 0 degrees C using a simple organ flush technique. After storage alone, isotonic saline flush resulted in significantly raised indices of lipid peroxidation in vitro (Schiff bases and thiobarbituric-acid-reactive material [TBAR]). Lungs flushed with hypertonic citrate (HCA) had significantly less oxidative damage than saline-flushed lungs. The addition to the HCA flush of verapamil, a calcium channel blocker, or desferrioxamine, an iron chelator, significantly reduced TBA reactivity in stored lungs compared with HCA alone. After 1-hr reperfusion in vivo, lipid peroxidation was reduced in HCA-flushed lungs compared with saline flush (TBAR alone), but no additional protection from the use of desferrioxamine or verapamil was demonstrated. Electron microscopy after saline flush and storage alone showed gross endothelial swelling and fragmentation. Reperfusion with blood for 1 hr resolved cell swelling, but alveolar/capillary wall rupture occurred. HCA protected against cell swelling, but endothelial vesiculation and widening of the basement membrane were observed. After reperfusion, HCA-flushed lungs developed much endothelial loss that was considerably reduced by the use of desferrioxamine and verapamil. The lipid peroxidation results suggest that iron- and calcium-mediated free radical production may be important mechanisms in oxidative damage to stored rat lungs. Electron microscopy findings correlated with biochemical evidence of free-radical-mediated injury. Reduction of endothelial loss on reperfusion by the use of verapamil and desferrioxamine provides circumstantial evidence that ischemia and reperfusion damage of organs stored for transplantation is partly due to Fe++(+)- and Ca+(+)-dependent mechanisms that probably involve increased free radical production.

Protection against endotoxin-induced foetal resorption in mice by desferrioxamine and ebselen.

Endotoxin was administered to mice on their 13th day of pregnancy at doses which caused the resorption of approximately 50% of the implanted foetuses. The iron chelator desferrioxamine was found to significantly inhibit the percentage of resorptions induced by endotoxin in a dose-dependent manner. The highest dose of desferrioxamine (5 mg) given intravenously 30 min prior to, immediately after, and 4 and 24 h after endotoxin inoculation, reduced the percentage of resorptions from 56.9 to 17.9%. Administration of the novel selenium-containing compound ebselen, which is both an antioxidant and an inhibitor of leukotriene synthesis, was also found to significantly protect against endotoxin-induced foetal resorptions, reducing the percentage of resorbed foetuses from 52.9 to 26.0% when given at a dose of 50 mg/kg (s.c.) at the time of endotoxin inoculation and 24 and 48 h following. Both these compounds also significantly reduced the increase in spleen weights observed when the mice were given endotoxin. These results provide evidence that the iron-catalysed production of hydroxyl radicals from other oxygen-derived species and the formation of leukotrienes play an important role in the mechanism by which endotoxin causes foetal resorptions in the mouse.

Intracellular iron redistribution. An important determinant of reperfusion damage to rabbit kidneys.

These studies were designed to examine the possible role of low molecular weight intracellular iron chelates (desferrioxamine-available (DFX-A) iron) in the damage which occurs during cold storage and subsequent reperfusion of kidneys. The level of DFX-A iron increased significantly (P less than 0.005) in the cortex of rabbit kidneys rendered cold ischaemic (CI) for 24 hr and the amount of iron available for DFX chelation increased significantly (P less than 0.05) in both the cortex and medulla of kidneys stored for 48 or 72 hr compared with fresh non-ischaemic controls. During ex vivo reperfusion of the organs with an oxygenated asanguinous perfusate, DFX-A iron returned rapidly to pre-ischaemic levels in 24 hr CI kidneys, but remained elevated following 48 and 72 hr CI (P less than 0.05 compared with 24 hr CI kidneys after 5 min reperfusion), returning to control levels only after 30 min reperfusion. There was no concurrent increase in total iron levels, indicating that a redistribution of iron to more accessible pools had occurred within the tissue. We suggest that decompartmentalization of intracellular iron during ischaemia and raised DFX-A iron levels over an extended period during subsequent reperfusion are responsible for increased catalysis of oxygen-derived free radical-mediated lipid peroxidation, and are an important factor in the deterioration of physiological function observed in rabbit kidneys following extended periods of cold storage.