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Unless confirmation of a solitary brain metastasis is made in the context of absent extracranial disease and good performance status, patients with metastatic brain disease from non-small cell lung cancer fare badly. There are no level I recommendations for the management of those with multiple brain metastases. The role of whole brain radiotherapy is not certain in those of poorer performance status. This overview assesses what we know and what we are uncertain of in the context of a changing paradigm for some subsets of patients who may obtain superior palliation with treatments targeted at the histological or molecular level. Once the standard treatment is established (steroids plus or minus whole brain radiotherapy), those who are of better performance status may be considered for comparison of this standard with or without systemic management. © 2010 The Royal College of Radiologists.


O'Sullivan J.,Freeman Hospital
Current Hypertension Reports | Year: 2014

Coarctation of the aorta represents more than a simple obstructive lesion, as there is often evidence of hypertension and vascular dysfunction despite successful surgery at an early age. There are ample data showing that a large proportion of patients develop arterial hypertension, and this appears to increase with age. Our understanding of the pathogenesis of late hypertension is incomplete, and there is limited information on which drugs are most appropriate. Increased arterial rigidity is now well described in this patient group, although it is not known how this should influence therapy. The increase in afterload associated with this increased rigidity has been found to have an impact on the left ventricle at an early stage, and the interaction between the vascular dysfunction and the ventricle is an area of interest and active research. This article reviews some recent studies and highlights areas where research questions remain. © 2014 Springer Science+Business Media.


Andras A.,Freeman Hospital
Cochrane database of systematic reviews (Online) | Year: 2012

People with venous thromboembolism (VTE) are generally treated for five days with intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin (LMWH) followed by three months of vitamin K antagonist treatment. Treatment with vitamin K antagonists requires regular laboratory measurements and some patients have contraindications to treatment. This is an update of a review first published in 2000 and updated in 2002. To evaluate the efficacy and safety of long term treatment of VTE with LMWH compared to vitamin K antagonists. For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched their Specialised Register (last searched February 2012) and CENTRAL (2012, Issue 1). Two authors evaluated trials independently for methodological quality. The review authors extracted data independently. Primary analysis included all trial participants randomised to the allocated treatment groups. Separate analyses were performed according to the quality of the trials and for subgroups such as trials initially using similar treatments in both trial arms and those that did not, trials concerning deep vein thrombosis (DVT) and pulmonary embolism (PE) and the different periods of follow-up. All 15 trials, with a combined total of 3197 patients, fulfilling our criteria were combined in a meta-analysis. We found a non-statistically significant reduction in the risk of recurrent VTE between the two treatments (odds ratio (OR) 0.82, 95% CI 0.59 to 1.13). Analysis of pooled data for category I trials (those with a high methodological quality) showed a non-significant reduction in the odds of recurrent VTE favouring LMWH treatment (OR 0.80, 95% CI 0.54 to 1.18).For all trials combined, the difference in bleeding significantly favoured treatment with LMWH (OR 0.50, 95% CI 0.31 to 0.79). Considering only category I trials, a non-significant trend favouring LMWH remained (OR 0.62, 95% CI 0.36 to 1.07). No difference was observed in mortality (OR 1.06, 95% CI 0.74 to 1.54). LMWHs are possibly as effective as vitamin K antagonists in preventing symptomatic VTE after an episode of symptomatic deep venous thrombosis, but are much more expensive. Treatment with LMWH is significantly safer than treatment with vitamin K antagonists. LMWH may result in fewer episodes of bleeding and is possibly a safe alternative in some patients, especially those in geographically inaccessible areas, are reluctant to visit the thrombosis service regularly, or with contraindications to vitamin K antagonists. However, treatment with vitamin K antagonists remains the treatment of choice for the majority of patients.


The use of impaction grafting in revisions with larger acetabular bone defects has mixed outcomes and sometimes high failures rates. This prospective, single-center study involved a consecutive series of 24 patients who underwent complex reconstruction of the acetabulum using a trabecular metal augment, impaction bone grafting, and a cemented high-density polyethylene cup. Patients were followed for median 5 (3-7) years. The 2-year WOMAC pain, function, and stiffness scores improved, as did certain components (bodily pain, physical function, role physical, role emotional, physical component score, and social function) of the SF-36 (p < 0.05). 23 of the patients were very satisfied with the overall outcome of the surgery and would have undergone the surgery again for a similar problem, and 19 reported great improvement in their quality of life after surgery. Radiographs at the latest follow-up revealed incorporation of the augment with mean change in acetabular component inclination of less than 1 degree (p > 0.05) and cup migration of less than 5 mm in both horizontal and vertical axes (p > 0.05). 1 patient required further revision at 13 months and was found to have a fractured augment at re-revision. This study shows that trabecular metal augments are effective in filling the bone defect and provide a stable foundation for impaction bone grafting. We found satisfactory clinical and radiographic results using this technique, with low failure rate at a median follow-up time of 5 years.


Wong S.S.,Freeman Hospital
Cochrane database of systematic reviews (Online) | Year: 2012

Strictures of the urethra are the most common cause of obstructed micturition in younger men and frequently recur after initial treatment. Standard treatment comprises internal widening of the strictured area by simple dilatation or by telescope-guided internal cutting (optical urethrotomy), but these interventions are associated with a high failure rate requiring repeated treatment. The alternative option of open urethroplasty whereby the urethral lumen is permanently widened by removal or grafting of the strictured segment is less likely to fail but requires greater expertise. Findings of Improved choice of graft material and shortened hospital stay suggest that urethroplasty may be under utilised. The extent and quality of evidence guiding treatment choice for this condition are uncertain.   To determine which is the best surgical treatment for male urethral stricture disease taking into account relative efficacy, adverse event rates and cost-effectiveness.   We searched the Cochrane Incontinence Group Specialised Register (searched 21 June 2012), CENTRAL (2012, Issue 6), MEDLINE (January 1946 to week 2 June 2012), EMBASE (January 1980 to week 25 2012), OpenSIGLE (searched 26 June 2012), clinical trials registries and reference lists of relevant articles. We included publications reporting data from randomised or quasi-randomised controlled trials comparing the effectiveness of dilatation, urethrotomy and urethroplasty in the treatment of adult men with urethral stricture disease. Two authors evaluated trials for appropriateness for inclusion and methodological quality. Data extraction was performed using predetermined criteria. Analyses were carried out using the Cochrane Review Manager software (RevMan 5). Two randomised trials were identified. One trial compared the outcomes of surgical urethral dilatation and optical urethrotomy in 210 adult men with urethral stricture disease. No significant difference was found in the proportion of men being stricture free at three years or in the median time to recurrence. The second trial compared the outcomes of urethrotomy and urethroplasty in 50 men with traumatic stricture of the posterior urethra following pelvic fracture injury. In the first six months, men were more likely to require further surgery in the urethrotomy group than in the primary urethroplasty group (RR 3.39, 95% CI 1.62 to 7.07). After two years, 16 of 25 (64%) men initially treated by urethrotomy required continued self-dilatation or further surgery for stricture recurrence compared to 6 of 25 (24%) men treated by primary urethroplasty. There were insufficient data to perform meta-analysis or to reliably determine effect size. There were insufficient data to determine which intervention is best for urethral stricture disease in terms of balancing efficacy, adverse effects and costs. Well designed, adequately powered multi-centre trials are needed to answer relevant clinical questions regarding treatment of men with urethral strictures.


Pharmacological prophylaxis has been proven to reduce the risk of cardiovascular events in patients with atherosclerotic occlusive arterial disease. However, the role of prophylaxis in patients with abdominal aortic aneurysm (AAA) remains unclear. Several studies have shown that despite successful repair, those with AAA have a poorer rate of survival than healthy controls. People with AAA have an increased prevalence of coronary heart disease and risk of cardiovascular events. Despite this association, little is known about the effectiveness of pharmacological prophylaxis in reducing cardiovascular risk in people with AAA. To determine the long-term effectiveness of antiplatelet, antihypertensive or lipid-lowering medication in reducing mortality and cardiovascular events in people with abdominal aortic aneurysm (AAA). The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched April 2013) and CENTRAL (2013, Issue 3). Reference lists of relevant articles were also checked. Randomised controlled trials in which people with AAA were randomly allocated to one prophylactic treatment versus another, a different regimen of the same treatment, a placebo, or no treatment were eligible for inclusion in this review. Primary outcomes included all-cause mortality and cardiovascular mortality. Selection of the studies, quality assessment and data extraction were completed independently by two review authors. Any disagreements were resolved by discussion. Only one study was included in the review, therefore meta-analysis could not be performed. One randomised controlled study was included in the review. A subgroup of 227 patients with AAA received either metoprolol (N = 111) or placebo (N = 116). There was no clear evidence that metoprolol reduced all-cause mortality (odds ratio (OR) 0.17, 95% confidence interval (CI) 0.02 to 1.41), cardiovascular death (OR 0.20, 95% CI 0.02 to 1.76), AAA-related death (OR 1.05, 95% CI 0.06 to 16.92) or increased nonfatal cardiovascular events (OR 1.44, 95% CI 0.58 to 3.57) 30 days postoperatively. Furthermore, at six months postoperatively, estimated effects were compatible with benefit and harm for all-cause mortality (OR 0.71, 95% CI 0.26 to 1.95), cardiovascular death (OR 0.73, 95% CI 0.23 to 2.39) and nonfatal cardiovascular events (OR 1.41, 95% CI 0.59 to 3.35). Adverse drug effects were reported for the whole study population and were not available for the subgroup of participants with AAA. The study was deemed to be at a generally low risk of bias. Due to the limited number of trials, there is insufficient evidence to draw any conclusions about the effectiveness of cardiovascular prophylaxis in reducing mortality and cardiovascular events in people with AAA. Further good-quality randomised controlled trials examining many types of prophylaxis with long-term follow-up are required before firm conclusions can be made.


Kamali F.,Northumbria University | Wynne H.,Freeman Hospital
Annual Review of Medicine | Year: 2010

Warfarin is a drug with a narrow therapeutic index and a wide interindividual variability in dose requirement. Because it is difficult to predict an accurate dose for an individual, patients starting the drug are at risk of thromboembolism or bleeding associated with underdosing or overdosing, respectively. Single nucleotide polymorphisms in the cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKOR) genes have been shown to have a significant effect on warfarin dose requirement. Other genes mediating the action of warfarin make either little or no contribution to dose requirement. Although the polymorphisms in CYP2C9 and VKORC1 explain a significant proportion of the interindividual variability in warfarin dose requirement, currently available evidence based on a few small studies relating to the use of pharmacogenetics-guided dosing in the initiation of warfarin therapy has not shown improved outcomes in either safety or efficacy of therapy. Better clinical evidence of beneficial effects on patient outcome, particularly at the extremes of the dose requirements in geographically and ethnically diverse patient populations, is needed before the role of a pharmacogenomic approach to oral anticoagulation therapy in clinical practice can be established. © 2010 by Annual Reviews All rights reserved.


To determine whether low-dose ciclosporin was a more effective corticosteroid-sparing agent than AZA in patients with SLE. Patients with SLE requiring a change or initiation of a corticosteroid-sparing agent and who were taking > or =15 mg of prednisolone/day were randomized to receive either ciclosporin or AZA during this 12-month open-label multi-centre trial. There were strict guidelines for the reduction of prednisolone. The primary outcome was the absolute mean change in prednisolone. Eighty-nine patients were randomized. Using an intention-to-treat analysis, the absolute mean change in prednisolone dose between baseline and 12 months, adjusted for baseline prednisolone dose, was 9.0 mg for ciclosporin (95% CI 7.2, 10.8) and 10.7 mg for AZA (95% CI 8.8, 12.7). The difference in the change between treatment groups was -1.7 mg (95% CI -4.4, 0.9; P = 0.2). No significant differences were detected for the secondary outcomes: change in disease activity [classic British Isles Lupus Assessment Group (BILAG) index], number of flares, development of new damage or change in quality of life. A similar number of patients in each arm stopped the study drugs due to adverse events and ineffectiveness. No patient developed severe hypertension or a persistent rise in creatinine. One patient in the ciclosporin arm developed a significant increase in proteinuria due to disease activity. Both drugs were effective corticosteroid-sparing agents. Ciclosporin was not a more effective corticosteroid-sparing agent. Ciclosporin may be considered in patients who are unable to tolerate AZA. Patients on ciclosporin require close monitoring of blood pressure and creatinine. Current Controlled Trials, http://www.controlled-trials.com/, ISRCTN35919612.


MacDonald S.,Freeman Hospital
CardioVascular and Interventional Radiology | Year: 2012

The carotid stenting trialists have demonstrated persistence and determination in comparing an evolving technique, carotid artery stenting (CAS), against a mature and exacting standard for carotid revascularisation, carotid endarterectomy (CEA). This review focuses on their endeavours. A total of 12 1-on-1 randomised trials comparing CAS and CEA have been reported; 6 of these can be considered major, and 5 of these reflect (in part) current CAS standards of practice and form the basis of this review. At least 18 meta-analyses seeking to compare CAS and CEA exist. These are limited by the quality and heterogeneity of the data informing them (e.g., five trials were stopped prematurely such that they collectively failed to reach recruitment target by >4000 patients). The Carotid Stenting Trialists' Collaboration Publication represents a prespecified meta-analysis of European trials that were sufficiently similar to allow valid conclusions to be drawn; these trials and conclusions will be explored. When the rate of myocardial infarction (MI) is rigorously assessed, CAS and CEA are equivalent for the composite end point of stroke/death and MI, with more minor strokes for CAS and more MIs for CEA. These outcomes have a discrepant impact on quality of life and subsequent mortality. The all-stroke death outcomes for patients <70 years old are equivalent, with more minor strokes occurring in the elderly during CAS than CEA. There are significantly more severe haematomas and cranial nerve injuries after CEA. The influence of experience on outcome cannot be underestimated. © 2011 Springer Science+Business Media, LLC and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).


Ferguson L.P.,Freeman Hospital | Durward A.,Evelina Childrens Hospital | Tibby S.M.,Evelina Childrens Hospital
Circulation | Year: 2012

Background-Observational studies in adults have shown a worse outcome associated with hyperoxia after resuscitation from cardiac arrest. Extrapolating from adult data, current pediatric resuscitation guidelines recommend avoiding hyperoxia. We investigated the relationship between arterial partial oxygen pressure and survival in patients admitted to the pediatric intensive care unit (PICU) after cardiac arrest. Methods and Results-We conducted a retrospective cohort study using the Pediatric Intensive Care Audit Network (PICANet) database between 2003 and 2010 (n=122 521). Patients aged <16 years with documented cardiac arrest preceding PICU admission and arterial blood gas analysis taken within 1 hour of PICU admission were included. The primary outcome measure was death within the PICU. The relationship between postarrest oxygen status and outcome was modeled with logistic regression, with nonlinearities explored via multivariable fractional polynomials. Covariates included age, sex, ethnicity, congenital heart disease, out-of-hospital arrest, year, Pediatric Index of Mortality-2 (PIM2) mortality risk, and organ supportive therapies. Of 1875 patients, 735 (39%) died in PICU. Based on the first arterial gas, 207 patients (11%) had hyperoxia (PaO 2 ≥300 mm Hg) and 448 (24%) had hypoxia (PaO 2 <60 mm Hg). We found a significant nonlinear relationship between PaO 2 and PICU mortality. After covariate adjustment, risk of death increased sharply with increasing hypoxia (odds ratio, 1.92; 95% confidence interval, 1.80-2.21 at PaO 2 of 23 mm Hg). There was also an association with increasing hyperoxia, although not as dramatic as that for hypoxia (odds ratio, 1.25; 95% confidence interval, 1.17-1.37 at 600 mm Hg). We observed an increasing mortality risk with advancing age, which was more pronounced in the presence of congenital heart disease. Conclusions-Both severe hypoxia and, to a lesser extent, hyperoxia are associated with an increased risk of death after PICU admission after cardiac arrest. © 2012 American Heart Association, Inc.

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