Bethan Copsey

A Multi-institutional Analysis of Perioperative Outcomes in 106 Men Who Underwent Radical Prostatectomy for Distant Metastatic Prostate Cancer at Presentation

BACKGROUND Current trials are investigating radical intervention in men with metastatic prostate cancer. However, there is a lack of safety data for radical prostatectomy as therapy in this setting. OBJECTIVE To examine perioperative outcomes and short-term complications after radical prostatectomy for locally resectable, distant metastatic prostate cancer. DESIGN, SETTING, AND PARTICIPANTS A retrospective case series from 2007 to 2014 comprising 106 patients with newly diagnosed metastatic (M1) prostate cancer from the USA, Germany, Italy, and Sweden. INTERVENTION Radical prostatectomy and extended pelvic lymphadenectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Descriptive statistics were used to present margin status, continence, and readmission, reoperation, and overall complication rates at 90 d, as well as for 21 specific complications. Kaplan-Meier plots were used to estimate survival function. Intercenter variability and M1a/ M1b subgroups were examined. RESULTS AND LIMITATIONS Some 79.2% of patients did not suffer any complications; positive-margin (53.8%), lymphocele (8.5%), and wound infection (4.7%) rates were higher in our cohort than in a meta-analysis of open radical prostatectomy performed for standard indications. At a median follow-up of 22.8 mo, 94/106 (88.7%) men were still alive. The study is limited by its retrospective design, differing selection criteria, and short follow-up. CONCLUSIONS Radical prostatectomy for men with locally resectable, distant metastatic prostate cancer appears safe in expert hands for meticulously selected patients. Overall and specific complication rates related to the surgical extirpation are not more frequent than when radical prostatectomy is performed for standard indications, and the use of extended pelvic lymphadenectomy in all of this cohort compared to its selective use in localized/locally advanced prostate cancer accounts for any extra morbidity. PATIENT SUMMARY Men presenting with advanced prostate cancer that has spread beyond the prostate are increasingly being considered for treatments directed at the prostate itself. On the basis of results for our international series of 106 men, surgery appears reasonably safe in this setting for certain patients.

The Effectiveness of Cognitive Behavioural Treatment for Non-Specific Low Back Pain: A Systematic Review and Meta-Analysis.

Objectives To assess whether cognitive behavioural (CB) approaches improve disability, pain, quality of life and/or work disability for patients with low back pain (LBP) of any duration and of any age. Methods Nine databases were searched for randomised controlled trials (RCTs) from inception to November 2014. Two independent reviewers rated trial quality and extracted trial data. Standardised mean differences (SMD) and 95% confidence intervals were calculated for individual trials. Pooled effect sizes were calculated using a random-effects model for two contrasts: CB versus no treatment (including wait-list and usual care (WL/UC)), and CB versus other guideline-based active treatment (GAT). Results The review included 23 studies with a total of 3359 participants. Of these, the majority studied patients with persistent LBP (>6 weeks; n=20). At long term follow-up, the pooled SMD for the WL/UC comparison was -0.19 (-0.38, 0.01) for disability, and -0.23 (-0.43, -0.04) for pain, in favour of CB. For the GAT comparison, at long term the pooled SMD was -0.83 (-1.46, -0.19) for disability and -0.48 (-0.93, -0.04) for pain, in favour of CB. While trials varied considerably in methodological quality, and in intervention factors such as provider, mode of delivery, dose, duration, and pragmatism, there were several examples of lower intensity, low cost interventions that were effective. Conclusion CB interventions yield long-term improvements in pain, disability and quality of life in comparison to no treatment and other guideline-based active treatments for patients with LBP of any duration and of any age. Systematic Review Registration PROSPERO protocol registration number: CRD42014010536.

Physiotherapist-delivered cognitive-behavioural interventions are effective for low back pain, but can they be replicated in clinical practice? A systematic review

Abstract Purpose: To determine if physiotherapist-led cognitive-behavioural (CB) interventions are effective for low back pain (LBP) and described sufficiently for replication. Method: Randomised controlled trials (RCTs) of patients with LBP treated by physiotherapists using a CB intervention were included. Outcomes of disability, pain, and quality of life were assessed using the GRADE approach. Intervention reporting was assessed using the Template for Intervention Description and Replication. Results: Of 1898 titles, 5 RCTs (n = 1390) were identified. Compared to education and/or exercise interventions, we found high-quality evidence that CB had a greater effect (SMD; 95% CI) on reducing disability (−0.19; −0.32, −0.07), pain (−0.21; −0.33, −0.09); and moderate-quality evidence of little difference in quality of life (−0.06; −0.18 to 0.07). Sufficient information was provided on dose, setting, and provider; but not content and procedural information. Studies tended to report the type of CB component used (e.g., challenging unhelpful thoughts) with little detail on how it was operationalised. Moreover, access to treatment manuals, patient materials and provider training was lacking. Conclusions: With additional training, physiotherapists can deliver effective CB interventions. However, without training or resources, successful translation and implementation remains unlikely. Researchers should improve reporting of procedural information, provide relevant materials, and offer accessible provider training. Implications for Rehabilitation Previous reviews have established that traditional biomedical-based treatments (e.g., acupuncture, manual therapy, massage, and specific exercise programmes) that focus only on physical symptoms do provide short-term benefits but the sustained effect is questionable. A cognitive-behavioural (CB) approach includes techniques to target both physical and psychosocial symptoms related to pain and provides patients with long-lasting skills to manage these symptoms on their own. This combined method has been used in a variety of settings delivered by different health care professionals and has been shown to produce long-term effects on patient outcomes. What has been unclear is if these programmes are effective when delivered by physiotherapists in routine physiotherapy settings. Our study synthesises the evidence for this context. We have confirmed with high-quality evidence that with additional training, physiotherapists can deliver CB interventions that are effective for patients with back pain. Physiotherapists who are considering enhancing their treatment for patients with low back pain should consider undertaking some additional training in how to incorporate CB techniques into their practice to optimise treatment benefits and help patients receive long-lasting treatment effects. Importantly, our results indicate that using a CB approach, including a variety of CB techniques that could be easily adopted in a physical therapy setting, provides greater benefits for patient outcomes compared to brief education, exercise or physical techniques (such as manual therapy) alone. This provides further support that a combined treatment approach is likely better than one based on physical techniques alone. Notably, we identified a significant barrier to adopting any of these CB interventions in practice. This is because no study provided a description of the intervention or accessible training materials that would allow for accurate replication. Without access to provider training and/or resources, we cannot expect this evidence to be implemented in practice with optimal effects. Thus, we would urge physiotherapists to directly contact authors of the studies for more information on how to incorporate their interventions into their settings.

Association between trial registration and positive study findings: cross sectional study (Epidemiological Study of Randomized Trials-ESORT).

Abstract Objective To assess whether randomised controlled trials (RCTs) that were registered were less likely to report positive study findings compared with RCTs that were not registered and whether the association varied by funding source. Design Cross sectional study. Study sample All primary RCTs published in December 2012 and indexed in PubMed by November 2013. Trial registration was determined based on the report of a trial registration number in published RCTs or the identification of the trial in a search of trial registries. Trials were separated into prospectively and retrospectively registered studies. Main outcome measure Association between trial registration and positive study findings. Results 1122 eligible RCTs were identified, of which 593 (52.9%) were registered and 529 (47.1%) were not registered. Overall, registration was marginally associated with positive study findings (adjusted risk ratio 0.87, 95% confidence interval 0.78 to 0.98), even with stratification as prospectively and retrospectively registered trials (0.87, 0.74 to 1.03 and 0.88, 0.78 to 1.00, respectively). The interaction term between overall registration and funding source was marginally statistically significant and relative risk estimates were imprecise (0.75, 0.63 to 0.89 for non-industry funded and 1.03, 0.79 to 1.36 for industry funded, P interaction=0.046). Furthermore, a statistically significant interaction was not maintained in sensitivity analyses. Within each stratum of funding source, relative risk estimates were also imprecise for the association between positive study findings and prospective and retrospective registration. Conclusion Among published RCTs, there was little evidence of a difference in positive study findings between registered and non-registered clinical trials, even with stratification by timing of registration. Relative risk estimates were imprecise in subgroups of non-industry and industry funded trials.

Study protocol: A multi-centre, double blind, randomised, placebo-controlled, parallel group, phase II trial (RIDD) to determine the efficacy of intra-nodular injection of anti-TNF to control disease progression in early Dupuytren's disease, with an embedded dose response study.

Dupuytrens disease is a common fibrotic condition of the hand affecting 4% of the population and causes the fingers to curl irreversibly into the palm. It has a strong familial tendency, there is no approved treatment for early stage disease, and patients with established digital contractures are most commonly treated by surgery. This is associated with prolonged recovery, and less invasive techniques have high recurrence rates.The myofibroblasts, the cells responsible for the excessive matrix deposition and contraction, are aggregated in nodules. Using excised diseased and control human tissue, we found that immune cells interspersed amongst the myofibroblasts secrete cytokines. Of these, only tumour necrosis factor (TNF) promoted the development of myofibroblasts. The clinically approved anti-TNF agents led to inhibition of the myofibroblast phenotype in vitro. This clinical trial is designed to assess the efficacy of the anti-TNF agent adalimumab on participants with early disease. The first part is a dose-ranging study where nodules of participants already scheduled for surgery will be injected with either placebo (saline) or varying doses of adalimumab. The excised tissue will then be analysed for markers of myofibroblast activity.The second part of the study will recruit participants with early stage disease. They will be randomised 1: 1 to receive either adalimumab or placebo at 3 month intervals over 1 year and will then be followed for a further 6 months. Outcome measures will include nodule hardness, size and disease progression. The trial will also determine the cost-effectiveness of adalimumb treatment for this group of participants.

Current practice in methodology and reporting of the sample size calculation in randomised trials of hip and knee osteoarthritis: a protocol for a systematic review.

BackgroundA key aspect of the design of randomised controlled trials (RCTs) is determining the sample size. It is important that the trial sample size is appropriately calculated. The required sample size will differ by clinical area, for instance, due to the prevalence of the condition and the choice of primary outcome. Additionally, it will depend upon the choice of target difference assumed in the calculation. Focussing upon the hip and knee osteoarthritis population, this study aims to systematically review how the trial size was determined for trials of osteoarthritis, on what basis, and how well these aspects are reported.MethodsSeveral electronic databases (Medline, Cochrane library, CINAHL, EMBASE, PsycINFO, PEDro and AMED) will be searched to identify articles on RCTs of hip and knee osteoarthritis published in 2016. Articles will be screened for eligibility and data extracted independently by two reviewers. Data will be extracted on study characteristics (design, population, intervention and control treatments), primary outcome, chosen sample size and justification, parameters used to calculate the sample size (including treatment effect in control arm, level of variability in primary outcome, loss to follow-up rates). Data will be summarised across the studies using appropriate summary statistics (e.g. n and %, median and interquartile range). The proportion of studies which report each key component of the sample size calculation will be presented. The reproducibility of the sample size calculation will be tested.DiscussionThe findings of this systematic review will summarise the current practice for sample size calculation in trials of hip and knee osteoarthritis. It will also provide evidence on the completeness of the reporting of the sample size calculation, reproducibility of the chosen sample size and the basis for the values used in the calculation.Trial registrationAs this review was not eligible to be registered on PROSPERO, the summary information was uploaded to Figshare to make it publicly accessible in order to avoid unnecessary duplication amongst other benefits (https://doi.org/10.6084/m9.figshare.5009027.v1); Registered January 17, 2017.

Aerobic and strength training exercise programme for cognitive impairment in people with mild to moderate dementia: the DAPA RCT.

BACKGROUND Approximately 670,000 people in the UK have dementia. Previous literature suggests that physical exercise could slow dementia symptom progression. OBJECTIVES To estimate the clinical effectiveness and cost-effectiveness of a bespoke exercise programme, in addition to usual care, on the cognitive impairment (primary outcome), function and health-related quality of life (HRQoL) of people with mild to moderate dementia (MMD) and carer burden and HRQoL. DESIGN Intervention development, systematic review, multicentred, randomised controlled trial (RCT) with a parallel economic evaluation and qualitative study. SETTING 15 English regions. PARTICIPANTS People with MMD living in the community. INTERVENTION A 4-month moderate- to high-intensity, structured exercise programme designed specifically for people with MMD, with support to continue unsupervised physical activity thereafter. Exercises were individually prescribed and progressed, and participants were supervised in groups. The comparator was usual practice. MAIN OUTCOME MEASURES The primary outcome was the Alzheimers Disease Assessment Scale - Cognitive Subscale (ADAS-Cog). The secondary outcomes were function [as measured using the Bristol Activities of Daily Living Scale (BADLS)], generic HRQoL [as measured using the EuroQol-5 Dimensions, three-level version (EQ-5D-3L)], dementia-related QoL [as measured using the Quality of Life in Alzheimers Disease (QoL-AD) scale], behavioural symptoms [as measured using the Neuropsychiatric Inventory (NPI)], falls and fractures, physical fitness (as measured using the 6-minute walk test) and muscle strength. Carer outcomes were HRQoL (Quality of Life in Alzheimers Disease) (as measured using the EQ-5D-3L) and carer burden (as measured using the Zarit Burden Interview). The economic evaluation was expressed in terms of incremental cost per quality-adjusted life-year (QALY) gained from a NHS and Personal Social Services perspective. We measured health and social care use with the Client Services Receipt Inventory. Participants were followed up for 12 months. RESULTS Between February 2013 and June 2015, 494 participants were randomised with an intentional unequal allocation ratio: 165 to usual care and 329 to the intervention. The mean age of participants was 77 years [standard deviation (SD) 7.9 years], 39% (193/494) were female and the mean baseline ADAS-Cog score was 21.5 (SD 9.0). Participants in the intervention arm achieved high compliance rates, with 65% (214/329) attending between 75% and 100% of sessions. Outcome data were obtained for 85% (418/494) of participants at 12 months, at which point a small, statistically significant negative treatment effect was found in the primary outcome, ADAS-Cog (patient reported), with a mean difference of -1.4 [95% confidence interval (CI) -2.62 to -0.17]. There were no treatment effects for any of the other secondary outcome measures for participants or carers: for the BADLS there was a mean difference of -0.6 (95% CI -2.05 to 0.78), for the EQ-5D-3L a mean difference of -0.002 (95% CI -0.04 to 0.04), for the QoL-AD scale a mean difference of 0.7 (95% CI -0.21 to 1.65) and for the NPI a mean difference of -2.1 (95% CI -4.83 to 0.65). Four serious adverse events were reported. The exercise intervention was dominated in health economic terms. LIMITATIONS In the absence of definitive guidance and rationale, we used a mixed exercise programme. Neither intervention providers nor participants could be masked to treatment allocation. CONCLUSIONS This is a large well-conducted RCT, with good compliance to exercise and research procedures. A structured exercise programme did not produce any clinically meaningful benefit in function or HRQoL in people with dementia or on carer burden. FUTURE WORK Future work should concentrate on approaches other than exercise to influence cognitive impairment in dementia. TRIAL REGISTRATION Current Controlled Trials ISRCTN32612072. FUNDING This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full programme and will be published in full in Health Technology Assessment Vol. 22, No. 28. See the NIHR Journals Library website for further project information. Additional funding was provided by the Oxford NIHR Biomedical Research Centre and the Oxford NIHR Collaboration for Leadership in Applied Health Research and Care.

The mediating effect of changes in hand impairments on hand function in patients with rheumatoid arthritis: Exploring the mechanisms of an effective exercise programme.

To determine whether the effect of the Strengthening and Stretching for Rheumatoid Arthritis of the Hand (SARAH) exercise program on hand function was mediated by changes in the proposed active ingredients: strength, dexterity, and/or range of motion.

Problems persist in reporting of methods and results for the WOMAC measure in hip and knee osteoarthritis trials

PurposeThe Western Ontario and McMaster Universities Arthritis Index (WOMAC) is a commonly used outcome measure for osteoarthritis. There are different versions of the WOMAC (Likert, visual analogue or numeric scales). A previous review of trials published before 2010 found poor reporting and inconsistency in how the WOMAC was used. This review explores whether these problems persist.MethodsThis systematic review included randomised trials of hip and/or knee osteoarthritis published in 2016 that used the WOMAC. Data were extracted on the version used, score range, analysis and results of the WOMAC, and whether these details were clearly reported.ResultsThis review included 62 trials and 41 reported the WOMAC total score. The version used and item range for the WOMAC total score were unclear in 44% (n = 18/41) and 24% (n = 10/41) of trials, respectively. The smallest total score range was 0–10 (calculated by averaging 24 items scored 0–10); the largest was 0–2400 (calculated by summing 24 items scored 0–100). All trials reported the statistical analysis methods but only 29% reported the between-group mean difference and 95% confidence interval.ConclusionDetails on the use and scoring of the WOMAC were often not reported. We recommend that trials report the version of the WOMAC and the score range used. The between-group treatment effect and corresponding confidence interval should be reported. If all the items of the WOMAC are collected, the total score and individual subscale scores should be presented. Better reporting would facilitate the interpretation, comparison and synthesis of the WOMAC score in trials.

Anti-Tumour Necrosis Factor Therapy for Dupuytren's Disease: A Randomised Dose Response Proof of Concept Phase 2a Clinical Trial.

Background Dupuytrens disease is a common fibrotic condition of the hand that causes irreversible flexion contractures of the fingers, with no approved therapy for early stage disease. Our previous analysis of surgically-excised tissue defined tumour necrosis factor (TNF) as a potential therapeutic target. Here we assessed the efficacy of injecting nodules of Dupuytrens disease with a TNF inhibitor. Methods Patients were randomised to receive adalimumab on one occasion in dose cohorts of 15 mg in 0.3 ml, 35 mg in 0.7 ml, or 40 mg in 0.4 ml, or an equivalent volume of placebo in a 3:1 ratio. Two weeks later the injected tissue was surgically excised and analysed. The primary outcome measure was levels of mRNA expression for α-smooth muscle actin (ACTA2). Secondary outcomes included levels of α-SMA and collagen proteins. The trial was registered with ClinicalTrial.gov (NCT03180957) and the EudraCT (2015-001780-40). Findings We recruited 28 patients, 8 assigned to the 15 mg, 12 to the 35 mg and 8 to the 40 mg adalimumab cohorts. There was no change in mRNA levels for ACTA2, COL1A1, COL3A1 and CDH11. Levels of α-SMA protein expression in patients treated with 40 mg adalimumab (1.09 ± 0.09 ng per μg of total protein) were significantly lower (p = 0.006) compared to placebo treated patients (1.51 ± 0.09 ng/μg). The levels of procollagen type I protein expression were also significantly lower (p < 0.019) in the sub group treated with 40 mg adalimumab (474 ± 84 pg/μg total protein) compared with placebo (817 ± 78 pg/μg). There were two serious adverse events, both considered unrelated to the study drug. Interpretation In this dose-ranging study, injection of 40 mg of adalimumab in 0.4 ml resulted in down regulation of the myofibroblast phenotype as evidenced by reduction in expression of α-SMA and type I procollagen proteins at 2 weeks. These data form the basis of an ongoing phase 2b clinical trial assessing the efficacy of intranodular injection of 40 mg adalimumab in 0.4 ml compared to an equivalent volume of placebo in patients with early stage Dupuytrens disease. Funding Health Innovation Challenge Fund (Wellcome Trust and Department of Health) and 180 Therapeutics LP.