Imaging biomarker roadmap for cancer studies.

Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing 'translational gaps' through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored 'roadmap'. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use.Development of this roadmap received support from Cancer Research UK and the Engineering and Physical Sciences Research Council (grant references A/15267, A/16463, A/16464, A/16465, A/16466 and A/18097), the EORTC Cancer Research Fund, and the Innovative Medicines Initiative Joint Undertaking (grant agreement number 115151), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies' in kind contribution

Imaging biomarker roadmap for cancer studies.

Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing 'translational gaps' through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored 'roadmap'. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use.Development of this roadmap received support from Cancer Research UK and the Engineering and Physical Sciences Research Council (grant references A/15267, A/16463, A/16464, A/16465, A/16466 and A/18097), the EORTC Cancer Research Fund, and the Innovative Medicines Initiative Joint Undertaking (grant agreement number 115151), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies' in kind contribution

Dose in stroke rehabilitation trials

Background: the dose and the length of rehabilitative interventions for optimal motor recovery after stroke are unknown. Dose optimization studies are required as precursors to efficacy trials, but are rarely conducted in stroke rehabilitation research. Objective: to overcome the knowledge gap on appropriate dose and length of rehabilitative interventions guiding the implementation of novel effective approaches to dose optimization in stroke rehabilitation research. Method: two systematic reviews on dose optimization in exercise-based training and pharmaceutical clinical research guided the development of a new approach to dose-finding suitable for physical interventions. The feasibility of a novel phase I 3+3 rule-based, outcome-adaptive dose-finding design was assessed with stroke survivors with moderate upper limb paresis. Moreover, the feasibility of a repetitive assessment procedure to identify the appropriate length of motor interventions was explored in stroke rehabilitation research. Results: the first literature review showed a lack of reliable approaches to dose optimization in exercise-based training. The review of pharmaceutical research highlighted dose optimization “gold” standard approaches, and helped in devising the dose-finding study for physical intervention. The dose-finding study was feasible using the applied model-task intervention. Preliminary explorations on the dose-response relationship were possible indicating a maximum tolerable dose and a potential recommended dose of 209 and 162 repetitions respectively of the applied intervention-task. The repetitive assessment procedure was found feasible in a clinical efficacy stroke rehabilitative trial. The repetitive assessment procedure provided relevant data on the therapy effect over-time showing that more than six weeks of the applied upper limb intervention may be necessary to reach maximal therapy effects. Whereas, five weeks of intervention appeared enough to exploit therapy effects for the lower limb. Conclusions: results are promising on identifying relevant dose and protocol endpoints implementing dose-finding and repetitive assessments approaches in stroke rehabilitation. Further confirmative data are needed to validate these findings

Type 2 diabetes prevention in high-risk individuals :how might effective, equitable and sustainable service provison be achieved?

PhD ThesisBackground: Prevalence of type 2 diabetes (T2D) is rapidly increasing worldwide, linked to the obesity epidemic. There is substantial research evidence for T2D prevention by lifestyle interventions in high-risk individuals. The span of this research provides a unique case study with which to critically examine general guidance for development and evaluation of interventions to improve health. My research question is how might can effective, equitable and sustainable service provision for T2D prevention in high-risk individuals be achieved? Methods: Five papers reporting my empirical T2D prevention research form the core of my thesis. This research extends from the European Diabetes Prevention Study (EDIPS) RCT to the ‘New life, New you’ (NLNY) feasibility study. NLNY is a community based lifestyle intervention to reduce T2D incidence that is delivered by fitness trainers in North East England. To inform my research question I have reviewed intervention guidance history. I have then used T2D prevention as a case study, supported by my empirical research experience, to analyse this guidance Findings: Development of the NLNY intervention built on the EDIPS RCT evidence and experience. Pilot evaluation of NLNY suggests a feasible and acceptable intervention that is likely to be effective in preventing T2D. Prevention of T2D provided a useful exemplar for analysis of intervention guidance and highlighted strengths and limitations of existing guidance models. This analysis led to a proposed new guidance framework. Conclusions: The NLNY intervention provides a potential service provision model for T2D prevention in high-risk individuals. Well planned effectiveness and cost-effectiveness evaluation of the NLNY intervention is now needed. The analysis of intervention guidance and the proposed new framework will contribute to developing a robust study design. If effectiveness of the NLNY intervention is demonstrated there is potential for this community based intervention model to be further developed and adapted

Rehabilitation for improving automobile driving after stroke

Publisher version made available in accordance with the publisher's policy. This item is under embargo for a period of 12 months from the date of publication, in accordance with the publisher's policy. 'This review is published as a Cochrane Review in the Cochrane Database of Systematic Reviews 2014, Issue 2. Cochrane Reviews are regularly updated as new evidence emerges and in response to comments and criticisms, and the Cochrane Database of Systematic Reviews should be consulted for the most recent version of the Review.’Background Interventions to improve driving ability after stroke, incl uding driving simulation and retraining visual skills, hav e limited evaluation of their effectiveness to guide policy and practice. Objectives To determine whether any intervention, with the specific aim o f maximising driving skills, improves the driving performa nce of people after stroke. Search methods WesearchedtheCochrane Stroke GroupTrialsregister(August 2 013), theCochrane Central Registerof ControlledTrials( The Cochrane Library 2012, Issue 3), MEDLINE (1950 to October 2013), EMBASE (1980 to Octo ber 2013), and six additional databases. To identify further published, unpublished and ongoing trial s, we handsearched relevant journals and conference proceeding s, searched trials and research registers, checked reference lists and conta cted key researchers in the area. Selection criteria Randomised controlled trials (RCTs), quasi-randomised trials and cluster studies of rehabilitation interventions, with t he specific aim of maximising driving skills or with an outcome of assessing d riving skills in adults after stroke. The primary outcome of i nterest was the performance in an on-road assessment after training. Secon dary outcomes included assessments of vision, cognition and dr iving behaviour. Data collection and analysis Two review authors independently selected trials based on pr e-defined inclusion criteria, extracted the data and assessed ri sk of bias. A third review author moderated disagreements as required. T he review authors contacted all investigators to obtain missi ng information. Main results We included four trials involving 245 participants in the revi ew. Study sample sizes were generally small, and interventi ons, controls and outcome measures varied, and thus it was inappropriate to pool studies. Included studies were at a low risk of bias for th e majority of domains, with a high/unclear risk of bias identified in the a reas of: performance (participants not blinded to allocation), a nd attrition (incomplete outcome data due to withdrawal) bias. Interventio n approaches included the contextual approach of driving simula tion and underlying skill development approach, including the ret raining of speed of visual processing and visual motor skills . The studies were conducted with people who were relatively young and the ti ming after stroke was varied. Primary outcome: there was no cle ar evidence of improved on-road scores immediately after trainin g in any of the four studies, or at six months (mean difference 15 points on the Test Ride for Investigating Practical Fitness to Drive - Belgian version, 95% confidence intervals (CI) 4.56 to 34.56, P v alue = 0.15, one study, 83 participants). Secondary outcomes: road sig n recognition was better in people who underwent training comp ared with control (mean difference 1.69 points on the Road Sign Recogn ition Task of the Stroke Driver Screening Assessment, 95% CI 0 .51 to 2.87, P value = 0.007, one study, 73 participants). Significan t findings were in favour of a simulator-based driving rehabil itation programme (based on one study with 73 participants) but these r esults should be interpreted with caution as they were based o n a single study. Adverse effects were not reported. There was insufficie nt evidence to draw conclusions on the effects on vision, other me asures of cognition, motor and functional activities, and driving beh aviour with the intervention. Authors’ conclusions There was insufficient evidence to reach conclusions about the use of rehabilitation to improve on-road driving skills after st roke. We found limited evidence that the use of a driving simulator m ay be beneficial in improving visuocognitive abilities, such as road sign recognition that are related to driving. Moreover, we we re unable to find any RCTs that evaluated on-road driving lesso ns as an intervention. At present, it is unclear which impairments tha t influence driving ability after stroke are amenable to rehab ilitation, and whether the contextual or remedial approaches, or a combinatio n of both, are more efficacious

Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer

INTRODUCTION Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice. METHODS More than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer 'stem' cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account. RESULTS The 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working. CONCLUSIONS With resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years

Preoperative supervised exercise and outcomes following elective abdominal aortic aneurysm repair

ObjectiveThe aim of this research was to evaluate the role of preoperative supervised exercise training on perioperative outcomes and cardiopulmonary exercise testing (CPET) parameters in patients undergoing elective abdominal aortic aneurysm (AAA) repair, and to analyse the value of different preoperative risk assessment tools in predicting postoperative complications following this intervention.MethodsParticipants in this project were patients with large AAA (≥ 5.5 cm), awaiting elective open or endovascular repair.Study 1: was a prospective randomised controlled trial. Participants were randomised in two parallel groups: a 6-week preoperative exercise training programme or standard treatment.The primary outcome measure was the composite endpoint of postoperative cardiac, pulmonary and renal complications. Secondary outcome measures were: lengths of hospital and critical care stay, APACHE II scores recorded within 6 hours postoperatively, SIRS criteria, thirty-day mortality, reoperation and postoperative bleeding. Patients were followed up for 3 months postoperatively.Study 2: was a sub-group study within Study 1.A sub-group of patients from Study 1 consented to undergo two rather than one preoperative CPETs: the first at baseline, and a second following completion of 6 weeks of exercise or on the day immediately prior to surgery. The primary outcome measure was the effect of exercise on CPET parameters.Study 3 utilised univariate and multivariate analysis to assess the value of different preoperative risk assessment tools in predicting postoperative complications in patients undergoing elective AAA repair.Results:Study 1: 136 patients were recruited, 12 withdrew before operative interventions and were not included in the analysis. A total of 124 patients (62 in each group) were included (111 men, mean (s.d.) age 73 (7) years), of which 46 patients underwent EVAR (23 in each group).14 patients (22.6 per cent) sustained postoperative complications in the exercise group, compared to 26 (41.9 per cent) in the non-exercise group (P=0.021). Four patients (3.2 per cent; 2 in each group) died within 30 days postoperatively.Length of hospital stay was significantly shorter in the exercise group (median (IQR) 7 (5-9) days) than the control group (median (IQR) 8 (6.0 - 12.3) days) (P=0.025).There were no significant differences in the length of critical care stay (P=0.845), APACHE II scores (P=0.256), incidence of re-operations (P=1.000) or postoperative bleeding (P=0.343) between the two study groups.Study 2: 48 patients were recruited: 33 patients in the exercise group, and 15 in the control group. All participants completed their two CPET assessments. A 6-week exercise schedule improved aerobic fitness parameters compared to the control group. Median (IQR) VO2 peak improved from 18.4 (15.0-20.9) to 20.0 (16.9-21.3) ml O2/kg/min; P=0.004, and median AT improved from 12.0 (10.4-14.5) to 13.9 (10.6-15.1) ml O2/kg/min; P=0.012. There were no statistically significant changes in CPET parameters in the control group.Study 3: In 124 patients undergoing elective AAA repair, lower AT (OR 0.59, 9% C.I. 0.38 to 0.89, p=0.014) and higher V-POSSUM scores (OR 1.42, 95% C.I. 1.16 to 1.75, p=0.001) were the only independent predictors of postoperative complications.A low AT was an independent predictor of cardiac complications (OR 0.59, 95% C.I. 0.36 to 0.96, p=0.034) and a high VE/VCO2 predicted pulmonary complications (OR 1.24, 95% C.I. 1.03 to 1.51, p=0.027).ConclusionPreoperative supervised exercise training appears to reduce postoperative complications and length of hospital stay in patients undergoing elective AAA repair. The mechanism appears to be an improvement in aerobic fitness preoperatively.CPET is a valuable preoperative assessment tool for elective AAA patients as it predicts organ-specific complications and may be useful in directing perioperative care

Timely and reliable evaluation of the effects of interventions: a framework for adaptive meta-analysis (FAME)

Most systematic reviews are retrospective and use aggregate data AD) from publications, meaning they can be unreliable, lag behind therapeutic developments and fail to influence ongoing or new trials. Commonly, the potential influence of unpublished or ongoing trials is overlooked when interpreting results, or determining the value of updating the meta-analysis or need to collect individual participant data (IPD). Therefore, we developed a Framework for Adaptive Metaanalysis (FAME) to determine prospectively the earliest opportunity for reliable AD meta-analysis. We illustrate FAME using two systematic reviews in men with metastatic (M1) and non-metastatic (M0)hormone-sensitive prostate cancer (HSPC)