Keith Wheatley

University of Birmingham, Birmingham, England, United Kingdom

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Publications (203)1918.1 Total impact

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    ABSTRACT: Results. Recruitment and retention: N=47 participants were randomised over 17 months from 3 acute hospital trusts and 3 community therapy service locations in south west England (Fig. 2). N=32 (66.7%) completed the study. Study population: Participants had substantial loss of arm function at baseline: ARAT median score = 5, IQR= 14; WMFT median score = 6, IQR = 7. Median ratings for MAL amount of use and quality of movement in both groups were 0 at all time points. The SIS results were more normally distributed. Fidelity : The RTG intervention was feasible to deliver and well accepted by participants with 94% of intended visits completed. RTG participants performed a median of 157 repetitions per visit IQR (96, 211). It was difficult to determine the amount of independent practice as compliance with practice logging was limited. Acceptability: 96% participants rated the RTG training acceptable, 71% rated 1 hour of independent practice/day acceptable and 83% reported it improved arm function (Fig. 3). Treatment response: ARAT scores show improvements in median scores for the RTG group, while medians remained low and stable across time for the usual care group (Table 1, Fig. 4). Median number of WMFT tasks completed in less than 120 seconds increased in both groups over time. These results indicate that both assessments are sensitive to performance changes of the sample. Adverse events: the reported severity of upper limb pain on a 0-10 visual analogue scale at the end of the intervention period (7 weeks) was: RTG median (IQR) = 1.3 (0.0-3.3); usual care median (IQR) = 2.7 (0.0-5.0). The incidence of upper limb pain, reported at each of the therapy visits, was: RTG = 40/86 ; usual care = 40/82. Conclusions This study has shown that home-based task-specific RTG training appears to be an acceptable intervention and it is feasible to conduct an RCT with a usual care comparator. It was feasible to undertake a relatively high number of repetitions without additional adverse effects. The results from this study will provide valuable information for the planning of a Phase III RCT.
    The European Stroke Organisation Conference 2015, Glasgow, UK; 04/2015
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    ABSTRACT: Conventional chemotherapy is ineffective in the majority of patients with acute myeloid leukaemia (AML), and monoclonal antibodies recognising CD33 expressed on myeloid progenitors (e.g. gemtuzumab ozogamicin (GO)) have been reported to improve outcome in patients with AML. Reports of excess toxicity have resulted in GO’s licence being withdrawn. As a result, the role of these agents remains unclear. A systematic review and meta-analysis included studies of patients with AML who had entered a randomised control trial (RCT), where one arm included anti-CD33 antibody therapy. Fixed effect meta-analysis was used, involving calculation of observed minus expected number of events, and variance for each endpoint in each trial, with the overall treatment effect expressed as Peto’s odds ratio with 95 % confidence interval. Meta-analysis of 11 RCTs with 13 randomisations involving GO was undertaken. Although GO increased induction deaths (p = 0.02), it led to a reduction in resistant disease (p = 0.0009); hence, there was no improvement in complete remission. Whilst GO improved relapse-free survival (hazard ratio (HR) = 0.90, 95 % confidence interval (CI) = 0.84–0.98, p = 0.01), there was no overall benefit of GO in overall survival (OS) (HR = 0.96, 95 % CI = 0.90–1.02, p = 0.2). GO improved OS in patients with favourable cytogenetics, with no evidence of benefit in patients with intermediate or adverse cytogenetics (test for heterogeneity between subtotals p = 0.01). GO has a potent clinically detectable anti-leukaemic effect. Further trials to investigate its optimum delivery and identification of patient populations who may benefit are needed.
    Annals of Hematology 03/2015; 94(3). DOI:10.1007/s00277-014-2218-6 · 2.40 Impact Factor
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    ABSTRACT: Objective To evaluate the clinical efficacy of an established programme of occupational therapy in maintaining functional activity and reducing further health risks from inactivity in care home residents living with stroke sequelae. Design Pragmatic, parallel group, cluster randomised controlled trial. Setting 228 care homes (>10 beds each), both with and without the provision of nursing care, local to 11 trial administrative centres across the United Kingdom. Participants 1042 care home residents with a history of stroke or transient ischaemic attack, including those with language and cognitive impairments, not receiving end of life care. 114 homes (n=568 residents, 64% from homes providing nursing care) were allocated to the intervention arm and 114 homes (n=474 residents, 65% from homes providing nursing care) to standard care (control arm). Participating care homes were randomised between May 2010 and March 2012. Intervention Targeted three month programme of occupational therapy, delivered by qualified occupational therapists and assistants, involving patient centred goal setting, education of care home staff, and adaptations to the environment. Main outcome measures Primary outcome at the participant level: scores on the Barthel index of activities of daily living at three months post-randomisation. Secondary outcome measures at the participant level: Barthel index scores at six and 12 months post-randomisation, and scores on the Rivermead mobility index, geriatric depression scale-15, and EuroQol EQ-5D-3L questionnaire, at all time points. Results 64% of the participants were women and 93% were white, with a mean age of 82.9 years. Baseline characteristics were similar between groups for all measures, personal characteristics, and diagnostic tests. Overall, 2538 occupational therapy visits were made to 498 participants in the intervention arm (mean 5.1 visits per participant). No adverse events attributable to the intervention were recorded. 162 (11%) died before the primary outcome time point, and 313 (30%) died over the 12 months of the trial. The primary outcome measure did not differ significantly between the treatment arms. The adjusted mean difference in Barthel index score at three months was 0.19 points higher in the intervention arm (95% confidence interval −0.33 to 0.70, P=0.48). Secondary outcome measures also showed no significant differences at all time points. Conclusions This large phase III study provided no evidence of benefit for the provision of a routine occupational therapy service, including staff training, for care home residents living with stroke related disabilities. The established three month individualised course of occupational therapy targeting stroke related disabilities did not have an impact on measures of functional activity, mobility, mood, or health related quality of life, at all observational time points. Providing and targeting ameliorative care in this clinically complex population requires alternative strategies. Trial registration Current Controlled Trials ISRCTN00757750.
    British medical journal 02/2015; 350:h468. DOI:10.1136/bmj.h468
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    ABSTRACT: There is no consensus on the association between exposure to hydrocarbons and the risk of Parkinson's disease (PD). We conducted a systematic review and meta-analysis to summarise the epidemiological evidence and included a new large case-control study. Data were extracted following a predefined protocol. Risk estimates regarding the association between hydrocarbon exposure and PD were consolidated to produce a summary odds ratio (OR), 95% confidence intervals (CI), and p-value. In our case-control study, 1463 PD patients and 685 controls were recruited from clinical trials and completed a structured questionnaire describing their previous working exposure to hydrocarbons and other demographic measures. The association between exposure to hydrocarbons and risk of PD was evaluated using logistic regression. The systematic search identified 13 case-control studies matching the inclusion criteria. The meta-analysis included 3020 PD cases and 6494 controls. The summary OR was 1.32 (95% CI 1.08-1.62, p = 0.006) for hydrocarbon exposure (ever versus never). In the PD GEN study, occupational exposure to hydrocarbons significantly increased the risk of PD (OR = 1.61; 95% CI 1.10-2.36, p = 0.014), and risk dose-dependently increased for subjects exposed greater than 10 years compared to subjects never exposed (OR = 2.19; 95% CI 1.13-4.26, p = 0.021). The addition of PD GEN data increased the total numbers to 4483 PD cases and 7179 controls and strengthened the significant association (summary OR = 1.36; 95% CI 1.13-1.63, p = 0.001). This systematic review supports a positive association between hydrocarbon exposure and PD. Data from prospective studies are required to reinforce the relationship between hydrocarbon exposure and PD. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Parkinsonism & Related Disorders 12/2014; 21(3). DOI:10.1016/j.parkreldis.2014.12.017 · 4.13 Impact Factor
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    ABSTRACT: The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research. The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional - usually randomised - clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed. The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design. Trials can be designed using a wide array of possibilities. There is no 'one size fits all' solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.
    European journal of cancer (Oxford, England: 1990) 12/2014; 51(3). DOI:10.1016/j.ejca.2014.10.027 · 4.82 Impact Factor
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    ABSTRACT: Background Lee Silverman Voice Therapy (LSVT) is an intensive speech treatment offered to approximately a fifth of people with dysarthria associated with Parkinson’s Disease (PD). In NHS Greater Glasgow and Clyde we offer patients LSVT if they are (i) able to attend 16 one hour treatment sessions over 4 weeks (supplemented by home-based exercises), (ii) cope with the physical demands of attendance, (iii) appear motivated to change and (iv) have typical hypophonic dysarthria. In the context of a UK-wide phase II Dunhill Medical Trust funded pilot randomised controlled trial (PDCOMM: comparing LSVT versus standard NHS treatment versus no SLT) patients presenting with self reported voice or speech problems and idiopathic PD are eligible for inclusion. SLT within the previous 2 years, a diagnosis of dementia or laryngeal pathology are exclusion criteria. PDCOMM participants meeting inclusion criteria and randomised to receive LSVT may not always reflect those patients offered LSVT within NHS contexts. Aims: To examine the participation of one individual considered to have challenging social and contextual factors in intensive LSVT in the context of a clinical trial Methodology Following a neurology review which identified speech problems, ‘Scott’ was approached to participate in PDCOMM. Following baseline measures [Vocal Handicap Index (VHI), Voice Related Quality Of Life Questionnaire (V-RQoL), Parkinson's Disease Questionnaire-39 (PDQ-39)] Scott was randomised to the LSVT treatment arm and invited to attend LSVT. Previous medical history, social and contextual factors were also documented and indicated that Scott had a history of (i) angina and shortness of breath, (ii) depression (iii) a pre-morbid dysarthria following closed head injury (2006) but appeared motivated. In generating a treatment goal Scott stated he wanted to reduce the numbers of repetition requests from conversation partners. At each LSVT session decibel ratings (sustained phonation, conversation and reading) were recorded by the SLTs using a Radioshak Sound Level Meter positioned 30cms from the mouth. The SLT completed the Frenchay Dysarthria Assessment-2 and initial PDCOMM SLT assessment. VHI and V-RQoL were also captured at 3 and 6 months after LSVT by the research nurse. Results Scott attended all 16 LSVT treatment sessions delivered by two SLTs. Due to shortness of breath, he did not always tolerate the full 60 minute sessions. At therapy end Scott reported he had met his pre-treatment goal - “People no longer ask me to repeat”. Before and after treatment measures indicated an increase in vocal decibel levels (sustained phonation, conversation, reading) and a reduction in VHI, VRQOL and PDQ39 scores. Baseline Post treatment 6 months Sustained phonation- Decibels 64.6 89.7 86.9 Conversational Volume - Decibels 63.9 75.9 73 Reading Volume - Decibels 65.2 83.9 80.2 Baseline 3 months 6 months Vocal Handicap Index 61 8 2 VRQOL 31 12 10 PDQ39 90 68 50 Conclusion This single case study challenges SLT perceptions of patients considered ‘suitable’ for LSVT. Following an intensive course of LSVT Scott achieved his therapy goal, demonstrated an increase in vocal volume at conversation level and a positive attitude change towards communication. PDCOMM findings are expected in 2015.
    Royal College of Speech and Language Therapists, Leeds; 09/2014
  • Journal of Neurology Neurosurgery & Psychiatry 09/2014; 85(10):e4-e4. DOI:10.1136/jnnp-2014-309236.21 · 5.58 Impact Factor
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    ABSTRACT: PURPOSE: Relative efficacy and toxicity of cyclophosphamide compared with ifosfamide are debatable. The Euro-EWING99-R1 trial asked whether cyclophosphamide may replace ifosfamide in combination with vincristine and dactinomycin (vincristine, dactinomycin, and cyclophosphamide [VAC] v vincristine, dactinomycin, and ifosfamide [VAI]) after an intensive induction chemotherapy containing vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in standard-risk localized disease (NCT00020566). METHODS: Standard-risk Ewing sarcomas were localized tumors with either a good histologic response to chemotherapy (< 10% cells) or small tumors (< 200 mL) resected at diagnosis or receiving radiotherapy alone as local treatment. Patients entered the trial after six VIDE+1 VAI courses. Allocated treatment was either 7 VAC courses with 1.5 g/m2 of cyclophosphamide or seven VAI-courses with 6 g/m2 ifosfamide. The limit of noninferiority was set at -8.5% for the 3-year event-free survival rate (EFS), equivalent to 1.43 in terms of the hazard ratio of event (HRevent). RESULTS: This large international trial recruited 856 patients between February 2000 and March 2010 (n = 431 receiving VAC and n = 425 receiving VAI). With a median follow-up of 5.9 years, the 3-year EFSs were 75.4% and 78.2%, respectively, the 3-year EFS difference was -2.8% (91.4% CI, -7.8 to 2.2%), the HRevent was 1.12 (91.4% CI, 0.89 to 1.41), and the HRdeath was 1.09 (91.4% CI, 0.84 to 1.42; intention-to-treat). The HRevent was 1.22 (91.4% CI, 0.96 to 1.54) on the per-protocol population. Major treatment modifications were significantly less frequent in the VAC arm (< 1%) than in the VAI arm (7%), mainly resulting from toxicity. Patients experienced more frequent thrombocytopenia in the VAC arm (45% v 35%) but fewer grade 2 to 4 acute tubular toxicities (16% v 31%). CONCLUSION: Cyclophosphamide may be able to replace ifosfamide in consolidation treatment of standard-risk Ewing sarcoma. However, some uncertainty surrounding the noninferiority of VAC compared with VAI remains at this stage. The ongoing comparative evaluation of long-term renal and gonadal toxicity is crucial to decisions regarding future patients. ©American Society of Clinical Oncology.
    Journal of Clinical Oncology 06/2014; · 17.88 Impact Factor
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    ABSTRACT: Relative efficacy and toxicity of cyclophosphamide compared with ifosfamide are debatable. The Euro-EWING99-R1 trial asked whether cyclophosphamide may replace ifosfamide in combination with vincristine and dactinomycin (vincristine, dactinomycin, and cyclophosphamide [VAC] v vincristine, dactinomycin, and ifosfamide [VAI]) after an intensive induction chemotherapy containing vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in standard-risk localized disease (NCT00020566).
    Journal of Clinical Oncology 06/2014; 32(23). DOI:10.1200/JCO.2013.54.4833 · 17.88 Impact Factor
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    ABSTRACT: Despite medical therapies and surgical interventions for Parkinson's disease (PD), patients develop progressive disability. The role of physiotherapy is to maximise functional ability and minimise secondary complications through movement rehabilitation within a context of education and support for the whole person. The overall aim is to optimise independence, safety and wellbeing, thereby enhancing quality of life. Trials have shown that physiotherapy has short-term benefits in PD. However, which physiotherapy intervention is most effective remains unclear.
    Cochrane database of systematic reviews (Online) 06/2014; 6(6):CD002815. DOI:10.1002/14651858.CD002815.pub2 · 5.94 Impact Factor
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    ABSTRACT: Parkinson's disease is a common movement disorder affecting approximately 127,000 people in the UK, with an estimated two thirds having speech-related problems. Currently there is no preferred approach to speech and language therapy within the NHS and there is little evidence for the effectiveness of standard NHS therapy or Lee Silverman voice treatment. This trial aims to investigate the feasibility and acceptability of randomizing people with Parkinson's disease-related speech or voice problems to Lee Silverman voice treatment or standard speech and language therapy compared to a no-intervention control.
    Trials 06/2014; 15(1):213. DOI:10.1186/1745-6215-15-213 · 2.12 Impact Factor
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    ABSTRACT: Background and purpose To evaluate feasibility and toxicity of Hyperfractionated Accelerated Radiotherapy (HART) 1.24 Gy b.i.d. followed by chemotherapy for M1–3 Medulloblastoma (MB). The aim of HART was to use hyperfractionation to improve therapeutic ratio combined with acceleration to minimise tumour cell repopulation during radiotherapy (RT). Materials and methods Between February 2002 and May 2008, 34 eligible patients (22 male, 12 female) aged 3–15 years (median 7) with metastatic MB (M1–9; M2–3, M3–22) received HART with a craniospinal radiotherapy (CSRT) dose of 39.68 Gy followed by 22.32 Gy boost to the whole posterior fossa and 9.92 Gy metastatic boosts. The 8th and subsequent patients received vincristine (VCR) 1.5 mg/m2 weekly × 8 doses over 8 weeks starting during the 1st week of RT. Maintenance chemotherapy comprised 8 six-weekly cycles of VCR 1.5 mg/m2 weekly × 3, CCNU 75 mg/m2 and cisplatin 70 mg/m2. Results Median duration of HART was 34 days (range 31–38). Grade 3–4 toxicities included mucositis (8), nausea (10), anaemia (5), thrombocytopaenia (2), leucopaenia (24). With 4.5-year median follow-up, 3-year EFS and OS were 59% and 71%, respectively. Of 10 relapses, 1 was outside the central nervous system (CNS), 1 posterior fossa alone and 8 leptomeningeal with 3 also associated with posterior fossa. Conclusion HART with or without VCR was well tolerated and may have a place in the multi-modality management of high-risk MB.
    Radiotherapy and Oncology 04/2014; 111(1). DOI:10.1016/j.radonc.2014.01.022 · 4.86 Impact Factor
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    ABSTRACT: The optimal use and effectiveness of (131)I-meta iodobenzylguanidine ((131)I-mIBG) molecular radiotherapy for neuroblastoma remain unclear despite extensive clinical experience. This systematic review aimed to improve understanding of the current data and define uncertainties for future clinical trials. Bibliographic databases were searched for neuroblastoma and (131)I-mIBG. Clinical trials and non-comparative case series of (131)I-mIBG therapy for neuroblastoma were included. Two reviewers assessed papers for inclusion using the title and abstract with consensus achieved by discussion. Data were extracted by one reviewer and checked by a second. Studies with multiple publications were reported as a single study. The searches yielded 1216 citations, of which 51 publications reporting 30 studies met our inclusion criteria. No randomised controlled trials (RCTs) were identified. In two studies (131)I-mIBG had been used as induction therapy and in one study it had been used as consolidation therapy. Twenty-seven studies for relapsed and refractory disease were identified. Publication dates ranged from 1987 to 2012. Total number of patients was 1121 with study sizes ranging from 10 to 164. There was a large amount of heterogeneity between the studies with regard to patient population, treatment schedule and response assessment. Study quality was highly variable. The objective tumour response rate reported in 25 studies ranged from 0% to 75%, mean 32%. We conclude that (131)I-mIBG is an active treatment for neuroblastoma, but its place in the management of neuroblastoma remains unclear. Prospective randomised trials are essential to strengthen the evidence base.
    European journal of cancer (Oxford, England: 1990) 12/2013; 50(4). DOI:10.1016/j.ejca.2013.11.016 · 4.82 Impact Factor
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    ABSTRACT: Diffuse intrinsic pontine glioma (DIPG) has a dismal prognosis with no chemotherapy regimen so far resulting in any significant improvement over standard radiotherapy. In this trial, a prolonged regimen (21/28 d) of temozolomide was studied with the aim of overcoming O6-methylguanine methyltransferase (MGMT) mediated resistance. Forty-three patients with a defined clinico-radiological diagnosis of DIPG received radiotherapy and concomitant temozolomide (75 mg/m2) after which up to 12 courses of 21 d of adjuvant temozolomide (75–100 mg/m2) were given 4 weekly. The trial used a 2-stage design and passed interim analysis. At diagnosis median age was 8 years (2–20 years), 81% had cranial nerve abnormalities, 76% ataxia and 57% long tract signs. Median Karnofsky/Lansky score was 80 (10–100). Patients received a median of three courses of adjuvant temozolomide, five received all 12 courses and seven did not start adjuvant treatment. Three patients were withdrawn from study treatment due to haematological toxicity and 10 had a dose reduction. No other significant toxicity related to temozolomide was noted. Overall survival (OS) (95% confidence interval (CI)) was 56% (40%, 69%) at 9 months, 35% (21%, 49%) at 1 year and 17% (7%, 30%) at 2 years. Median survival was 9.5 months (range 7.5–11.4 months). There were five 2-year survivors with a median age of 13.6 years at diagnosis. This trial demonstrated no survival benefit of the addition of dose dense temozolomide, to standard radiotherapy in children with classical DIPG. However, a subgroup of adolescent DIPG patients did have a prolonged survival, which needs further exploration.
    European journal of cancer (Oxford, England: 1990) 09/2013; 49(18). DOI:10.1016/j.ejca.2013.08.006 · 4.82 Impact Factor
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    ABSTRACT: PURPOSETreatment outcomes in younger patients with acute myeloid leukemia (AML) have improved, but optimization and new combinations are needed. We assess three combinations in induction and consolidation. PATIENTS AND METHODS Younger untreated patients with AML (median age, 49 years; range, 0 to 73 years) were randomly allocated to two induction courses of daunorubicin and cytarabine (DA) with or without etoposide (ADE; n = 1983) or ADE versus fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-Ida; n = 1268), and to amsacrine, cytarabine, etoposide, and then mitoxantrone/cytarabine (MACE-MidAC) or high-dose cytarabine (n = 1,445) 3 g/m(2) or 1.5 g/m(2) (n = 657) in consolidation, and finally to a fifth course (cytarabine) or not (n = 227).ResultsOverall remission rates were similar for DA versus ADE (84% v 86%; P = .14) and ADE versus FLAG-Ida (86% v 85%; P = .7), with more course 1 remissions after FLAG-Ida (77%) reducing relapse (38% v 55%; P < .001) and improving relapse-free survival (45% v 34%; P = .01), overall and in subgroups, but with increased myelosuppression, reducing participation in the consolidation randomization. Overall outcomes were similar between MACE/MidAc and high-dose cytarabine (1.5/3.0 g/m(2)), but cytarabine required less supportive care. MACE/MidAc was superior for high-risk patients. A fifth course provided no benefit. The outcome for recipients of only two FLAG-Ida courses were not different from that with DA/ADE with consolidation. CONCLUSIONFLAG-Ida is an effective remission induction treatment, with a high complete remission rate after course 1 and reduced relapse. Consolidation with MACE/MidAc is similar overall to high-dose cytarabine, but superior in high-risk patients. Cytarabine at 1.5 g/m(2) is equivalent to a 3 g/m(2) dose. A fifth course is unnecessary. In patients receiving FLAG-Ida (two courses) and cytarabine (two courses), 8-year survival was 63% for patients with intermediate-risk and 95% for those with favorable-risk disease.
    Journal of Clinical Oncology 08/2013; 31(27). DOI:10.1200/JCO.2012.47.4874 · 17.88 Impact Factor
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    ABSTRACT: Better treatment is required for older patients with acute myeloid leukaemia (AML) not considered fit for intensive chemotherapy. We report a randomised comparison of Low Dose Ara-C (LDAC) versus the novel nucleoside, Clofarabine, in untreated older patients with AML and high risk Myelodysplastic Syndrome (MDS). Four hundred and six patients with de novo (62%), secondary disease (24%) or high risk MDS (>10%marrow blasts)(15%), median age 74 years, were randomised to LDAC 20mg bid for 10 days every 6 weeks or clofarabine 20mg/m(2) days 1-5, both for up to 4 courses. These patients had more adverse demographics than contemporaneous intensively treated patients. The overall remission rate was 28% and 2-year survival was 13%. Clofarabine significantly improved complete remission: 22% vs 12% (HR 0.47(0.28-0.79); p=0.005) and overall response: 38% vs 19% (HR 0.41 (0.26-0.62); p=<0.0001), but there was no difference in overall survival, explained by poorer survival in the clofarabine patients who did not gain CR and also following relapse. Clofarabine was more myelosuppressive and required more supportive care. Although clofarabine doubled remission rates, overall survival was not improved overall or in any subgroup. The treatment of patients of the type treated here remains a major unmet need. (Trial registered with ID: ISRCTN 11036523).
    Blood 07/2013; 122(8). DOI:10.1182/blood-2013-04-496596 · 10.43 Impact Factor
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    ABSTRACT: Background: The randomized Euro-EWING99-R1 trial assessed noninferiority of cyclophosphamide- vs ifosfamide-based consolidation regimens (VAC vs VAI) in SR localized ES patients. Overall, efficacy of VAC was deemed acceptable compared to VAI, with hazard ratio of event HR = 1.12 [0.89 - 1.41]. Based on its gender-stratified randomization, influence of gender on efficacy and acute toxicity were additionally explored. Methods: Impact of gender on EFS, acute toxicity by course, switches between treatment arms, and cumulative dose of alkylating agents was evaluated in multivariable models, including terms to test for heterogeneity of treatment effect by gender. Analysis was performed on the intention to treat population. Results: 856 patients (509 males, 347 females) were recruited between 2000 and 2010: 425 VAI and 431 VAC. EFS did not significantly differ between genders (p=0.33), but a marginal interaction was seen between treatment and gender (p=0.083): VAC was associated with poorer EFS in males than VAI, HR(VAC/VAI) = 1.34 [0.96 - 1.86], whereas, in females, VAC was slightly better than VAI, HR = 0.83 [0.54 - 1.28]. Similarly, males had a worse EFS than females with VAC, HR(M/F) = 1.42 [0.97 – 2.08], whereas results by gender were very similar with VAI, HR = 0.91 [0.62 – 1.33]. Severe hematological toxicity was more frequent with VAC than VAI whereas tubular renal impairment was more frequent with VAI. Severe toxicity was more frequent in females than in males, whatever the toxicity type, with no significant interaction between treatment and gender effect. 30 patients switched from VAI to VAC (21 F, 9 M) mostly due to renal toxicity, and 3 from VAC to VAI (1 F, 2 M). A reduction of alkylating agent cumulative dose >20% was more frequent in females (15% vs 9%, p=0.01), with no major difference between VAI and VAC (13% vs 10%, p=0.21). Conclusions: The marginal interaction between gender and type of alkylating agent on EFS has to be validated on external data. Differences of acute toxicity rate and compliance are not sufficient explanation. Effects of gender-dependant polymorphism/activity of metabolic enzymes (e.g. known for CYP2B6) of ifosfamide vs cyclophosphamide should be explored. Clinical trial information: NCT00020566.
    Journal of Clinical Oncology 06/2013; 31(suppl):10031. · 17.88 Impact Factor
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    ABSTRACT: BACKGROUND: This feasibility study is intended to assess the acceptability of home-based task-specific reach-to-grasp (RTG) training for people with stroke, and to gather data to inform recruitment, retention, and sample size for a definitive randomized controlled trial.Methods/designThis is to be a randomized controlled feasibility trial recruiting 50 individuals with upper-limb motor impairment after stroke. Participants will be recruited after discharge from hospital and up to 12 months post-stroke from hospital stroke services and community therapy-provider services. Participants will be assessed at baseline, and then electronically randomized and allocated to group by minimization, based on the time post-stroke and extent of upper-limb impairment. The intervention group will receive 14 training sessions, each 1 hour long, with a physiotherapist over 6 weeks and will be encouraged to practice independently for 1 hour/day to give a total of 56 hours of training time per participant. Participants allocated to the control group will receive arm therapy in accordance with usual care. Participants will be measured at 7 weeks post-randomization, and followed-up at 3 and 6 months post-randomization. Primary outcome measures for assessment of arm function are the Action Research Arm Test (ARAT) and Wolf Motor Function Test (WMFT). Secondary measures are the Motor Activity Log, Stroke Impact Scale, Carer Strain Index, and health and social care resource use. All assessments will be conducted by a trained assessor blinded to treatment allocation. Recruitment, adherence, withdrawals, adverse events (AEs), and completeness of data will be recorded and reported. DISCUSSION: This study will determine the acceptability of the intervention, the characteristics of the population recruited, recruitment and retention rates, descriptive statistics of outcomes, and incidence of AEs. It will provide the information needed for planning a definitive trial to test home-based RTG training.Trial registration: ISRCTN56716589.
    Trials 04/2013; 14(1):109. DOI:10.1186/1745-6215-14-109 · 2.12 Impact Factor
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    ABSTRACT: BACKGROUND: Granulomatosis with polyangiitis (GPA, Wegener's) and microscopic polyangiitis (MPA) are small vessel vasculitides collectively referred to as anti-neutrophil cytoplasm antibody-associated vasculitis (AAV). AAV is associated with high rates of morbidity and mortality due to uncontrolled disease and treatment toxicity. Small randomized trials suggest adjunctive plasma exchange may improve disease control, while observational evidence suggests that current oral glucocorticoid doses are associated with severe infections in patients with AAV. A randomized study of both plasma exchange and glucocorticoids is required to evaluate plasma exchange and oral glucocorticoid dosing in patients with AAV.Methods/design: PEXIVAS is a two-by-two factorial randomized trial evaluating adjunctive plasma exchange and two oral glucocorticoid regimens in severe AAV. Five hundred patients are being randomized at centers across Europe, North America, Asia, and Australasia to receive plasma exchange or no plasma exchange, and to receive standard or reduced oral glucocorticoid dosing. All patients receive immunosuppression with either cyclophosphamide or rituximab. The primary outcome is the time to the composite of all-cause mortality and end-stage renal disease.PEXIVAS is funded by the National Institute of Health Research (UK), the Food and Drug Administration (USA), the National Institutes of Health (USA), the Canadian Institute of Health Research (Canada), the National Health and Medical Research Council (Australia), and Assistance Publique (France). Additional in-kind supplies for plasma exchange are provided by industry partners (TerumoBCT, Gambro Australia, and Fresenius Australia). DISCUSSION: This is the largest trial in AAV undertaken to date. PEXIVAS will inform the future standard of care for patients with severe AAV. The cooperation between investigators, funding agencies, and industry provides a model for conducting studies in rare diseases.Trial registration: Current Controlled Trials: and
    Trials 03/2013; 14(1):73. DOI:10.1186/1745-6215-14-73 · 2.12 Impact Factor
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    ABSTRACT: The standard European radiotherapy technique for children with neuroblastoma is a conventional parallel opposed pair. This frequently results in compromise on planning target volume coverage to stay within normal tissue tolerances. This study investigates the use of an intensity-modulated arc therapy (IMAT) technique to improve dose distribution and allow better protocol compliance. Among 20 previously treated patients, ten had received the full prescribed dose with conventional planning (protocol compliant) and ten had a compromise on planning target volume coverage (protocol noncompliant). All patients were replanned with IMAT. Dosimetric parameters of the conventional radiotherapy and IMAT were compared. The dose received by 98% of the planning target volume, homogeneity and conformity indices were all improved with IMAT (p < 0.001). IMAT would have enabled delivery of the full protocol dose in eight out of ten protocol-noncompliant patients. IMAT may improve outcomes through improved protocol compliance and better dose distributions.
    Future Oncology 03/2013; 9(3):439-49. DOI:10.2217/fon.12.199 · 2.61 Impact Factor

Publication Stats

14k Citations
1,918.10 Total Impact Points


  • 1999–2015
    • University of Birmingham
      • • Cancer Research UK Clinical Trials Unit (CRCTU)
      • • Birmingham Clinical Trials Unit
      Birmingham, England, United Kingdom
  • 2012
    • Wellcome Trust Sanger Institute
      • Cancer Genome Project
      Cambridge, ENG, United Kingdom
  • 2011
    • University of Newcastle
      Newcastle, New South Wales, Australia
  • 2007–2011
    • Cardiff University
      • School of Medicine
      Cardiff, Wales, United Kingdom
  • 2009
    • Sapienza University of Rome
      • Department of Cellular Biotechnology and Hematology BCE
      Roma, Latium, Italy
    • King's College London
      • Department of Medical and Molecular Genetics
      London, ENG, United Kingdom
  • 1996–2009
    • University of Cambridge
      • Department of Haematology
      Cambridge, ENG, United Kingdom
  • 2006
    • British Society for Haematology
      Londinium, England, United Kingdom
  • 2001–2006
    • Worldwide Clinical Trials
      Nottigham, England, United Kingdom
  • 2005
    • Ninewells Hospital
      Dundee, Scotland, United Kingdom
  • 2001–2005
    • University College London
      • Department of Haematology
      London, ENG, United Kingdom
  • 2004
    • University of Aberdeen
      Aberdeen, Scotland, United Kingdom
    • Stanford University
      Palo Alto, California, United States
  • 2003
    • Erasmus Universiteit Rotterdam
      Rotterdam, South Holland, Netherlands
    • Queen Elizabeth Hospital Birmingham
      Birmingham, England, United Kingdom