Keith Wheatley

University of Birmingham, Birmingham, England, United Kingdom

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Publications (182)1650.46 Total impact

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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 Reports of excess toxicity have resulted in GO’s licence being withdrawn.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). · 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.
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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; · 4.13 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
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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:CD002815. · 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. · 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; · 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; · 4.12 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 (21/28d) of temozolomide was studied with the aim of overcoming O(6)-methylguanine methyltransferase (MGMT) mediated resistance. Forty-three patients with a defined clinico-radiological diagnosis of DIPG received radiotherapy and concomitant temozolomide (75mg/m(2)) after which up to 12 courses of 21d of adjuvant temozolomide (75-100mg/m(2)) were given 4 weekly. The trial used a 2-stage design and passed interim analysis. At diagnosis median age was 8years (2-20years), 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 9months, 35% (21%, 49%) at 1year and 17% (7%, 30%) at 2years. Median survival was 9.5months (range 7.5-11.4months). There were five 2-year survivors with a median age of 13.6years 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; · 4.12 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; · 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; · 9.78 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. · 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: http://www.controlled-trials.com/ISRCTN07757494 and clinicaltrials.gov: http://clinicaltrials.gov/ct2/show/NCT00987389.
    Trials 03/2013; 14(1):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. · 2.61 Impact Factor
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    ABSTRACT: PURPOSEThe aims of this study were to quantify the prospects of salvage treatment of patients who did not undergo transplantation in first complete remission (CR1) and to assess the contribution of allograft in second complete remission (CR2) with respect to major risk groups. This evaluation can inform the decision whether to offer a transplant in CR1. PATIENTS AND METHODS Of 8,909 patients who entered the Medical Research Council AML10, AML12, and AML15 trials, 1,271 of 3,919 patients age 16 to 49 years who did not receive a transplant in CR1 relapsed. Of these patients, 19% are alive beyond 5 years compared with 7% of patients who relapsed after an allograft in CR1. Overall survival and the contribution of a transplant in CR2 were assessed overall and by cytogenetic risk group by using Mantel-Byar analysis. RESULTS: favorable (82%), intermediate (54%), adverse (27%), and unknown (53%), which resulted in 5-year survivals of 32%, 17%, 7%, and 23%, respectively. Sixty-seven percent of remitters received an allotransplant that delivered superior survival compared with patients who did not receive a stem-cell transplant (42% v 16%). A more-stringent assessment of a transplant by using delayed-entry (Mantel-Byar) analysis confirmed the benefit of transplant overall and within intermediate and adverse risk groups but not the favorable subgroup. CONCLUSION Successful salvage treatment of patients who do not undergo transplantation in CR1 and relapse can be achieved in 19% of patients, which is improved by a transplant except in favorable risk disease. This result suggests that, for intermediate-risk patients in particular, equivalent overall survival can be achieved by delaying transplantation until after relapse, which would require many fewer transplants.
    Journal of Clinical Oncology 02/2013; · 17.88 Impact Factor
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    ABSTRACT: Two hundred eighty-five patients, median age 42, with PML-RARá positive APL were randomised to Ara-C-containing 'MRC Chemotherapy' + ATRA or anthracycline + ATRA (modified 'Spanish') therapy. MRC treatment comprised 4 courses with ATRA in courses 1-2. Spanish treatment comprised 4 anthracycline based courses with ATRA in courses 1-3. In course 3 patients were randomised to gemtuzumab ozogamicin(GO) or not. The Spanish arm received 24 month maintenance. Patients were sequentially molecularly monitored. Quality-of-Life was assessed at baseline, 3,6,9,12,24 months. Remission rates were similar in both arms (93%): cumulative incidence of haematological relapse (CIHR) was 6% at 5 years; 5 patients relapsed molecularly. Survival post-relapse was 80%. There were more deaths in remission in the MRC arm (4 vs 10%: P=0·2). The overall 5-year relapse-free and overall survival was similar between arms (81 vs 82% and 84 vs 83% respectively). More supportive care and hospitalisation (81.8 vs 63 days P<0.0001) was required in the MRC arm. GO did not provide benefit. High white count (>10 × 10(9)/l) was not prognostic overall, or within treatment arms. Both approaches deliver similar results with minor differences in quality of life. MRC treatment required more hospitalisation. This suggests that additional chemotherapy, Ara-C in particular, is not required.Leukemia accepted article preview online, 10 December 2012; doi:10.1038/leu.2012.360.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 12/2012; · 10.16 Impact Factor
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    ABSTRACT: The treatment of older patients with acute myeloid leukaemia, who are not considered suitable for conventional intensive therapy, is unsatisfactory. Low-dose Ara-C(LDAC) has been established as superior to best supportive care, but only benefits the few patients who enter complete remission. Alternative or additional treatments are required to improve the situation. This randomised trial compared the addition of the immunoconjugate, gemtuzumab ozogamicin (GO), at a dose of 5 mg on day 1 of each course of LDAC, with the intention of improving the remission rate and consequently survival. Between June 2004 and June 2010, 495 patients entered the randomisation. The addition of GO significantly improved the remission rate (30% vs 17%; odds ratio(OR) 0.48 (0.32-0.73); P=0.006), but not the 12 month overall survival (25% vs 27%). The reason for the induction benefit failing to improve OS was two-fold: survival of patients in the LDAC arm who did not enter remission and survival after relapse were both superior in the LDAC arm. Although the addition of GO to LDAC doubled the remission rate it did not improve overall survival. Maintaining remission in older patients remains elusive.Leukemia advance online publication, 11 September 2012; doi:10.1038/leu.2012.229.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 08/2012; · 10.16 Impact Factor
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    ABSTRACT: The clinical value of serial minimal residual disease (MRD) monitoring in core binding factor (CBF) acute myeloid leukemia (AML) by quantitative RT-PCR was prospectively assessed in 278 patients [163 with t(8;21) and 115 with inv(16)] entered in the United Kingdom MRC AML 15 trial. CBF transcripts were normalized to 10(5) ABL copies. At remission, after course 1 induction chemotherapy, a > 3 log reduction in RUNX1-RUNX1T1 transcripts in BM in t(8;21) patients and a > 10 CBFB-MYH11 copy number in peripheral blood (PB) in inv(16) patients were the most useful prognostic variables for relapse risk on multivariate analysis. MRD levels after consolidation (course 3) were also informative. During follow-up, cut-off MRD thresholds in BM and PB associated with a 100% relapse rate were identified: for t(8;21) patients BM > 500 copies, PB > 100 copies; for inv(16) patients, BM > 50 copies and PB > 10 copies. Rising MRD levels on serial monitoring accurately predicted hematologic relapse. During follow-up, PB sampling was equally informative as BM for MRD detection. We conclude that MRD monitoring by quantitative RT-PCR at specific time points in CBF AML allows identification of patients at high risk of relapse and could now be incorporated in clinical trials to evaluate the role of risk directed/preemptive therapy.
    Blood 08/2012; 120(14):2826-35. · 9.78 Impact Factor
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    ABSTRACT: To assess the effectiveness of physiotherapy compared with no intervention in patients with Parkinson's disease. Systematic review and meta-analysis of randomised controlled trials. Literature databases, trial registries, journals, abstract books, and conference proceedings, and reference lists, searched up to the end of January 2012. Randomised controlled trials comparing physiotherapy with no intervention in patients with Parkinson's disease were eligible. Two authors independently abstracted data from each trial. Standard meta-analysis methods were used to assess the effectiveness of physiotherapy compared with no intervention. Tests for heterogeneity were used to assess for differences in treatment effect across different physiotherapy interventions used. Outcome measures were gait, functional mobility and balance, falls, clinician rated impairment and disability measures, patient rated quality of life, adverse events, compliance, and economic analysis outcomes. 39 trials of 1827 participants met the inclusion criteria, of which 29 trials provided data for the meta-analyses. Significant benefit from physiotherapy was reported for nine of 18 outcomes assessed. Outcomes which may be clinically significant were speed (0.04 m/s, 95% confidence interval 0.02 to 0.06, P<0.001), Berg balance scale (3.71 points, 2.30 to 5.11, P<0.001), and scores on the unified Parkinson's disease rating scale (total score -6.15 points, -8.57 to -3.73, P<0.001; activities of daily living subscore -1.36, -2.41 to -0.30, P=0.01; motor subscore -5.01, -6.30 to -3.72, P<0.001). Indirect comparisons of the different physiotherapy interventions found no evidence that the treatment effect differed across the interventions for any outcomes assessed, apart from motor subscores on the unified Parkinson's disease rating scale (in which one trial was found to be the cause of the heterogeneity). Physiotherapy has short term benefits in Parkinson's disease. A wide range of physiotherapy techniques are currently used to treat Parkinson's disease, with little difference in treatment effects. Large, well designed, randomised controlled trials with improved methodology and reporting are needed to assess the efficacy and cost effectiveness of physiotherapy for treating Parkinson's disease in the longer term.
    BMJ (online) 08/2012; 345:e5004. · 16.38 Impact Factor
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    ABSTRACT: PURPOSEThere has been little survival improvement in older patients with acute myeloid leukemia (AML) in the last two decades. Improving induction treatment may improve the rate and quality of remission and consequently survival. In our previous trial, in younger patients, we showed improved survival for the majority of patients when adding gemtuzumab ozogamicin (GO) to induction chemotherapy. PATIENTS AND METHODS Untreated patients with AML or high-risk myelodysplastic syndrome (median age, 67 years; range, 51 to 84 years) were randomly assigned to receive induction chemotherapy with either daunorubicin/ara-C or daunorubicin/clofarabine, with (n = 559) or without (n = 556) GO 3 mg/m(2) on day 1 of course one of therapy. The primary end point was overall survival (OS).ResultsThe overall response rate was 69% (complete remission [CR], 60%; CR with incomplete recovery [CRi], 9%), with no difference between GO (70%) and no GO (68%) arms. There was no difference in 30- or 60-day mortality and no major increase in toxicity with GO. With median follow-up of 30 months (range, 5.5 to 54.6 months), 3-year cumulative incidence of relapse was significantly lower with GO (68% v 76%; hazard ratio [HR], 0.78; 95% CI, 0.66 to 0.93; P = .007), and 3-year survival was significantly better (25% v 20%; HR, 0.87; 95% CI, 0.76 to 1.00; P = .05). The benefit was apparent across subgroups. There was no interaction with other treatment interventions. A meta-analysis of 2,228 patients in two United Kingdom National Cancer Research Institute trials showed significant improvements in relapse (HR, 0.82; 95% CI, 0.72 to 0.93; P = .002) and OS (HR, 0.88; 95% CI, 0.79 to 0.98; P = .02). CONCLUSION Adding GO (3 mg/m(2)) to induction chemotherapy reduces relapse risk and improves survival with little increase in toxicity.
    Journal of Clinical Oncology 07/2012; · 17.88 Impact Factor

Publication Stats

13k Citations
1,650.46 Total Impact Points

Institutions

  • 2000–2015
    • 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
  • 2010–2012
    • University of South Florida
      • Center for Evidence Based Medicine and Health Outcomes Research
      Tampa, FL, United States
  • 2007–2012
    • Cardiff University
      • School of Medicine
      Cardiff, Wales, United Kingdom
  • 2011
    • University of Newcastle
      Newcastle, New South Wales, Australia
    • University of Cologne
      • Department of Internal Medicine
      Köln, North Rhine-Westphalia, Germany
    • Sandwell and West Birmingham Hospitals NHS Trust
      Birmingham, England, United Kingdom
  • 2009
    • King's College London
      Londinium, England, 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
    • The Bracton Centre, Oxleas NHS Trust
      Дартфорде, England, United Kingdom
    • University College London Hospitals NHS Foundation Trust
      • Department of Haematology
      London, ENG, United Kingdom
    • Great Ormond Street Hospital for Children NHS Foundation Trust
      • Department of Haematology and Oncology
      London, ENG, United Kingdom
  • 2005
    • Ninewells Hospital
      Dundee, Scotland, United Kingdom
  • 1997–2005
    • University College London
      • Department of Haematology
      London, ENG, United Kingdom
    • Medical Research Council (UK)
      Londinium, England, United Kingdom
  • 2004
    • Stanford University
      Palo Alto, California, United States
  • 2003
    • Queen Elizabeth Hospital Birmingham
      Birmingham, England, United Kingdom
  • 1999
    • University of Wales
      Cardiff, Wales, United Kingdom