A Randomised Phase II Trial to Evaluate the Feasibility of Radiotherapy Dose Escalation, Facilitated by Intensity-Modulated Arc Radiotherapy Techniques, in High-Risk Neuroblastoma.

BACKGROUND AND PURPOSE: For high-risk neuroblastoma, planning target volume coverage is often compromised to respect adjacent kidney tolerance. This trial investigated whether intensity-modulated arc radiotherapy techniques (IMAT) could facilitate dose escalation better than conventional techniques. MATERIALS AND METHODS: Children with high-risk abdominal neuroblastoma referred for radiotherapy to the primary tumour site and involved regional lymph nodes were randomised to receive either standard dose (21 Gy in 14 fractions) or escalated dose (36 Gy in 24 fractions) radiotherapy. Dual planning with both a conventional anterior-posterior parallel opposed pair radiotherapy technique and an IMAT technique was performed. The quality of target volume and organ-at-risk delineation, and dosimetric plans, were externally reviewed. Dosimetric parameters were used to judge the superior technique for treatment. This feasibility trial was not powered to detect improvement in outcome with dose escalation. RESULTS: Between 2017 and 2020, 50 patients were randomised and dual-planned. The IMAT technique was judged more favourable in 48 patients. In all patients randomised to receive 36 Gy, IMAT would have permitted delivery of the full dose (median D50% 36.0 Gy, inter-quartile range 36.0-36.1 Gy) to the target volume, whereas dose compromise would have been required with conventional planning (median D50% 35.6 Gy, inter-quartile range 28.7-35.9 Gy). CONCLUSION: IMAT facilitates safe dose escalation to 36 Gy in patients receiving radiotherapy for neuroblastoma. The value of dose escalation is now being evaluated in a current prospective phase III randomised trial.

FLT3 inhibitors in acute myeloid leukaemia: assessment of clinical effectiveness, adverse events and future research-a systematic review and meta-analysis.

BACKGROUND: FMS-like tyrosine kinase 3 (FLT3) is the most frequent mutation in AML. With two FLT3 inhibitors recently approved by the FDA (midostaurin and gilteritinib), there is a need to evaluate these targeted agents. PURPOSE: To assess the clinical effectiveness of FLT3 inhibitors in AML patients. METHODS: Standard systematic review methods were utilised. Searches were conducted to July 2020 for completed and in-progress randomised controlled trials of FLT3 inhibitors in AML. A fixed-effect meta-analysis was undertaken. RESULTS: Eight completed trials involving 2656 patients and assessing five different FLT3 inhibitors (sorafenib, lestaurtinib, midostaurin, gilteritinib and quizartinib) were included. The pooled results were as follows (FLT3 inhibitor/control): overall survival hazard ratio (HR) = 0.83 (95% confidence interval [CI] 0.75 to 0.92, p = 0.0005), event-free survival HR = 0.85 (95% CI 0.77 to 0.94, p = 0.002), relapse-free survival HR = 0.76 (95% CI 0.64 to 0.90, p = 0.001), complete remission relative risk (RR) = 1.11 (95% CI 1.00 to 1.22. p = 0.05) and 60-day mortality RR = 1.04 (95% CI 0.77 to 1.40, p = 0.79). Relative risk of grade 3 and above vascular, dermatological, respiratory and hepatobiliary adverse events were found to be statistically significantly higher in the FLT3 inhibitor group compared to control, but the actual numbers of events were relatively small. Nineteen ongoing trials are still in progress, only one of which specifically targets older patients with AML. CONCLUSIONS: There is evidence to support the use of FLT3 inhibitors in patients with AML, but more data is needed to verify the optimum use of the drugs regarding type of inhibitor, disease stage and patient characteristics, not only in relation to disease control, but adverse events and quality of life. There are a large number of ongoing trials; therefore, the results of this review are not a fait accompli; thus, is it recommended that the review be updated in a couple of years' time. Given the challenges in extracting the complete data set required to assess clinical effectiveness, it is highly recommended that ongoing and future trials improve transparency and consistency of reporting of all trial outcomes, particularly disease control and adverse events, to enable a global clinical effectiveness assessment. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017055581.

Investigating the heterogeneity of alkylating agents' efficacy and toxicity between sexes: A systematic review and meta-analysis of randomized trials comparing cyclophosphamide and ifosfamide (MAIAGE study).

BACKGROUND: A marginal interaction between sex and the type of alkylating agent was observed for event-free survival in the Euro-EWING99-R1 randomized controlled trial (RCT) comparing cyclophosphamide and ifosfamide in Ewing sarcoma. To further evaluate this interaction, we performed an individual patient data meta-analysis of RCTs assessing cyclophosphamide versus ifosfamide in any type of cancer. METHODS: A literature search produced two more eligible RCTs (EICESS92 and IRS-IV). The endpoints were progression-free survival (PFS, main endpoint) and overall survival (OS). The hazard ratios (HRs) of the treatment-by-sex interaction and their 95% confidence interval (95% CI) were assessed using stratified multivariable Cox models. Heterogeneity of the interaction across age categories and trials was explored. We also assessed this interaction for severe acute toxicity using logistic models. RESULTS: The meta-analysis comprised 1,528 pediatric and young adult sarcoma patients from three RCTs: Euro-EWING99-R1 (n = 856), EICESS92 (n = 155), and IRS-IV (n = 517). There were 224 PFS events in Euro-EWING99-R1 and 200 in the validation set (EICESS92 + IRS-IV), and 171 and 154 deaths in each dataset, respectively. The estimated treatment-by-sex interaction for PFS in Euro-EWING99-R1 (HR = 1.73, 95% CI = 1.00-3.00) was not replicated in the validation set (HR = 0.97, 95% CI = 0.55-1.72), without heterogeneity across trials (P = 0.62). In the pooled analysis, the treatment-by-sex interaction was not significant (HR = 1.31, 95% CI = 0.89-1.95, P = 0.17), without heterogeneity across age categories (P = 0.88) and trials (P = 0.36). Similar results were observed for OS. No significant treatment-by-sex interaction was observed for leucopenia/neutropenia (P = 0.45), infection (P = 0.64), or renal toxicity (P = 0.20). CONCLUSION: Our meta-analysis did not confirm the hypothesis of a treatment-by-sex interaction on efficacy or toxicity outcomes.

Effect of topical imiquimod as primary treatment for lentigo maligna: the LIMIT-1 study.

BACKGROUND: Topical imiquimod is sometimes used for lentigo maligna (LM) in situ melanoma instead of surgery, but frequency of cure is uncertain. Pathological complete regression (pCR) is a logical surrogate marker for cure after imiquimod, although residual LM and atypical melanocytic hyperplasia may not be reliably distinguished. A trial comparing imiquimod vs. surgery might be justified by a high imiquimod pCR rate. OBJECTIVES: Primary: to estimate the pCR rate for LM following imiquimod. Secondary: to assess the accuracy of prediction of pCR, using clinical complete regression (cCR) plus negative post-treatment biopsies, tolerability, resource use, patients' preferences and induced melanoma immunity. METHODS: This was a single-arm phase II trial of 60 imiquimod applications over 12 weeks for LM then radical resection. A pCR rate ≥ 25 out of 33 would reliably discriminate between pCR rates < 60% and ≥ 85%. Clinical response was assessed and biopsies taken after imiquimod. Patients recorded adverse events in diaries. Patient preference was measured after surgery using a standard gamble tool. RESULTS: The pCR rate was 10 of 27 (37%, 95% confidence interval 19-58%). The rate of cCR plus negative biopsies was 12 of 28, of whom seven of 11 had pCR on subsequent surgery. The median dose intensity was 86·7%. Of the 16 surveyed patients, eight preferred primary imiquimod over surgery if the cure rate for imiquimod was 80%, and four of 16 if it was ≤ 40%. CONCLUSIONS: The pCR rate was insufficient to justify phase III investigation of imiquimod vs. SURGERY: Clinical complete response and negative targeted biopsies left uncertainty regarding pathological clearance. Some patients would trade less aggressive treatment of LM against efficacy.

Home-based Reach-to-Grasp training for people after stroke is feasible: a pilot randomised controlled trial.

OBJECTIVE: To determine feasibility of a randomised controlled trial (RCT) of home-based Reach-to-Grasp training after stroke. DESIGN: single-blind parallel group RCT. PARTICIPANTS: Residual arm deficit less than 12 months post-stroke. INTERVENTIONS: Reach-to-Grasp training in 14 one-hour therapist's visits over 6 weeks, plus one hour self-practice per day (total 56 hours). CONTROL: Usual care. MAIN MEASURES: Action Research Arm Test (ARAT), Wolf Motor Function Test (WMFT), pre-randomisation, 7, 12, 24 weeks post-randomisation. RESULTS: Forty-seven participants (Reach-to-Grasp=24, usual care=23) were randomised over 17 months. Reach-to-Grasp participants received a median (IQR) 14 (13,14) visits, and performed 157 (96,211) repetitions per visit; plus 30 minutes (22,45) self-practice per day. Usual care participants received 10.5 (5,14) therapist visits, comprising 38.6 (30,45) minutes of arm therapy with 16 (6,24) repetitions of functional tasks per visit. Median ARAT scores in the reach-to-grasp group were 8.5 (3.0,24.0) at baseline and 14.5 (3.5,26.0) at 24 weeks compared to median of 4 at both time points (IQR: baseline (3.0,14.0), 24 weeks (3.0,30.0)) in the usual-care group. Median WMFT tasks completed at baseline and 24 weeks were 6 (3.0,11.5) and 8.5 (4.5,13.5) respectively in the reach-to-grasp group and 4 (3.0,10.0), 6 (3.0,14.0) in the usual care group. Incidence of arm pain was similar between groups. The study was stopped before 11 patients reached the 24 weeks assessment. CONCLUSIONS: An RCT of home-based Reach-to-Grasp training after stroke is feasible and safe. With ARAT being our preferred measure it is estimated that 240 participants will be needed for a future two armed trial.

Mylotarg has potent anti-leukaemic effect: a systematic review and meta-analysis of anti-CD33 antibody treatment in acute myeloid leukaemia.

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.

Diffuse intrinsic pontine glioma treated with prolonged temozolomide and radiotherapy--results of a United Kingdom phase II trial (CNS 2007 04).

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 (75 mg/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 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.

The addition of gemtuzumab ozogamicin to low-dose Ara-C improves remission rate but does not significantly prolong survival in older patients with acute myeloid leukaemia: results from the LRF AML14 and NCRI AML16 pick-a-winner comparison.

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.

Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial.

Two hundred eighty-five patients, median age 42, with PML-RARα-positive acute promyelocytic leukaemia were randomised to Ara-C-containing 'Medical Research Council (MRC) Chemotherapy'+ATRA (All-trans-retinoic acid) or anthracycline+ATRA (modified 'Spanish') therapy. MRC treatment comprised four courses with ATRA in courses 1-2. Spanish treatment comprised four 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 blood cell 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.

The addition of arsenic trioxide to low-dose Ara-C in older patients with AML does not improve outcome.

Most patients with acute myeloid leukaemia (AML) are older, with many unsuitable for conventional chemotherapy. Low-dose Ara-C (LDAC) is superior to best supportive care but is still inadequate. The combination of arsenic trioxide (ATO) and LDAC showed promise in an unrandomised study. We report a randomised trial of LDAC versus LDAC+ATO. Patients with AML according to WHO criteria or myelodysplastic syndrome with >10% blasts, considered as unfit for conventional chemotherapy, were randomised between subcutaneous Ara-C (20 mg b.d. for 10 days) and the same LDAC schedule with ATO (0.25 mg/kg) on days 1-5, 9 and 11, for at least four courses every 4 to 6 weeks. Overall 166 patients were entered; the trial was terminated on the advice of the DMC, as the projected benefit was not observed. Overall 14% of patients achieved complete remission (CR) and 7% CRi. Median survival was 5.5 months and 19 months for responders (CR: not reached; CRi: 14 months; non-responders: 4 months). There were no differences in response or survival between the arms. Grade 3/4 cardiac and liver toxicity, and supportive care requirements were greater in the ATO arm. This randomised comparison demonstrates that adding ATO to LDAC provides no benefit for older patients with AML.

Haematological changes at altitude.

Hypobaric hypoxia is associated with an increase in erythropoesis and an increased thrombotic risk. This is true of long haul air travel, mountaineering expeditions and longer stays at altitude. Studies looking at clotting on mountaineering expeditions are further complicated by the effects of exercise, plasma volume changes and the catecholamine response to hypoxia. This review examines the evidence for changes in clotting factors and functional clotting at altitude and considers the implications of altitude travel for those with pre-existing medical conditions.

Clinical significance of flowcytometric minimal residual disease detection in pediatric acute myeloid leukemia patients treated according to the DCOG ANLL97/MRC AML12 protocol.

Analysis of minimal residual disease (MRD) in childhood acute myeloid leukemia (AML) may predict for clinical outcome. MRD levels were assessed by flowcytometric immunophenotyping in 94 children with AML enrolled into a single trial (United Kingdom Medical Research Council AML12 and similar Dutch Childhood Oncology Group ANLL97). An aberrant immunophenotype could be detected in 94% of patients. MRD levels after the first course of chemotherapy predicted for clinical outcome: 3-year relapse-free survival was 85%+/-8% (s.e.) for MRD-negative patients (MRD<0.1%), 64%+/-10% for MRD-low-positive patients (0.1%or=0.5%; P<0.001), whereas overall survival was 95%+/-5%, 70%+/-10% and 40%+/-13%, respectively, (P<0.001). Multivariate analysis allowing for age, karyotype, FLT3-internal tandem duplications and white blood cell count at diagnosis showed that MRD after the first course of chemotherapy was an independent prognostic factor. Although comparison of paired diagnosis-relapse samples (n=23) showed immunophenotypic shifts in 91% of cases, this did not hamper MRD analysis. In conclusion, flowcytometric MRD detection is possible in children with AML. The level of MRD after the first course of chemotherapy provides prognostic information that may be used to guide therapy.

Pilot randomised controlled trial of occupational therapy to optimise independence in Parkinson's disease: the PD OT trial.

OBJECTIVE: To perform a pilot trial of occupational therapy (OT) to optimise functional independence in Parkinson disease (PD) to assess accrual/withdrawal rates, acceptability, outcome measures, and inform sample-size calculation. METHOD: Non-demented patients with idiopathic PD and difficulties with activities of daily living (ADL) were recruited provided they had not received OT in the last 2 years and/or physiotherapy in the last year. Patients were randomised to immediate OT or OT after completion of the trial. Patients randomised to OT were assessed at home by an experienced therapist and then received six home treatment sessions over 2 months. Interventions were targeted at functional independence and mobility goals. Outcome measures were: Nottingham Extended Activity of Daily Living Scale, Rivermead Mobility Index, Unified Parkinson's Disease Rating Scale ADL scale, Parkinson's Disease Questionnaire 39, EuroQol-EQ-5D, Hospital Anxiety and Depression Scale, and health economics analysis. RESULTS: 39 patients (25 male; mean age 73 years) were recruited from four centres over 16 months. The mean difference in NEADL at 8 months was 3.5 (95% CI -3.2 to 10.2). The mean difference in PDQ-39 Summary Score was 3.8 (95% CI -4.94 to 12.6). There were strong correlations between the PDQ-39 and other outcomes. The intervention was acceptable to patients, with a low withdrawal rate and good questionnaire completion. CONCLUSION: Randomisation to a trial of OT in PD is feasible. NEADL and PDQ-39 are relevant outcomes and provided data to inform sample size for an adequately powered randomised trial for which there is pressing need.

Dopamine agonist therapy in early Parkinson's disease.

BACKGROUND: Dopamine agonists are being used increasingly as first line treatment for Parkinson's disease, but there remains uncertainty about their clinical and cost-effectiveness relative to levodopa. OBJECTIVES: This meta-analysis aims to quantify more reliably the benefits and risks of dopamine agonists compared to placebo or levodopa in early Parkinson's disease. SEARCH STRATEGY: We searched CENTRAL (The Cochrane Library), MEDLINE, EMBASE, PubMed, LILACS and Web of Science, plus major journals in the field, abstract books, conference proceedings and reference lists of retrieved publications. SELECTION CRITERIA: Randomised trials comparing an orally administered dopamine agonist (with or without levodopa) versus placebo or levodopa or both placebo and levodopa in participants with early Parkinson's disease. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data on clinician-rated disability, motor complications, other side-effects, treatment concordance, levodopa dose and mortality. MAIN RESULTS: Twenty-nine eligible trials, involving 5247 participants, were identified. Participants randomised to a dopamine agonist were less likely to develop dyskinesia (odds ratio (OR) 0.51, 95% confidence interval (CI) 0.43 to 0.59; P < 0.00001), dystonia (OR 0.64, 95% CI 0.51 to 0.81; P = 0.0002) and motor fluctuations (OR 0.75, 95% CI 0.63 to 0.90; P = 0.002) than levodopa-treated participants. However, various 'non-motor' side-effects, including oedema (OR 3.68, 95% CI 2.62 to 5.18; P < 0.00001), somnolence (OR 1.49, 95% CI 1.12 to 2.00; P = 0.007), constipation (OR 1.59, 95% CI 1.11 to 2.28; P = 0.01), dizziness (OR 1.45, 95% CI 1.09 to 1.92; P = 0.01), hallucinations (OR 1.69, 95% CI 1.13 to 2.52; P = 0.01) and nausea (OR 1.32, 95% CI 1.05 to 1.66; P = 0.02) were all increased in agonist-treated participants (compared with levodopa-treated participants). Agonist-treated participants were also significantly more likely to discontinue treatment due to adverse events (OR 2.49, 95% CI 2.08 to 2.98; P < 0.00001). Finally symptomatic control of Parkinson's disease was better with levodopa than with agonists, but data were reported too inconsistently and incompletely to meta-analyse. AUTHORS' CONCLUSIONS: This meta-analysis confirms that motor complications are reduced with dopamine agonists compared to levodopa, but also establishes that other important side-effects are increased and symptom control is poorer with agonists. Larger, long-term comparative trials assessing patient-rated quality of life are needed to assess more reliably the balance of benefits and risks of dopamine agonists compared to levodopa.

Angioplasty and STent for Renal Artery Lesions (ASTRAL trial): rationale, methods and results so far.

Atherosclerotic renovascular disease (ARVD) is a relatively common condition which may lead to progressive renal dysfunction, and eventually to end-stage renal failure. Revascularization has been used in an attempt to prevent progression of ARVD, despite a lack of evidence for a benefit on kidney function. Therefore, large-scale randomized trials are needed to determine reliably whether or not there is any worthwhile benefit. The Angioplasty and STent for Renal Artery Lesions (ASTRAL) trial comparing renal function in ARVD patients randomized to either revascularization or medical management alone was designed to provide this evidence. ASTRAL started recruiting in November 2000 and, as of the end of 2006, 731 patients have been randomized into the trial (19 patients short of its minimum target of 750 patients). A pooled analysis (not split by treatment arm) of all patients shows that serum creatinine increased in the first 6 months then remained relatively steady, whereas blood pressure has decreased from baseline. The trial is due to close to recruitment in April 2007, with the first presentation of the results of the randomized treatment comparison planned for the spring of 2008. To date ASTRAL is by far the largest randomized trial in ARVD, and will provide the most reliable and timely evidence on the role, if any, of revascularization in ARVD with which to guide the treatment of future patients.

VITATOPS, the VITAmins TO prevent stroke trial: rationale and design of a randomised trial of B-vitamin therapy in patients with recent transient ischaemic attack or stroke (NCT00097669) (ISRCTN74743444).

BACKGROUND: Epidemiological studies suggest that raised plasma concentrations of total homocysteine (tHcy) may be a common, causal and treatable risk factor for atherothromboembolic ischaemic stroke, dementia and depression. Although tHcy can be lowered effectively with small doses of folic acid, vitamin B(12) and vitamin B(6), it is not known whether lowering tHcy, by means of B vitamin therapy, can prevent stroke and other major atherothromboembolic vascular events. AIM: To determine whether the addition of B-vitamin supplements (folic acid 2 mg, B(6) 25 mg, B(12) 500 microg) to best medical and surgical management will reduce the combined incidence of stroke, myocardial infarction (MI) and vascular death in patients with recent stroke or transient ischaemic attack (TIA) of the brain or eye. DESIGN: A prospective, international, multicentre, randomised, double blind, placebo-controlled clinical trial. SETTING: One hundred and four medical centres in 20 countries on five continents. SUBJECTS: Eight thousand (6600 recruited as of 5 January, 2006) patients with recent (<7 months) stroke (ischaemic or haemorrhagic) or TIA (brain or eye). RANDOMISATION: Randomisation and data collection are performed by means of a central telephone service or secure internet site. INTERVENTION: One tablet daily of either placebo or B vitamins (folic acid 2 mg, B(6) 25 mg, B(12) 500 mug). PRIMARY OUTCOME: The composite of stroke, MI or death from any vascular cause, whichever occurs first. Outcome and serious adverse events are adjudicated blinded to treatment allocation. SECONDARY OUTCOMES: TIA, unstable angina, revascularisation procedures, dementia, depression. STATISTICAL POWER: With 8000 patients followed up for a median of 2 years and an annual incidence of the primary outcome of 8% among patients assigned placebo, the study will have at least 80% power to detect a relative reduction of 15% in the incidence of the primary outcome among patients assigned B vitamins (to 6.8%/year), applying a two-tailed level of significance of 5%. CONCLUSION: VITATOPS aims to recruit and follow-up 8000 patients between 1998 and 2008, and provide a reliable estimate of the safety and effectiveness of folic acid, vitamin B(12), and vitamin B(6) supplementation in reducing recurrent serious vascular events among a wide range of patients with TIA and stroke throughout the world.

Treatment strategy and long-term results in paediatric patients treated in consecutive UK AML trials.

Between 1988 and 2002, 758 children with acute myeloid leukaemia (AML) were treated on Medical Research Council (MRC) AML 10 and AML 12. MRC AML 10 tested the role of bone marrow transplantation following four blocks of intensive chemotherapy and found that while both allogeneic bone marrow transplant (allo-BMT) and autologous bone marrow transplant (A-BMT) significantly reduced the relapse risk (RR), this did not translate into a significant improvement in overall survival (OS). A risk group stratification based on cytogenetics and response to the first course of chemotherapy derived from MRC AML 10 was used to deliver risk-directed therapy in MRC AML 12. Allo-BMT was limited to standard and poor risk patients and A-BMT was not employed. Instead, the benefit of an additional block of treatment was tested by randomising children to receive either four or five blocks of treatment in total. While the results of MRC AML 12 remain immature, there appears to be no survival advantage for a fifth course of treatment. The 5 year OS, disease-free survival (DFS), event-free survival (EFS) and RR in MRC AML 12 are 66, 61, 56 and 35%, respectively; at present superior to MRC AML 10, which had a 5-year OS, DFS, EFS and RR of 58, 53, 49 and 42%, respectively. MRC AML trials employ a short course of triple intrathecal chemotherapy alone for CNS-directed treatment and CNS relapse is uncommon. Improvements in supportive care have contributed to improved outcomes and the number of deaths in remission fell between trials. Anthracycline-related cardiotoxicity remains a concern and the current MRC AML 15 trial tests the feasibility of reducing anthracycline dosage without compromising outcome by comparing standard MRC anthracycline-based consolidation with high-dose ara-C. MRC studies suggest that the role of allo-BMT is limited in 1st CR and that there may be a ceiling of benefit from current or conventional chemotherapy.