Effect of vitamins and aspirin on markers of platelet activation, oxidative stress and homocysteine in people at high risk of dementia.

OBJECTIVES: To examine the association of cognitive impairment with platelet activation and reactive oxygen species and total homocysteine levels; and to assess the biochemical efficacy of treatment with aspirin and vitamin supplements in people at high risk of dementia. SUBJECTS: People with dementia or mild cognitive impairment. DESIGN AND INTERVENTION: In a 2 x 2 x 2 factorial design trial, 149 people at high-risk of dementia were randomized to receive either low-dose aspirin (81 mg) or placebo; and folic acid (2 mg) plus vitamin B12 (1 mg) or placebo; and vitamins E (500 mg) plus C (200 mg) or placebo. Participants were seen twice before and once after 12 weeks of treatment. MAIN OUTCOME MEASURES: At each visit, participants had their cognitive function assessed and had blood collected for homocysteine, folate and vitamin B12 determination and urine collected for markers of platelet activation (11-dehydro-thromboxane B2) and reactive oxygen species (8-epi-PGF2 alpha). RESULTS: Prior to treatment, cognitive function was inversely related with homocysteine and with urinary thromboxane and isoprostane, and these associations were independent of age. Aspirin was associated with a median reduction in 11-dehydrothromboxane B2 of 73% (P < 0.001). B-vitamins lowered plasma homocysteine concentration by 30% (P < 0.0001) and antioxidant vitamins lowered isoprostane excretion by 26% (P < 0.1). No effect of treatment on cognitive function was detected. CONCLUSIONS: Aspirin and B-vitamins were effective in reducing biochemical factors associated with cognitive impairment in people at risk of dementia. Large-scale trials are now required to assess the relevance of aspirin and B-vitamins for the maintenance of cognitive function in people at risk of dementia.

Intraocular relapse of childhood acute lymphoblastic leukaemia.

Relapse of childhood acute lymphoblastic leukaemia (ALL) involving the eye is a rare but challenging problem. Twenty cases occurred in patients treated on the Medical Research Council United Kingdom Acute Lymphoblastic Leukaemia XI and ALL97 trials between 1991 and 2001, representing 2.2% of ALL relapses. Seventeen occurred as a first relapse, either in isolation or combined with relapse at another site, and three occurred as a second relapse. All patients with intraocular disease at first relapse were treated with both chemotherapy and radiotherapy, but the doses and protocols used varied. Eleven of these 17 patients are alive and in complete remission with a median follow up of 4 years 2 months from relapse. All 11 children that were treated with a full chemotherapy relapse protocol, together with local radiotherapy have survived. Patients treated with chemotherapy of shorter duration and intensity, despite radiotherapy and/or bone marrow transplantation, did poorly with only one survivor, currently in chronic relapse. Consequently, we suggest that children with eye relapse of ALL be treated with an intensive relapse chemotherapy protocol with local ocular radiotherapy, whether the relapse occurs in isolation or in combination with relapse at another site.

Prognostic factors and outcome for children after second central nervous system relapse of acute lymphoblastic leukaemia.

The Medical Research Council acute lymphoblastic leukaemia trials (UKALL X and XI) recruited 3,702 children with ALL between January 1985 and March 1997. Seventy-nine children had central nervous system (CNS) involvement in their first two relapses. Fourteen children survived at a median follow-up of 22 months from second relapse; seven (9%) in third remission, two in later remissions and five with disease. Factors predictive of survival from second relapse were site (isolated CNS was better than combined CNS, P = 0.02) and time from diagnosis to second CNS relapse (longer time was better, P = 0.004). Prognosis after second CNS relapse is extremely poor, and palliative therapy is appropriate.

P-glycoprotein (MDR1) expression in leukemic cells is regulated at two distinct steps, mRNA stabilization and translational initiation.

Multidrug resistance in acute myeloid leukemia is often conferred by overexpression of P-glycoprotein, encoded by the MDR1 gene. We have characterized the key regulatory steps in the development of multidrug resistance in K562 myelogenous leukemic cells. Unexpectedly, up-regulation of MDR1 levels was not due to transcriptional activation but was achieved at two distinct post-transcriptional steps, mRNA turnover and translational regulation. The short-lived (half-life 1 h) MDR1 mRNA of naive cells (not exposed to drugs) was stabilized (half-life greater than 10 h) following short-term drug exposure. However, this stabilized mRNA was not associated with translating polyribosomes and did not direct P-glycoprotein synthesis. Selection for drug resistance, by long-term exposure to drug, led to resistant lines in which the translational block was overcome such that the stabilized mRNA was translated and P-glycoprotein expressed. The absence of a correlation between steady-state MDR1 mRNA and P-glycoprotein levels was not restricted to K562 cells but was found in other lymphoid cell lines. These findings have implications for the avoidance or reversal of multidrug resistance in the clinic.

The value of allogeneic bone marrow transplant in patients with acute myeloid leukaemia at differing risk of relapse: results of the UK MRC AML 10 trial.

Patients under 55 years in the United Kingdom Medical Research Council Acute Myeloid Leukaemia 10 trial who entered complete remission were tissue typed (n = 1063). Four hundred and nineteen had a matched sibling donor and 644 had no match. When compared on a donor versus no donor basis the relapse risk was reduced in the donor arm (36%vs 52%; P = 0.001) and the disease-free survival (DFS) improved (50%vs 42%; P = 0.01), but overall survival (OS) was not different (55%vs 50%; P = 0.1). Sixty-one per cent of patients with a donor underwent transplantation. When patients were subdivided into risk groups based on cytogenetics alone or with the addition of blast response to course 1, a reduction in relapse risk was seen in all risk groups and in three age cohorts (0-14, 15-34 and 35+ years). Significant benefit in DFS was only seen in the intermediate-risk cytogenetic group (50%vs 39%; P = 0.004). The OS benefit was only seen in intermediate-risk patients (55%vs 44%; P = 0.02). The reduction in relapse risk in good-risk patients was attributable to patients with t(15;17) and not to patients with t(8;21) or inv(16). Allogeneic transplantation given after intensive chemotherapy was able to reduce relapse in all risk and age groups. However, due to the competing effects of procedural mortality and an inferior response to chemotherapy if relapse does occur, there was a survival advantage only in patients of intermediate risk. This trial found no survival advantage in children, patients over 35 years or good-risk disease.

Failure of a new protocol to improve treatment results in paediatric lymphoblastic leukaemia: lessons from the UK Medical Research Council trials UKALL X and UKALL XI.

The impact of various types of intensification therapy was examined in a cohort of 3617 children aged 1-14 years with acute lymphoblastic leukaemia (ALL) enrolled in the Medical Research Council (MRC) UKALL X (1985-90) and UKALL XI (1990-97) trials. UKALL XI was modified in 1992 to incorporate the "best arm" of UKALL X with two 5-d intensification blocks at 5 and 20 weeks, and an additional randomization in respect of a third intensification at 35 weeks but omission of two consecutive injections of daunorubicin during induction. All children were eligible for randomization irrespective of risk group. The impact of the various types of intensification therapy was examined in a stratified analysis. At a median follow up of 102 months, both trials had an identical event-free survival of 61% (95% CI 58-63%) at 8 years. Survival at 8 years in UKALL XI was significantly better in than in UKALL X, 81% (79-83%) compared with 74% (72-76%) (P = < 0.001), owing to improved management of relapse. There was a highly significant trend in reduction of the number of relapses and deaths with increased intensity of therapy both for children with initial leucocyte count < 50 x 10(9)/l (P = < 0.001) and > or = 50 x 10(9)/l (P = 0.002). Introduction of a third late intensification block compensated for omission of anthracyclines during induction but produced little additional benefit. These results show, in a large cohort of patients, that minor modifications of therapy may influence relapse rate and obviate the benefit of previous randomized trials. The failure to adapt treatment for higher risk children contributed to these disappointing results.

Results of treatment of children with refractory anaemia with excess blasts (RAEB) and RAEB in transformation (RAEBt) in Great Britain 1990-99.

Between 1990 and 1999, 36 children with refractory anaemia with excess blasts (RAEB) and RAEB in transformation (RAEBt), not associated with Down's syndrome, were diagnosed in Britain. A total of 31 children received intensive chemotherapy, six of whom proceeded to a bone marrow allograft in first remission, whereas two received an autograft. Of the 23 given chemotherapy only, four died of toxicity, 10 relapsed and nine are alive in first remission. Out of the 10 who relapsed, four are alive and disease-free following an allograft. Out of the 6 children given an allograft in first remission, two died of disease and four are alive in first remission. Both children given an autograft died of disease. Two children received an allograft without prior chemotherapy but died of toxicity. Three children received supportive care only, and one child survived. The overall survival was 51% at 5 years, and was superior in children with RAEBt (63%) compared with RAEB (28%, P = 0.03). Cytogenetics were available in 35 cases. Monosomy 7 was the most common abnormality (33% of cases). Survival in children with monosomy 7 was 22% at 5 years compared with 66% for the other patients (P = 0.05). Allowing for cytogenetics, outcomes of therapy appear similar to those for de novo acute myeloid leukaemia (AML), and it is appropriate for children with RAEB/RAEBt to be registered in AML trials.