Clinical Trial Service Unit

About: Clinical Trial Service Unit is a based out in . It is known for research contribution in the topics: Population & Stroke. The organization has 428 authors who have published 1387 publications receiving 181920 citations.

Incidence and outcome of pancreatitis in children and young adults with acute lymphoblastic leukaemia treated on a contemporary protocol, UKALL 2003.

Abstract: S.E. & Rees, R.C. (2009) Tumour antigentargeted immunotherapy for chronic myeloid leukaemia: is it still viable? Cancer Immunology, Immunotherapy, 58, 1489–1499. Savage, D.G., Szydlo, R.M. & Goldman, J.M. (1997) Clinical features at diagnosis in 430 patients with chronic myeloid leukaemia seen at a referral centre over a 16-year period. British Journal of Haematology, 96, 111–116. Waldhauer, I. & Steinle, A. (2008) NK cells and cancer immunosurveillance. Oncogene, 27, 5932– 5943. Yasuda, H., Aritaka, N., Ando, J., Hirama, M., Komatsu, N. & Hirano, T. (2011) Chronic myelogenous leukemia with mild basophilia as the predominant manifestation at presentation. Internal Medicine, 50, 501–502.

Rare Genomic Structural Variants in Complex Disease: Lessons from the Replication of Associations with Obesity

Abstract: The limited ability of common variants to account for the genetic contribution to complex disease has prompted searches for rare variants of large effect, to partly explain the ‘missing heritability’. Analyses of genome-wide genotyping data have identified genomic structural variants (GSVs) as a source of such rare causal variants. Recent studies have reported multiple GSV loci associated with risk of obesity. We attempted to replicate these associations by similar analysis of two familial-obesity case-control cohorts and a population cohort, and detected GSVs at 11 out of 18 loci, at frequencies similar to those previously reported. Based on their reported frequencies and effect sizes (OR≥25), we had sufficient statistical power to detect the large majority (80%) of genuine associations at these loci. However, only one obesity association was replicated. Deletion of a 220 kb region on chromosome 16p11.2 has a carrier population frequency of 2×10−4 (95% confidence interval [9.6×10−5–3.1×10−4]); accounts overall for 0.5% [0.19%–0.82%] of severe childhood obesity cases (P = 3.8×10−10; odds ratio = 25.0 [9.9–60.6]); and results in a mean body mass index (BMI) increase of 5.8 kg.m−2 [1.8–10.3] in adults from the general population. We also attempted replication using BMI as a quantitative trait in our population cohort; associations with BMI at or near nominal significance were detected at two further loci near KIF2B and within FOXP2, but these did not survive correction for multiple testing. These findings emphasise several issues of importance when conducting rare GSV association, including the need for careful cohort selection and replication strategy, accurate GSV identification, and appropriate correction for multiple testing and/or control of false discovery rate. Moreover, they highlight the potential difficulty in replicating rare CNV associations across different populations. Nevertheless, we show that such studies are potentially valuable for the identification of variants making an appreciable contribution to complex disease.

Results of Medical Research Council trial UKALL IX in acute lymphoblastic leukaemia in adults: report from the Medical Research Council Working Party on Adult Leukaemia

Abstract: The MRC UKALL IX trial for patients with untreated ALL aged 14 years and over was open to new patients from July 1980 to April 1985. 266 patients were randomized between two induction schedules. M (involving intermediate dose methotrexate with folinic acid rescue) and D (involving daunorubicin). Schedule M resembled that used in the previous MRC adult ALL trial (UKALL VI), while schedule D was somewhat more intensive. No difference in disease-free survival was found between the treatment arms, but patients on the daunorubicin arm went into remission earlier. The overall remission rate was 87%, which is at least as good as in contemporary studies elsewhere; factors predictive of a lower remission rate were older age and higher WBC. For those who entered remission. WBC, age and sex were the most important prognostic factors. Time to achieve remission was not a significant factor after allowance was made for these. An historical comparison does not show any improvement over the preceding MRC adult trial, although the subsequent trial does show a modest improvement at present. Because the improved outlook seen in children is not apparent in adults, and no other randomized trial has demonstrated substantial benefit for any particular regimen, the next trial, UKALL XII, will be investigating the benefit or otherwise of bone marrow transplantation.

Homocysteine and Cardiovascular Risk: Considering the Evidence in the Context of Study Design, Folate Fortification, and Statistical Power

Abstract: The hypothesis that moderately increased plasma total homocysteine (tHcy) concentrations are causally related to cardiovascular disease (CVD) originated from observations of vascular disease in patients with homocystinuria (1). tHcy concentrations are ∼10-fold higher in patients with untreated homocystinuria than in the general population, and these patients often suffer from CVD in early life. Homocystinuria may arise from one of several rare defects in genes involved in methionine metabolism, resulting in high tHcy concentrations, with cystathionine β-synthase ( CBS gene) deficiency being the most common. In responsive cases of homocystinuria, dietary supplementation with B-vitamins and betaine is remarkably effective at lowering plasma tHcy concentrations and decreasing the risk of CVD (2). In addition to suggesting that extremely high tHcy concentrations may be causally related to CVD in affected individuals with homocystinuria, McCully also suggested that moderately increased tHcy concentrations may be related to CVD risk in the general population (1). A single discrete mechanism of vascular injury has not been identified, but high homocysteine may have adverse effects on platelet function and clotting factors and may increase vascular smooth muscle cell proliferation. Furthermore, increased homocysteine concentrations provoke endothelial dysfunction, possibly mediated by oxidative stress or interference with nitric oxide function (3)(4). Over the last 3 decades, many observational epidemiological studies have reported associations between increased tHcy concentrations and risk of coronary heart disease (CHD) and stroke (5). Although results of prospective cohort studies (in which blood for tHcy determination was collected before the onset of disease) have been weaker and more inconsistent than those of retrospective studies (in which the blood was collected after the onset of disease), prospective studies are more reliable because they are not vulnerable to bias due to the effect of disease on tHcy (“reverse causality”) and because they control for confounding from established …

Clearance of marrow infiltration after 1 week of therapy for childhood lymphoblastic leukaemia: clinical importance and the effect of daunorubicin

Abstract: At the commencement of UKALL XI, a national MRC trial for childhood lymphoblastic leukaemia (ALL), the therapy included a bolus of daunorubicin (DR) on the first 2 d of the protocol. This component of treatment was subsequently withdrawn because of concern about long-term cardiotoxicity. All children both before and after this change of policy had their marrow status at the end of the first week assessed by central review as part of the trial to examine the clinical importance of the rate of disease clearance. This also afforded an opportunity to observe the effect of DR on gross residual disease at an early stage of therapy. 1419 children were studied: 342 received DR (‘recipients’), 1077 did not. 44% of the recipients completely cleared their marrow of blast cells after 8 d compared with 13% of the non-recipients (χ2=158.2, P 80% blasts) was less impressive but there was still a difference in favour of DR recipients (DR 9%, no DR 15%; χ2=7.7, P=0.006). The rate of disease clearance correlated with disease-free survival for both recipients and non-recipients, but there was no significant difference in outcome when comparing the two groups with each other, either in terms of disease-free or relapse-free survival. DR accelerated the rate of blast cell disappearance from the marrow but the difference this made to disease free survival is small or non-existent. It appears to be the relative speed of response to a given therapeutic regimen that is prognostically important rather than the absolute rate of response when comparing one treatment with another.