Showing papers by "Clinical Trial Service Unit published in 2010"

Radiation-related heart disease: current knowledge and future prospects.

Abstract: INTRODUCTIONIt has been recognized since the 1960s that the heart may bedamaged by substantial doses of radiation [>30 Gray (Gy)],such as used to occur during mantle radiotherapy for Hodg-kin lymphoma. During the last few years, however, evidencethat radiation-related heart disease (RRHD) can occur fol-lowing doses below 20 Gy has emerged from several inde-pendent sources. Those sources include studies of breastcancer patients who received mean cardiac doses of 3 to 17Gy when given radiotherapy following surgery and studiesof survivors of the atomic bombings of Japan who receiveddoses of up to 4 Gy.At doses above 30 Gy, an increased risk of RRHD can be-comes apparent within a year or two of exposure, and the riskincreases with higher radiotherapy dose, younger age at irra-diation, and the presence of conventional risk factors. Atlower doses, the typical latency period is much longer andis often more than a decade. The nature and magnitude ofthe risk following lower doses is not well characterized,and it is not yet clear whether there is a threshold dose belowwhich there is no risk.The evidence regarding RRHD comes from several differ-ent disciplines. The present review brings together informa-tion from pathology, radiobiology, cardiology, radiationoncology, and epidemiology; it summarizes current knowl-edge, identifies gaps in that knowledge, and outlines somepotential strategies for filling them.CURRENT KNOWLEDGEPathologyThe pathological expressions of RRHD documented fol-lowing therapeutic irradiation can be broadly reduced tofour conditions: pericarditis, pericardial fibrosis, diffusemyocardial fibrosis, and coronary artery disease (CAD)(1, 2). Radiation may also cause valvular disease, althoughtheevidence for this isnotasstrong.None of these conditionsis specific to radiation.Radiation-related pericarditis is characterized by an exu-date of a variable amount of protein-rich fluid within thepericardial sac (pericardial effusion). Rapid accumulationof this fluid can, in rare cases, cause potentially fatal cardiactamponade. Almost invariably, fibrin accumulates on the

Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial

Abstract: Summary Background Chromosomal abnormalities in childhood acute lymphoblastic leukaemia are well established disease markers and indicators of outcomes. However, the long-term prognosis and independent prognostic effect of some abnormalities has been questioned. Also, little is known about the association between cytogenetics and the characteristics of relapse (eg, time and site of relapse) that are known to predict outcome after relapse. Methods We analysed cytogenetic data from 1725 children with B-cell precursor acute lymphoblastic leukaemia who were included in the UK Medical Research Council ALL97/99 study and followed up for a median time of 8·2 years. Univariate and multivariate analysis were done to examine risk of relapse, event-free survival, and overall survival associated with 21 chromosomal abnormalities and three cytogenetic risk groups constructed from these data. Findings Two chromosomal abnormalities were associated with a significantly better outcome ( ETV6–RUNX1 , hazard ratio [HR] 0·51, 95% CI 0·38–0·70 and high hyperdiploidy, 0·60, 0·47–0·78), whereas five abnormalities were associated with an increased risk of relapse (intrachromosomal amplification of chromosome 21 [iAMP21], 6·04, 3·90–9·35; t(9;22), 3·55, 2·21–5·72; MLL translocations, 2·98, 1·71–5·20; abnormal 17p, 2·09, 1·30–3·37; and loss of 13q, 1·87, 1·09–3·20). Multivariate analysis incorporating age, white-cell count, and treatment parameters showed that six cytogenetic abnormalities ( ETV6–RUNX1 , high hyperdiploidy, iAMP21, t(9;22), loss of 13q, and abnormal 17p) retained their significance for effect on relapse risk. Based on these data, patients were classified into good, intermediate, and poor cytogenetic risk groups. Slow early treatment response correlated with cytogenetic risk group: 34 of 460 (7%) in the good-risk group, 22 of 211 (10%) in the intermediate-risk group, and 27 of 95 (28%) in the poor-risk group had a slow response (p Interpretation Individual chromosomal abnormalities are strong independent indicators of outcome, especially risk of relapse. Diagnostic cytogenetics identifies patients with a higher rate of relapse and those who are likely to have a high-risk relapse. Funding Leukaemia and Lymphoma Research (LLR).

Fifty years of cancer incidence: CI5 I-IX.

Abstract: The Cancer Incidence in Five Continents (CI5) series comprises nine volumes that bring together peer-reviewed results from population-based cancer registries worldwide. The aim of each is to make available comparable data on cancer incidence from as wide a range of geographical locations as possible. In addition, the existence of long time series of data allows the evolution of risk in different populations over time to be studied. The CI5 I-IX database brings together the results from all nine volumes, spanning a period of some 50 years. In addition, unpublished annual data, with more diagnostic detail, are made available for many cancer registries with 15 or more years of recent data. We describe the construction and composition of the CI5 databases, and provide examples of how they can be used to prepare tables and graphs comparing incidence rates between populations. This is the classical role of descriptive statistics: to allow formulation of hypotheses that might explain the observed differences (geographically, over time, in population subgroups) and that can be tested by further study. Such statistics are also essential components in the planning and evaluation of cancer control programmes.

Minimal residual disease is a significant predictor of treatment failure in non T-lineage adult acute lymphoblastic leukaemia: final results of the international trial UKALL XII/ECOG2993.

Abstract: The predictive value of molecular minimal residual disease (MRD) monitoring using polymerase chain reaction amplification of clone-specific immunoglobulin or T-cell Receptor rearrangements was analysed in 161 patients with non T-lineage Philadelphia-negative acute lymphoblastic leukaemia (ALL) participating in the UK arm of the international ALL trial UKALL XII/Eastern Cooperative Oncology Group (ECOG) 2993. MRD positivity (> or =10(-4)) in patients treated with chemotherapy alone was associated with significantly shorter relapse-free survival (RFS) at several time-points during the first year of therapy. MRD status best discriminated outcome after phase 2 induction, when the relative risk of relapse was 8.95 (2.85-28.09)-fold higher in MRD-positive (> or =10(-4)) patients and the 5-year RFS 15% [95% confidence interval (CI) 0-40%] compared to 71% (56-85%) in MRD-negative (<10(-4)) patients (P = 0.0002) When MRD was detected prior to autologous stem cell transplantation (SCT), a significantly higher rate of treatment failure was observed [5-year RFS 25% (CI 0-55%) vs. 77% (95% CI 54-100%) in MRD-negative/<10(-4), P = 0.01] whereas in recipients of allogeneic-SCT in first complete remission, MRD positivity pre-transplant did not adversely affect outcome. These data provide a rationale for introducing MRD-based risk stratification in future studies for the delineation of those at significant risk of treatment failure in whom intensification of therapy should be evaluated.

Presentation and survival of patients with severe acute kidney injury and multiple myeloma: a 20-year experience from a single centre

Abstract: Background. Myeloma is the second most common haematological malignancy and is a cause of severe acute kidney injury (serum creatinine ≥500 μmol/L) that has long been associated with a poor prognosis, although previous series have been small. Methods. We have therefore documented the natural history of all 107 patients referred to a large regional renal unit over a 20-year period and investigated factors associated with survival over a long period of time using Cox regression methods. Results. Three factors were found to be significantly and independently associated with survival: use of chemotherapy [hazard ratio (HR) 0.21, 95% CI: 0.08―0.46, P < 0.001], serum albumin (HR 0.49, 95% CI: 0.29―0.82, P = 0.02 for ≥35 g/L versus <35 g/L) and dialysis independence (HR 0.43, 95% CI: 0.24―0.76, P = 0.005). However, survival was not found to be better for patients presenting in the second decade compared to the first (HR 0.88, 95% CI: 0.52―1.50, P = 0.65). Conclusions. This analysis highlights the need for clinical trials of novel chemotherapy regimens in this complicated group of patients. Furthermore, whether strategies to restore or preserve dialysis-independent renal function provide additional benefit to effective chemotherapy also requires further investigation. The advent of efficacious low toxicity chemotherapy (such as thalidomide and bortezomib) and new dialysis techniques to remove free light chains may radically alter the outcome of this group of patients.

Long-term follow-up of the United Kingdom medical research council protocols for childhood acute lymphoblastic leukaemia, 1980-2001.

Abstract: Between 1980 and 2001, the United Kingdom Medical Research Council Childhood Leukemia Working Party conducted four clinical trials in acute lymphoblastic leukaemia (ALL), which recruited a total of 6516 patients. UKALL VIII examined the role of daunorubicin in induction chemotherapy, and UKALL X examined the role of post-induction intensification. Both resulted in major improvement in the outcomes. UKALL XI examined the efficacy of different methods of central nervous system-directed therapy and the effects of an additional intensification. ALL97, which was initially based on the UKALL XD template (two intensification phases), examined the role of different steroids in induction and of different thiopurines through continuing chemotherapy. A reappraisal of results from UKALL XI compared with other cooperative group results led to a redesign in 1999, which subsequently resulted in a major improvement in outcomes. In addition, ALL97 and ALL97/99 showed a significant advantage for the use of dexamethasone rather than prednisolone; although the use of 6-thioguanine resulted in fewer relapses, this advantage was offset by an increased incidence of deaths in remission. Over the era encompassed by these four trials, there has been a major improvement in both event-free and overall survival for children in the United Kingdom with ALL.

Genome-Wide Association Study Reveals Multiple Loci Associated with Primary Tooth Development during Infancy

Abstract: Tooth development is a highly heritable process which relates to other growth and developmental processes, and which interacts with the development of the entire craniofacial complex. Abnormalities of tooth development are common, with tooth agenesis being the most common developmental anomaly in humans. We performed a genome-wide association study of time to first tooth eruption and number of teeth at one year in 4,564 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966) and 1,518 individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC). We identified 5 loci at P<5×10−8, and 5 with suggestive association (P<5×10−6). The loci included several genes with links to tooth and other organ development (KCNJ2, EDA, HOXB2, RAD51L1, IGF2BP1, HMGA2, MSRB3). Genes at four of the identified loci are implicated in the development of cancer. A variant within the HOXB gene cluster associated with occlusion defects requiring orthodontic treatment by age 31 years.

The influence of EDTA and citrate anticoagulant addition to human plasma on information recovery from NMR-based metabolic profiling studies.

Abstract: The widely-used blood anticoagulants citrate and EDTA give rise to prominent peaks in (1)H NMR spectra of plasma samples collected in epidemiological and clinical studies, and these cause varying levels of interference in recovering biochemical information on endogenous metabolites. To investigate both the potential metabolic information loss caused by these substances and any possible inter-molecular interactions between the anticoagulants and endogenous components, the (1)H NMR spectra of 40 split human plasma samples collected from 20 individuals into either citrate or EDTA have been analysed. Endogenous metabolite peaks were selectively obscured by large citrate peaks or those from free EDTA and its calcium and magnesium complexes. It is shown that the endogenous metabolites that give rise to peaks obscured by those from EDTA or citrate almost invariably also have other resonances that allow their identification and potential quantitation. Also, metabolic information recovery could be maximised by use of spectral editing techniques such as spin-echo, diffusion-editing and J-resolved experiments. The NMR spectral effects of any interactions between the added citrate or EDTA and endogenous components were found to be negligible. Finally, identification of split samples was feasible using simple multivariate statistical approaches such as principal components analysis. Thus even when legacy epidemiological plasma samples have been collected using the NMR-inappropriate citrate or EDTA anticoagulants, useful biochemical information can still be recovered effectively.

Dietary Determinants of Obesity

Abstract: Obesity has become a serious public health problem worldwide, and dietary composition can play a role in its prevention and treatment. However, available literature on the impacts of different dietary factors on weight change is inconsistent, or even conflicting. In this review, we briefly summarized the mechanisms and influences of several major dietary determinants of weight change, with a focus on their potential in the prevention of weight gain or regain. We discussed the intake of fat, protein, total carbohydrates, fruits and vegetables, fibre, free sugars, fructose and sugar sweetened beverages, dietary energy density, portion size, eating outside home, glycaemic index and glycaemic load. Popular weight loss diets, including the Atkins diet, Weight Watchers, Ornish diet and Zone diet, are also briefly discussed for their safety and efficacy in the maintenance of weight loss.

Temporal changes in the incidence and pattern of central nervous system relapses in children with acute lymphoblastic leukaemia treated on four consecutive Medical Research Council trials, 1985–2001

Abstract: Despite the success of contemporary treatment protocols in childhood acute lymphoblastic leukaemia (ALL), relapse within the central nervous system (CNS) remains a challenge. To better understand this phenomenon, we have analysed the changes in incidence and pattern of CNS relapses in 5564 children enrolled in four successive Medical Research Council-ALL trials between 1985 and 2001. Changes in the incidence and pattern of CNS relapses were examined and the relationship with patient characteristics was assessed. The factors affecting outcome after relapse were determined. Overall, relapses declined by 49%. Decreases occurred primarily in non-CNS and combined relapses with a progressive shift towards later (> or =30 months from diagnosis) relapses (P<0.0001). Although isolated CNS relapses declined, the proportional incidence and timing of relapse remained unchanged. Age and presenting white blood cell (WBC) count were risk factors for CNS relapse. On multivariate analysis, the time to relapse and the trial period influenced outcomes after relapse. Relapse trends differed within biological subtypes. In ETV6-RUNX1 ALL, relapse patterns mirrored overall trends whereas in high hyperdiploidy (HH) ALL, these seem to have plateaued over the latter two trial periods. Intensive systemic and intrathecal chemotherapy have decreased the overall CNS relapse rates and changed the patterns of recurrence. The heterogeneity of therapeutic response in the biological subtypes suggests room for further optimization using currently available chemotherapy.

Risk factors for breast cancer among Filipino women in Manila

Abstract: Age-adjusted incidence rates of breast cancer vary greatly worldwide with highest rates found in the typically 'westernised' countries of North America and Europe. Much lower rates are observed in Asian and African populations but an exception to this has been reported for the Manila Cancer Registry in the Philippines. The reason for this high rate is unknown but may be associated with the change in lifestyle that has occurred in urban Manila since the 1960s. In 1995, a randomised controlled trial was set up in Manila to evaluate the feasibility of a screening intervention by clinical breast examination as an alternative to mammography. The cohort of 151,168 women was followed-up to 2001 for cancer incidence and a nested case-control study carried out. This aimed to evaluate the increase in breast cancer risk associated with known risk factors. Increased risks were seen for a high level of education (OR = 1.9 95%CI 1.1-3.3 for education stopped at > or =13 versus or =30 versus <20 years). We found no association with excess body weight, height, use of exogenous hormones or alcohol consumption. From this study, the recognised "classical" risk factors do not fully explain the high breast cancer incidence in Metro Manila, especially when compared to other urban Asian populations. We conclude that it is too simplistic to ascribe the high risk to 'westernisation'.

Temporal trends in childhood leukaemia incidence following exposure to radioactive fallout from atmospheric nuclear weapons testing.

Abstract: Notably raised rates of childhood leukaemia incidence have been found near some nuclear installations, in particular Sellafield and Dounreay in the United Kingdom, but risk assessments have concluded that the radiation doses estimated to have been received by children or in utero as a result of operations at these installations are much too small to account for the reported increases in incidence. This has led to speculation that the risk of childhood leukaemia arising from internal exposure to radiation following the intake of radioactive material released from nuclear facilities has been substantially underestimated. The radionuclides discharged from many nuclear installations are similar to those released into the global environment by atmospheric nuclear weapons testing, which was at its height in the late-1950s and early-1960s. Measurements of anthropogenic radionuclides in members of the general public resident in the vicinity of Sellafield and Dounreay have found levels that do not differ greatly from those in persons living remote from nuclear installations that are due to ubiquitous exposure to the radioactive debris of nuclear weapons testing. Therefore, if the leukaemia risk to children resulting from deposition within the body of radioactive material discharged from nuclear facilities has been grossly underestimated, then a pronounced excess of childhood leukaemia would have been expected as a consequence of the short period of intense atmospheric weapons testing. We have examined childhood leukaemia incidence in 11 large-scale cancer registries in three continents for which data were available at least as early as 1962. We found no evidence of a wave of excess cases corresponding to the peak of radioactive fallout from atmospheric weapons testing. The absence of a discernible increase in the incidence of childhood leukaemia following the period of maximum exposure to the radioactive debris of this testing weighs heavily against the suggestion that conventional methods are seriously in error when assessing the risk of childhood leukaemia from exposure to man-made radionuclides released from nuclear installations.

Cystatin C and risk of vascular and nonvascular mortality: a prospective cohort study of older men

Abstract: . Emberson JR, Haynes R, Dasgupta T, Mafham M, Landray MJ, Baigent C, Clarke R (University of Oxford, Oxford, UK). Cystatin C and risk of vascular and nonvascular mortality: a prospective cohort study of older men. J Intern Med 2010; 268: 145–154. Objective. To assess the relevance of cystatin C, as a marker of mild-to-moderate renal impairment, for vascular and nonvascular mortality in older people. Design. Prospective cohort study. Setting. Re-survey in 1997 to 1998 of survivors in the 1970 Whitehall study of London civil servants. Subjects. Five thousand three hundred and seventy-one men (mean age at resurvey: 77 years) who took part in the resurvey and had plasma cystatin C concentration measured. Main outcome measures. Cause-specific mortality over subsequent 11 years (1997 to 2008). Methods. Cox regression was used to estimate the associations of cystatin C with vascular and nonvascular mortality, before and after adjustment for prior disease and other risk factors (including lifetime blood pressure). Results. During an 11.0-year follow-up period, there were 1171 deaths from vascular causes [26 per 1000 per year (py)] and 1615 deaths from nonvascular causes (36 per 1000 py). Compared with men with cystatin C in the bottom fifth of the distribution, men in the top 10th had about two-fold higher mortality rates from vascular and nonvascular mortality (fully adjusted P both <0.001) even after adjustment for prior disease and all measured confounders, including lifetime blood pressure. The fully adjusted relative risks per 50% higher cystatin C concentrations were 1.66 [95% CI 1.48 to 1.85] for vascular mortality, 1.92 [95% CI 1.66 to 2.22] for ischaemic heart disease mortality and 1.46 [95% CI 1.31 to 1.61] for nonvascular mortality. Conclusions. In older men, plasma concentration of cystatin C, probably as a marker of mild renal disease, is a strong independent predictor of both vascular and nonvascular mortality.

Lipids in chronic kidney disease

Abstract: Patients with chronic kidney disease (CKD) develop premature cardiovascular disease. In the general population (without CKD), there are strong associations between cholesterol fractions and the risk of coronary disease and weaker associations with stroke. Randomised trials in the general population demonstrate that lowering blood cholesterol (chiefly with a statin) reduces the risk of vascular events. Patients with CKD differ significantly from the general population. They have markedly disturbed lipid metabolism manifesting as elevated triglyceride concentrations, reduced HDL cholesterol concentrations and a preponderance of small, dense LDL particles that are potentially more atherogenic; the observed association between lipids and vascular disease is bizarre, and is confounded by co-morbidity; the nature of the vascular disease appears less strongly associated with classical atherosclerosis. Randomised trials are required to determine the relevance of blood lipids to the development of vascular disease in CKD patients, but the results of such studies have been inconclusive to date. CKD patients are at risk of end-stage renal disease. Lipids may be involved in the progression of renal disease. Modifying them may delay the progression of CKD. The current data are based on effects on markers of progression (e.g. proteinuria). The ongoing SHARP (Study of Heart and Renal Protection) trial should provide reliable information about the effects of statins on both vascular and renal risk.

How the NHS research governance procedures could be modified to greatly strengthen clinical research.

Abstract: Randomised controlled trials are the gold stan- dard for testing the efficacy and safety of health interventions, especially medications, and researchers in the UK are required to gain approval from ethics committees, the regulatory body (Medicines and Healthcare products Regulatory Agency) and local NHS research governance departments for such trials. Although research governance is important to reassure trial participants that their rights and interests are protected, cur- rent practice is impeding research and presents a genuine threat to the UK and to the NHS's ability to deliver high-quality evidence on which doctors can base clinical decisions and improve the delivery of care. This article discusses recent experience of running large-scale clinical trials and suggests measures that could improve the current situation.

Commentary: Body weight and mortality in the late 19th century

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