Showing papers by "Clinical Trial Service Unit published in 2005"

Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300,000 women in US SEER cancer registries.

Abstract: Summary Background Radiotherapy for early breast cancer can decrease breast cancer mortality but increase other mortality, mainly from heart disease and lung cancer. The mean cardiac dose from irradiation of a left-sided breast cancer can be two or three times that for a right-sided breast cancer. The mean ipsilateral (ie, on the same side as the breast cancer) lung dose can also be two or three times the mean contralateral lung dose. Particularly during the 1970s, when typical heart and lung exposures were greater than now, the laterality of an irradiated breast cancer could measurably affect cardiac mortality and mortality from cancer of the right or the left lung decades later. This study aimed to assess the hazards in the general US population from routine cancer-registry and death-certificate data. Methods We analysed data for 308 861 US women with early breast cancer of known laterality (left-sided or right-sided) who were registered in the US Surveillance Epidemiology and End Results (SEER) cancer registries during 1973–2001 and followed prospectively for cause-specific mortality until Jan 1, 2002. Findings 115 165 (37%) received radiotherapy. Among those who did not, tumour laterality was of little relevance to subsequent mortality. For women diagnosed during 1973–82 and irradiated, the cardiac mortality ratio (left versus right tumour laterality) was 1·20 (95% CI 1·04–1·38) less than 10 years afterwards, 1·42 (1·11–1·82) 10–14 years afterwards, and 1·58 (1·29–1·95) after 15 years or more (trend: 2p=0·03). For women diagnosed during 1983–92 and irradiated, the cardiac mortality ratio was 1·04 (0·91–1·18) less than 10 years afterwards and 1·27 (0·99–1·63) 10 or more years afterwards. For women diagnosed during 1993–2001 and irradiated the cardiac mortality ratio was 0·96 (0·82–1·12), with none yet followed for 10 years. Among women irradiated for breast cancer who subsequently developed an ipsilateral or contralateral lung cancer, the lung cancer mortality ratio (ipsilateral versus contralateral) for women diagnosed during 1973–82 and irradiated was 1·17 (0·62–2·19), 2·00 (1·00–4·00), and 2·71 (1·65–4·48), respectively, less than 10 years, 10–14 years, and 15 or more years afterwards (trend: 2p=0·04). For women irradiated after 1982 there is, as yet, little information on lung cancer risks more than 10 years afterwards. Interpretation US breast cancer radiotherapy regimens of the 1970s and early 1980s appreciably increased mortality from heart disease and lung cancer 10–20 years afterwards with, as yet, little direct evidence on the hazards after more than 20 years. Since the early 1980s, improvements in radiotherapy planning should have reduced such risks, but the long-term hazards in the general populations of various countries still need to be monitored directly.

Mortality from cancer in relation to smoking: 50 years observations on British doctors

Abstract: A total of 34 439 male British doctors, who reported their smoking habits in November 1951, were followed, with periodic up date of changes in their habits, until death, emigration, censoring. or November 2001. Information was obtained about their mortality from 28 of the 30 types of cancer in men reviewed by the International Agency for Research on Cancer (no death was recorded from the other two). In all, 11 of the 13 types in men that the Agency classed as liable to be caused by smoking were significantly related to smoking and the findings for the other two, which caused only few deaths, suggested they might be. Of the 13 types in men for which the Agency found only sparse or inconsistent data and for which we had data, only two appeared to be possibly related (one positively, one negatively), and the 638 deaths for the summed group were clearly unrelated to smoking. Of the two types for which the Agency thought that the relationship with smoking might be due to bias or confounding, the findings for one (prostate cancer) tended to support the belief that smoking was unrelated, and those for the other (colorectal cancer) showed a weak relationship with smoking, which (in a small subset) could not be attributed to confounding with the consumption of alcohol.

Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial.

Abstract: Summary Corticosteroids are an essential component of treatment for acute lymphoblastic leukaemia (ALL). Prednisolone is the most commonly used steroid, particularly in the maintenance phase of therapy. There is increasing evidence that, even in equipotent dosage for glucocorticoid effect, dexamethasone has enhanced lymphoblast cytotoxicity and penetration of the central nervous system (CNS) compared with prednisolone. Substitution of dexamethasone for prednisolone in the treatment of ALL might, therefore, result in improved event-free and overall survival. Children with newly diagnosed ALL were randomly assigned to receive either dexamethasone or prednisolone in the induction, consolidation (all received dexamethasone in intensification) and continuation phases of treatment. Among 1603 eligible randomized patients, those receiving dexamethasone had half the risk of isolated CNS relapse (P = 0·0007). Event-free survival was significantly improved with dexamethasone (84·2% vs. 75·6% at 5 years; P = 0·01), with no evidence of differing effects in any subgroup of patients. The use of 6·5 mg/m2 dexamethasone throughout treatment for ALL led to a significant decrease in the risk of relapse for all risk-groups of patients and, despite the increased toxicity, should now be regarded as part of standard therapy for childhood ALL.

Cohort Profile: The Kadoorie Study of Chronic Disease in China (KSCDC)

Abstract: During recent decades China has undergone a rapid transition in the main disease patterns of its population. There has been a substantial decrease in maternal and child mortality and in adult mortality from themain infectious/parasitic diseases, whereas for ischaemic heart disease and some other non-communicable chronic diseases, there has been a moderate increase in mortality rates, at least in some parts of China. Consequently, most of the premature mortality that still remains in China now involves the chronic diseases of middle age, such as cancer, stroke, heart disease, or chronic lung disease. 1–4 In the mid-1970s a retrospective survey of the causes of 20 million deaths in China during 1973–75 showed that for each major disease there was large unexplained variation in the age-specific rates between different parts of China, indicating that there must be some large avoidable causes. 5 This finding was confirmed and extended in the late 1980s by a more careful retrospective survey of the causes of one million deaths during 1986–88 in 69 rural counties and 24 cities (Figure 1). 3,4 These big differences in disease rates between one area and another probably reflect differences in the ways people live rather than genetic differences. Moreover, even within one area there are likely to be substantial differences between individuals in genetic factors, as well as in patterns of chronic infection, personal biochemistry, physical characteristics, lifestyle, etc. that persist for many years and eventually influence the likelihood of particular individuals developing particular diseases. 3,4

Post-Lyme borreliosis syndrome: a meta-analysis of reported symptoms

Abstract: symptoms listed above that compared patients who had had LB with controls from the general population. Five studies with 504 patients and 530 controls were included in the meta-analysis. Results The prevalence of symptoms was significantly higher in the LB patients, with P-values between � 0.00001 and 0.007 for 8 of the 10 symptoms in the three categories listed above. The higher prevalence of certain neurocognitive symptoms but not others, in the same pattern as reported in the literature, is further confirmation of this syndrome. The pattern of symptoms appears to be different from that seen in fibromyalgia, depression, and chronic fatigue syndrome. Conclusions This meta-analysis provides strong evidence that some patients with LB have fatigue, musculoskeletal pain, and neurocognitive difficulties that may last for years despite antibiotic treatment.

Low Doses of Ionizing Radiation and Circulatory Diseases: A Systematic Review of the Published Epidemiological Evidence

Abstract: McGale, P. and Darby, S. C. Low Doses of Ionizing Radiation and Circulatory Diseases: A Systematic Review of the Published Epidemiological Evidence. Radiat. Res. 163, 247– 257 (2005). Recent analyses of mortality among atomic bomb survivors have suggested a linear dose–response relationship between ionizing radiation and diseases of the circulatory system for exposures in the range 0–4 Sv. If confirmed, this has substantial implications. We have therefore reviewed the published literature to see if other epidemiological data support this finding. Other studies allowing a comparison of the rates of circulatory disease in individuals drawn from the same population but exposed to ionizing radiation at different levels within the range 0–5 Gy or 0–5 Sv were identified through systematic literature searches. Twenty-six studies were identified. In some, disease rates among those exposed at different levels may have differed for reasons unrelated to radiation exposure, while many had low power to detect...

Individual patient data meta-analyses

Abstract: Systematic reviews help people to make well-informed decisions about health care by bringing together the relevant evidence, appraising it and, where appropriate, combining it in a meta-analysis. The ultimate aim for a systematic review should be to present all relevant data on all participants in all research judged to be eligible for the review. In reviews of the effects of interventions, this ultimate aim would be met through the collection and analyses of the results of all relevant randomized trials. Reviews that use individual patient data achieve this by the central collection and analyses of data on each participant in the trials. It allows the reviewer to overcome many of the problems associated with a reliance on published data alone, and some of the problems associated with using aggregate data supplied by the trialist, and will add to the analyses that can be performed. This chapter discusses the rationale for individual patient data reviews and describes some of their features.

Self-reported and serum cotinine-validated smoking in pregnant women in Estonia.

Abstract: Objectives: Although widely used in epidemiological studies, self-report has been shown to underestimate the prevalence of smoking among pregnant women. Objectives of this study were to examine the discrepancy between self-reported and cotinine-validated smoking status, and the sociodemographic characteristics associated with the misclassification of real smoking status among pregnant women in Tallinn, the capital of Estonia. Methods: Serum cotinine assays were performed on a subsample (n= 1360) of the pregnant women, who had participated in a recent study of human papillomavirus type 16 (HPV-16) seroprevalence in Estonia. In the present study, serum concentrations ≥15 ng/ml were used to distinguish current smokers from nonsmokers. The serum-validated smoking level was compared with the self-reported level in the records of the Estonian Medical Birth Registry. For the group of self-reported non-smokers, the differences between the cotinine-validated smokers and the cotinine-validated nonsmokers, with respect to their sociodemographic characteristics (age, ethnicity, educational level, employment status, marital status, parity), were estimated by logistic regression. Results: Of 1239 women who reported being nonsmokers, 259 (20.9%) had serum cotinine levels ≥15 ng/ml, and can be regarded as current smokers. Among self-reported nonsmokers, nondisclosure of current smoking was significantly more frequent in non-Estonian, less educated, socially inactive, cohabiting and multiparous women. Conclusions: Self-reported data on smoking in pregnant women underestimates the real smoking prevalence in Estonia. Maternal unwillingness to declare smoking during pregnancy needs to be taken into account in the practice of maternal and child health to better target prenatal smoking cessation interventions.

Del (9q) AML: clinical and cytological characteristics and prognostic implications.

Abstract: Del (9q) is a recurrent cytogenetic abnormality in acute myeloid leukaemia (AML). We report an analysis of 81 patients with del(9q) as a diagnostic karyotypic abnormality entered into the Medical Research Council AML trials 10, 11 and 12. Patients were divided into three groups: (i) Sole del (9q), 21 patients; (ii) Del(9q) in association with t(8;21), 29 patients; (iii) Del(9q) in association with other cytogenetic abnormalities, 31 patients. Sole del(9q) was associated with a characteristic bone marrow phenotype at diagnosis: a single Auer rod was found in all cases examined. There was also an association with erythroid dysplasia (74%) and granylocytic lineage vacuolation (90%). The incidence of all three of these features was significantly higher (P < 0.05) in the sole del(9q) group compared with control cases lacking del(9q). The overall survival (OS) of all 81 patients was compared with a control group of 1738 patients with normal cytogenetics entered in the same trials over the period of investigation. The 5-year OS for patients with del(9q) was 45%, compared with 35% for the control group (P = 0.09). Patients with del(9q) in association with t(8;21) had a 5-year OS of 75%, which was significantly better than the groups with either sole del(9q) (40%) and del(9q) with other abnormalities (26%; P = 0.008). Karyotyping indicated a common area of deletion in the region 9q21-22, which was present in 94% of cases. It is likely that the deletion of single or multiple tumour suppressor genes located in this region may underlie the pathogenesis of del (9q) AML.

Combined Effects of Systolic Blood Pressure and Total Cholesterol on Cardiovascular Disease Risk

Abstract: Half of all adult deaths (and much severe disability) are caused by cardiovascular diseases, and most of these deaths involve ischemic heart disease or stroke. The Asia-Pacific region accounts for about half of the global burden of cardiovascular disease and the proportion is likely to increase during the next few decades.1,2 Smoking and elevated levels of systolic blood pressure (SBP) and total blood cholesterol are major causes of cardiovascular disease,3 yet much of our knowledge about the associations between these risk factors and cardiovascular diseases comes from studies carried out in North American and western European countries. In most Asian countries, however, the mean levels of total cholesterol are lower than those found in Western countries and the incidence of coronary heart disease (CHD) is also lower, whereas the incidence of stroke, particularly hemorrhagic stroke, is higher. Article p 3384 The Asia Pacific Cohort Studies Collaboration report in this issue of Circulation investigates the combined effects of SBP and total cholesterol on risk of cardiovascular disease in a meta-analysis of 36 cohort studies (29 conducted in Asia and 7 from Australia and New Zealand) involving 380 000 individuals.4 This meta-analysis differs from previous studies in several ways: It is the largest study from this region, involving >3000 CHD events and 4000 stroke events; individual records were available for each of the participants in each study, with cause and age of death (if applicable); and information on several thousand repeat measurements of blood pressure and cholesterol made during prolonged follow-up allowed correction for “regression dilution.” These features …

Homocysteine-Lowering Trials for Prevention of Heart Disease and Stroke

Abstract: Dietary supplementation with B-vitamins that lower plasma total homocysteine concentrations are expected to lower the risk of cardiovascular disease. Folic acid and vitamin B (12) lower blood homocysteine concentrations by about 25-30% in populations without folic acid fortification, but by only 10-15% in populations with fortification. In observational studies, 25% lower homocysteine is associated with about 10% less coronary heart disease (CHD) and about 20% less stroke. This review examines the current status of 12 large-scale randomized trials of B-vitamin supplementation and risk of cardiovascular disease. Seven of these trials are being performed in populations without fortification (five involving participants with prior CHD, two with prior stroke) and five in populations with fortification (two with prior CHD, two with renal disease, and one with prior stroke). Many of these trials may not have included a sufficient number of people or lasted long enough to have adequate power to exclude false-negative results. Taken together, however, these trials involve 32,000 patients with prior vascular disease in unfortified populations and 20,000 (14,000 with vascular disease and 6000 with renal disease) patients in fortified populations. A metaanalysis of these trials should have adequate power to determine whether homocysteine-lowering vitamin supplements can reduce the risk of cardiovascular disease.

Aspirin for everyone older than 50? Against.

Abstract: Current population screening for vascular disease is neither efficient nor effective. Peter Elwood and colleagues believe we should have a public information strategy highlighting the benefits (and risks) of aspirin for older people, but Colin Baigent argues that the evidence of benefit is not yet strong enough An age threshold approach to aspirin prophylaxis in people without known vascular disease has two important problems. The balance of benefits and risks of aspirin in people aged 70 or over has not been clearly defined in randomised trials, and the benefits do not clearly exceed the risks in younger people without vascular disease. Consequently, it would be unwise to adopt such a policy, whatever age threshold is chosen, until we are sure that older patients will derive net benefit from it. Among high risk patients with known occlusive arterial disease and a greater than 3% annual risk of a vascular event (defined as non-fatal myocardial infarction, non-fatal stroke, or vascular death), the benefits of aspirin substantially outweigh the risks of bleeding. A recent meta-analysis of randomised trials of antiplatelet drugs versus control showed that for every 1000 such patients treated for a year, aspirin would be expected to prevent about 10-20 vascular events and cause one or two major gastrointestinal bleeds.1 In a wide range of high risk …

ETV6/RUNX1 fusion at diagnosis and relapse: some prognostic indications.

Abstract: This study was undertaken in order to compare the interphase and metaphase cytogenetics of 28 patients with ETV6/RUNX1 positive acute lymphoblastic leukemia, at diagnosis and relapse. The median time to relapse was 26 months. The significant fusion positive population heterogeneity revealed at interphase by a commercial probe for ETV6/RUNX1 fusion has not been described before. Six diagnostic samples had a single abnormal population; others had up to five each, which differed in the numbers of RUNX1 signals, and in the retention or loss of the second ETV6 signal. In contrast, the number of fusion signals was more constant. At relapse, there were fewer populations; the largest or unique clone was sometimes a re-emergence of a minor, diagnostic one, with a retained copy of ETV6 and the most RUNX1 signals. Abnormal, fusion negative clones were identified in bone marrow samples at extra-medullary relapse. Variant three or four-way translocations, which involved chromosomes 12 and 21, were prominent among the complex rearrangements revealed by metaphase FISH. The frequency of their occurrence at diagnosis and reappearance at relapse, sometimes accompanied by minor clonal evolution, was another new observation. Other recurrent cytogenetic features included a second copy of the fusion signal in six cases, partial duplication of the long arm of the X chromosome in two cases, and trisomy 10 in three cases. In comparing our data with previously reported cases, a picture is beginning to emerge of certain diagnostic features, which may provide circumstantial evidence of an increased risk of relapse.

Controlled trials testing two or more treatments simultaneously.

Abstract: In 1950, when I started clinical research in gastroenterology, the treatment of gastric ulcers was far from satisfactory. The role of Helicobacter pylori had not been discovered and the symptoms, although they could be relieved, kept on recurring irrespective of treatment and often eventually became so severe that the ulcer had to be resected with much of the acid secreting part of the stomach. Orthodox treatment consisted of five elements, which were combined with varying emphasis, depending on the views of the individual physicians. All of them prescribed alkalis for the relief of pain and all of them recommended bed rest if symptoms persisted. Nearly all advised a bland diet, varying from 2-hourly milk feeds to a convalescent diet that excluded fried foods, pastry, various meats, and raw vegetables. Nearly all sought to treat the postulated underlying emotional factors by discussion, reassurance, and a sedative. Lastly, in an attempt to reduce acid secretion and inhibit gastric tone, many also prescribed atropine or one of its synthetic analogues. To this schedule there was often added some new treatment that became popular for a while before being replaced by another: I had no difficulty in drawing up a list of remedies beginning with each letter of the alphabet. If, therefore, any substantial proportion of even the most promising remedies were to be properly evaluated it would take a very long time, so there would be considerable advantage in testing two or more in the same group of patients.

Homocysteine, B-vitamins, and the risk of cardiovascular disease

Abstract: Featured Article: Clarke R, Daly L, Robinson K, Naughton E, Cahalane S, Fowler B, Graham I. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991;324:1149 –55. Our report, published in the New England Journal of Medicine in 1991, demonstrated that hyperhomocysteinemia was present in about one-third of cases with early-onset coronary heart disease, cerebral vascular disease, and peripheral vascular disease, compared with none in the ageand sex-matched controls. The results were striking and suggested that hyperhomocysteinemia was associated with at least a 3-fold excess risk of vascular disease, after adjustment for established risk factors in this population. We defined hyperhomocysteinemia on the basis of the peak homocysteine concentrations after methionine loading in 25 obligate heterozygotes (i.e., parents of children with homozygous homocystinuria), compared with 28 ageand sexmatched controls. Using assays for cystathionine -synthase activity in a small number of cases and controls, we erroneously attributed most of the hyperhomocysteinemia to heterozygosity for cystathionine -synthase deficiency. Nevertheless, the report attracted considerable interest because homocysteine concentrations are easily lowered with folic acid, raising the prospect that such treatment might lower the risk of cardiovascular disease. The development of assays for total homocysteine in the early 1990s replaced the methionine-loading test and led to an exponential increase in the evidence on this topic. Our main findings were subsequently tested in tens of thousands of vascular disease cases and controls in many diverse settings and populations (1– 4 ). Our report was careful to state that it remained to be seen whether lowering homocysteine would reduce the risk of cardiovascular disease. After completing my doctoral thesis on this topic at the National University of Ireland, I started work with Sir Rory Collins and Sir Richard Peto in the Clinical Trial Service Unit (CTSU) at the University of Oxford in 1991. I then spent the greater part of the subsequent 2 decades seeking to establish the causal relevance and clinical significance of the associations defined in our original report (1– 4 ). CTSU specializes in the conduct of large-scale trials, observational studies, and metaanalyses of such studies. We carried out 4 large-scale collaborative metaanalyses, mostly based on individual participant data, from the (a) dose-finding trials of folic acid assessing the effects on homocysteine concentrations, (b) the observational studies of homocysteine and cardiovascular disease, (c) the genetic studies of MTHFR [methylenetetrahydrofolate reductase (NAD(P)H)] variants and coronary disease, and (d) the large-scale homocysteine-lowering trials for the prevention of cardiovascular disease (4 ). The chief credit for these metaanalyses is to the many investigators worldwide who agreed to collaborate and provide individual participant data from their studies to these collaborative metaanalyses. With data on about 2000 individuals in the Homocysteine Lowering Trialists’ Collaboration, 20 000 individuals in the Homocysteine Studies Collaboration, 50 000 cases in the B-Vitamin Treatment Trialists’ Collaboration, and 120 000 individuals in the MTHFR Studies Collaboration, we were able to influence both the design of homocysteine-lowering trials worldwide and the interpretation of the observational studies and randomized trials (1– 4 ). The SEARCH trial carried out by CTSU in Oxford tested the effects of almost 7 years of treatment with 2 mg folic acid and 1 mg vitamin B12, compared with placebo, in 12 064 patients with a prior myocardial infarction. Despite a 28% reduction in homocysteine concentrations in the SEARCH trial, B vitamins had no significant effects on vascular outcomes (3 ). Taken together with 7 other trials in the first cycle of the B-Vitamin Treatment Trialists’ Collaboration, we examined the effect of allocation to folic acid or placebo for 5 years (on average) on 9326 major vascular events, 3010 cancers, and 5125 deaths (4 ). Allocation to folic acid yielded a mean 25% reduction in homocysteine concentrations but had no significant effect on major vascular events in 37 500 participants, overall or in any of the prespecified subgroups. Folic acid was also not associated with any significant excess risk of cancer or cause-specific mortality. Although the lack of any 1 Clinical Trial Service Unit, University of Oxford, Oxford, UK. 2 This article has been cited more than 1450 times since publication. * Address correspondence to the author at: Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Richard Doll Bldg., Old Road Campus, Roosevelt Dr., Oxford OX3 7LF, UK. Fax 44-1865-743985; e-mail robert.clarke@ctsu.ox.ac.uk. Received March 28, 2011; accepted May 16, 2011. Previously published online at DOI: 10.1373/clinchem.2011.164855 Clinical Chemistry 57:8 1201–1202 (2011) Citation Classic