Preconceptual folic acid: opportunity for preconceptual counseling offers opportunity to help prevent neural tube defects.
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Counseling↗
Biomedical subjects
M Buyse
Publications and source records attributed to M Buyse.
Tumour site, sex, and survival in colorectal cancer.
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Colorectal Neoplasms↗
Relation between tumour response to first-line chemotherapy and survival in advanced colorectal cancer: a meta-analysis. Meta-Analysis Group in Cancer.
BACKGROUND: Treatment of advanced colorectal cancer has progressed substantially. However, improvements in response rates have not always translated into significant survival benefits. Doubts have therefore been raised about the usefulness of tumour response as a clinical endpoint. METHODS: This meta-analysis was done on individual data from 3791 patients enrolled in 25 randomised trials of first-line treatment with standard bolus intravenous fluoropyrimidines versus experimental treatments (fluorouracil plus leucovorin, fluorouracil plus methotrexate, fluorouracil continuous infusion, or hepatic-arterial infusion of floxuridine). Analyses were by intention to treat. FINDINGS: Compared with bolus fluoropyrimidines, experimental fluoropyrimidines led to significantly higher tumour response rates (454 responses among 2031 patients vs 209 among 1760; odds ratio 0.48 [95% CI 0.40-0.57], p<0.0001) and better survival (1808 deaths among 2031 vs 1580 among 1760; hazard ratio 0.90 [0.84-0.97], p=0.003). The survival benefits could be explained by the higher tumour response rates. However, a treatment that lowered the odds of failure to respond by 50% would be expected to decrease the odds of death by only 6%. In addition, less than half of the variability of the survival benefits in the 25 trials could be explained by the variability of the response benefits in these trials. INTERPRETATION: These analyses confirm that an increase in tumour response rate translates into an increase in overall survival for patients with advanced colorectal cancer. However, in the context of individual trials, knowledge that a treatment has benefits on tumour response does not allow accurate prediction of the ultimate benefit on survival.
Antimetabolites, Antineoplastic↗
R(2): a useful measure of model performance when predicting a dichotomous outcome.
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Acquired Immunodeficiency Syndrome↗
Meta-analysis of observed mortality data from all-controlled, double-blind, multiple-dose studies of losartan in heart failure. Losartan Heart Failure Mortality Meta-analysis Study Group.
Clinical studies of heart failure utilizing losartan, an angiotensin-II receptor antagonist, found that this drug is well tolerated and demonstrates hemodynamic, neurohormonal, and symptomatic improvement. To assess all-cause mortality in heart failure patients treated with losartan, a meta-analysis including 1,896 patients was performed on 6 controlled, double-blind, multiple-dose studies, regardless of sample size or duration of follow-up. A combination of logarithmic (log) odds ratios with a continuity correction was utilized for the meta-analysis. Treatment groups were comparable with regard to demographic characteristics, heart failure characteristics, and concomitant cardiovascular therapies. Concomitant use of open-label angiotensin-converting enzyme (ACE) inhibitors was not allowed in any study. The mean left ventricular ejection fraction obtained in individual studies ranged from 23% to 31%. Seven hundred forty patients were randomized to control therapy and 1,154 patients were randomized to losartan therapy. There were 36 deaths (3.12%) in the losartan groups compared with 47 in the control groups (6.35%) during the double-blind periods. The odds of dying in the losartan groups were 0.51 times (0.31 to 0.81) that of dying in the control groups (p = 0.004). In this analysis, treatment with losartan provided a beneficial effect upon survival. However, because the number of deaths in these studies is relatively small and the follow-up relatively short, a large confirmatory study is needed to assess the mortality benefit of losartan compared with an ACE inhibitor.
Adult↗
Fraud in medical research: an international survey of biostatisticians. ISCB Subcommittee on Fraud.
The characteristics of scientific fraud and its impact on medical research are in general not well known. However, the interest in the phenomenon has increased steadily during the last decade. Biostatisticians routinely work closely with physicians and scientists in many branches of medical research and have therefore unique insight into data. In addition, they have methodological competence to detect fraud and could be expected to have a professional interest in valid results. Biostatisticians therefore are likely to provide reliable information on the characteristics of fraud in medical research. The objective of this survey of biostatisticians, who were members of the International Society for Clinical Biostatistics, was to assess the characteristics of fraud in medical research. The survey was performed between April and July 1998. The participation rate was only 37%. We report the results because a majority (51%) of the participants knew about fraudulent projects, and many did not know whether the organization they work for has a formal system for handling suspected fraud or not. Different forms of fraud (e.g., fabrication and falsification of data, deceptive reporting of results, suppression of data, and deceptive design or analysis) had been observed in fairly similar numbers. We conclude that fraud is not a negligible phenomenon in medical research, and that increased awareness of the forms in which it is expressed seems appropriate. Further research, however, is needed to assess the prevalence of different types of fraud, as well as its impact on the validity of results published in the medical literature.
Biometry↗
The validation of surrogate endpoints in meta-analyses of randomized experiments.
The validation of surrogate endpoints has been studied by Prentice (1989). He presented a definition as well as a set of criteria, which are equivalent only if the surrogate and true endpoints are binary. Freedman et al. (1992) supplemented these criteria with the so-called 'proportion explained'. Buyse and Molenberghs (1998) proposed replacing the proportion explained by two quantities: (1) the relative effect linking the effect of treatment on both endpoints and (2) an individual-level measure of agreement between both endpoints. The latter quantity carries over when data are available on several randomized trials, while the former can be extended to be a trial-level measure of agreement between the effects of treatment of both endpoints. This approach suggests a new method for the validation of surrogate endpoints, and naturally leads to the prediction of the effect of treatment upon the true endpoint, given its observed effect upon the surrogate endpoint. These ideas are illustrated using data from two sets of multicenter trials: one comparing chemotherapy regimens for patients with advanced ovarian cancer, the other comparing interferon-alpha with placebo for patients with age-related macular degeneration.
Journal Article↗
Recent meta-analyses in colorectal cancer.
Meta-analyses play an important role in the current emergence of evidence-based medicine. This paper reviews the meta-analyses reported in the past 3 years in colorectal cancer, from a clinical as well as a statistical perspective. The usefulness of meta-analyses in our understanding and management of colorectal cancer is highlighted for screening, risk of colorectal cancer occurrence, outcome of colorectal cancer, adjuvant treatment, follow-up, and treatment of advanced disease.
Adjuvants, Immunologic↗
Leptin secretion and leptin receptor in the human stomach.
BACKGROUND AND AIM: The circulating peptide leptin produced by fat cells acts on central receptors to control food intake and body weight homeostasis. Contrary to initial reports, leptin expression has also been detected in the human placenta, muscles, and recently, in rat gastric chief cells. Here we investigate the possible presence of leptin and leptin receptor in the human stomach. METHODS: Leptin and leptin receptor expression were assessed by immunohistochemistry, reverse transcriptase-polymerase chain reaction (RT-PCR), and western blot analysis on biopsy samples from 24 normal individuals. Fourteen (10 healthy volunteers and four patients with non-ulcer dyspepsia and normal gastric mucosa histology) were analysed for gastric secretions. Plasma and fundic mucosa leptin content was determined by radioimmunoassay. RESULTS: In fundic biopsies from normal individuals, immunoreactive leptin cells were found in the lower half of the fundic glands. mRNA encoding ob protein was detected in the corpus of the human stomach. The amount of fundic leptin was 10.4 (3.7) ng leptin/g mucosa, as determined by radioimmunoassay. Intravenous infusions of pentagastrin or secretin caused an increase in circulating leptin levels and leptin release into the gastric juice. The leptin receptor was present in the basolateral membranes of fundic and antral gastric cells. mRNA encoding Ob-RL was detected in both the corpus and antrum, consistent with a protein of approximately 120 kDa detected by immunoblotting. CONCLUSION: These data provide the first evidence of the presence of leptin and leptin receptor proteins in the human stomach and suggest that gastric epithelial cells may be direct targets for leptin. Therefore, we conclude that leptin may have a physiological role in the human stomach, although much work is required to establish this.
Adult↗
Meta-analysis: methods, strengths, and weaknesses.
Meta-analysis is a systematic, quantitative approach to the combination of data from several clinical trials that address the same question. This analytic approach can help resolve questions that remain unclear from the results of individual trials. Meta-analysis is of particular interest in oncology because of the small differences in efficacy between therapeutic alternatives. The large number of patients included in meta-analyses permit small to moderate benefits of a treatment to be reliably detected and larger treatment benefits to be quantified more accurately. Despite these apparent benefits, the use of meta-analysis has met with a great deal of resistance and has generated much controversy in clinical journals. After a brief description of the basic methods of conducting meta-analyses, this article will explore both their advantages and disadvantages.
Bias↗
The role of biostatistics in the prevention, detection and treatment of fraud in clinical trials.
Recent cases of fraud in clinical trials have attracted considerable media attention, but relatively little reaction from the biostatistical community. In this paper we argue that biostatisticians should be involved in preventing fraud (as well as unintentional errors), detecting it, and quantifying its impact on the outcome of clinical trials. We use the term 'fraud' specifically to refer to data fabrication (making up data values) and falsification (changing data values). Reported cases of such fraud involve cheating on inclusion criteria so that ineligible patients can enter the trial, and fabricating data so that no requested data are missing. Such types of fraud are partially preventable through a simplification of the eligibility criteria and through a reduction in the amount of data requested. These two measures are feasible and desirable in a surprisingly large number of clinical trials, and neither of them in any way jeopardizes the validity of the trial results. With regards to detection of fraud, a brute force approach has traditionally been used, whereby the participating centres undergo extensive monitoring involving up to 100 per cent verification of their case records. The cost-effectiveness of this approach seems highly debatable, since one could implement quality control through random sampling schemes, as is done in fields other than clinical medicine. Moreover, there are statistical techniques available (but insufficiently used) to detect 'strange' patterns in the data including, but no limited to, techniques for studying outliers, inliers, overdispersion, underdispersion and correlations or lack thereof. These techniques all rest upon the premise that it is quite difficult to invent plausible data, particularly highly dimensional multivariate data. The multicentric nature of clinical trials also offers an opportunity to check the plausibility of the data submitted by one centre by comparing them with the data from all other centres. Finally, with fraud detected, it is essential to quantify its likely impact upon the outcome of the clinical trial. Many instances of fraud in clinical trials, although morally reprehensible, have a negligible impact on the trial's scientific conclusions.
Biometry↗
Economic implications of hepatic arterial infusion versus intravenous chemotherapy or symptom palliation in the treatment of nonresectable colorectal liver metastases. Meta-Analysis Group In Cancer.
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Antineoplastic Agents↗
The role of anthracyclines in epithelial ovarian cancer.
This paper provides a survey on anthracycline treatment in ovarian cancer, focusing on toxicity and analysis of treatment results. Meta-analyses and studies in which anthracyclines have been combined with "standard" taxoid regimens are reviewed. The data suggest that the addition of an anthracycline to front-line non-taxoid based therapy is beneficial. The addition of an anthracycline to a combination of a taxoid and platinum derivative is rationale and feasible and randomised trials are on their way to completion. It is important that the final conclusions of these studies are based on long-term survival data, not just on the assessment of median differences in survival.
Antibiotics, Antineoplastic↗
Survival impact of chemotherapy in patients with colorectal metastases confined to the liver: a re-analysis of 1458 non-operable patients randomised in 22 trials and 4 meta-analyses. Meta-Analysis Group in Cancer.
BACKGROUND: Metastases confined to the liver is a frequent situation in patients with advanced colorectal cancer. For non-operable patients, 5-FU-based chemotherapy is often proposed but the importance of the choice of first line 5-FU regimen remains debatable. DESIGN: In four previously performed meta-analyses, our group had compared bolus intravenous fluoropyrimidines (bolus FU group) with experimental fluoropyrimidines (experimental FU group), consisting of 5-FU plus leucovorin, 5-FU plus methotrexate, continuous infusion 5-FU, or hepaticartery infusion FUDR. We re-analysed this data set to focus on 1458 patients with non-operable colorectal metastases confined to the liver, randomised in 22 trials. All analyses were stratified by trial and used individual patient data. RESULTS: Median survival times were 11.3 months in the bolus FU group (95% CI: 10.5-12.0 months) compared to 12.7 months in the experimental FU group (95% CI: 120-13.1 months). This difference, although clinically small, was statistically significant, with an overall survival hazard ratio of 0.88 (95% CI: 0.79-0.99, P = 0.037). In a multivariate analysis, performance status was the only significant predictor of survival (P < 10(-4)), whereas the statistical significance of allocated treatment was borderline (P = 0.058). CONCLUSIONS: The outcome of patient with non-operable colorectal metastases confined to the liver is poor, and mainly driven by their initial performance status. Experimental chemotherapy schedules yield a small improvement in their overall survival, indicating the importance of the choice of first-line chemotherapy.
Adenocarcinoma↗
Physiological role of cholecystokinin B/gastrin receptor in leptin secretion.
In the present study, we investigated whether cholecystokinin (CCK) or its structurally related peptide gastrin participates in long term regulation of adipocyte leptin secretion. The levels of circulating leptin observed after 2 and 6 h of refeeding in 18-h fast rats were significantly lowered by injection of the specific gastrin/CCK-B receptor antagonist YM022 at doses that did not affect feeding behavior. Moreover, in normally fed animals, circulating leptin was markedly decreased by chronic injection of YM022 (from 4 +/- 0.6 to 2.1 +/- 0.5 ng/ml). Consistent with these observations, YM022 treatment decreased leptin messenger RNA (mRNA) levels and increased the leptin content in rat epididymal fat tissue. Rat adipocytes exclusively contain gastrin/CCK-B receptor mRNA, but not CCK-A receptor mRNA. Furthermore, adipocyte membranes bound [125I]CCK-8 in a saturable manner, with kinetics consistent with a single class of high affinity sites with a Kd of 0.2 nM. These data argue for a physiological role for the CCK-B/gastrin receptor in adipocyte leptin regulation. We therefore propose that gastrin is involved in long term regulation of leptin expression and secretion in rat fat tissues through activation of an adipocyte gastrin/CCK-B receptor.
Adipose Tissue↗
[Resection of lung metastases: long-term results and prognostic analysis based on 5206 cases--the International Registry of Lung Metastases].
The International Registry of Lung Metastases was established in 1991 to asses the long-term results of pulmonary metastasectomy. The Registry has accrued 5206 cases of lung metastasectomy, from 18 departments of thoracic surgery in Europe (n = 13), USA (n = 4) and Canada (n = 1). Of these patients 4572 (88%) underwent complete surgical resection. The primary tumor was epithelial in 2260 (43%), sarcoma in 2173 (42%), germ cell in 363 (7%), and melanoma in 328 (6%) patients. The disease-free interval was 0 to 11 months in 1729 (33%) cases, 12 to 35 months in 1857 (36%) and more than 36 months in 1620 (31%). Single metastases accounted for 2383 (46%) cases and multiple lesions for 2726 (52%). Mean follow up was 46 months. Analysis was performed by Kaplan-Meier estimates of survival, relative risk of death and multivariate Cox model. The actuarial survival after complete metastasectomy was 36% at 5 years, 26% at 10 years and 22% at 15 years (median 35 months); the corresponding values for incomplete resection were 13% at 5 years and 7% at 10 years (median 15 months). Among complete resections, the 5-year survival was 33% for patients with a disease free-interval of 0 to 11 months and 45% for those with a disease-free interval of more than 36 months; 43% for single lesions and 27 for four or more lesions. Multivariate analysis showed a better prognosis for patients with germ cell tumors, disease-free interval of 36 months and more and single metastases. These results confirm that lung metastasectomy is a safe and potentially curative procedure.
Adolescent↗
Meta-analyses of published results are unreliable.
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Breast Neoplasms↗
Anemia in children with cancer is associated with decreased erythropoietic activity and not with inadequate erythropoietin production.
A defect in erythropoietin (EPO) production has been advocated as being the main cause of anemia presented at time of diagnosis or during treatment by adults with solid tumors. On the basis of this defect, anemic cancer patients, both adults and children, have been treated with recombinant human EPO (rHuEPO). To further elucidate the pathophysiology of anemia in children with cancer, we measured serum soluble transferrin receptor (sTfR), a quantitative marker of erythropoiesis, and serum EPO at time of diagnosis and during chemotherapy in children suffering from solid tumor or leukemia. We determined serum EPO in 111 children (55 leukemia, 56 solid tumors) at time of diagnosis. In the last 44 patients (23 leukemia and 21 solid tumors), sTfR levels were also measured. Serum EPO together with sTfR levels were also determined in 60 children receiving chemotherapy (29 leukemia, 31 solid tumors). These results were compared with those obtained from appropriate control groups. In all patients, we found a highly significant correlation between the logarithm of EPO (log[EPO]) and the hemoglobin (Hb) level. In all subsets of patients, sTfR levels were inappropriately low for the degree of anemia. Neither leukemic nor solid tumor groups showed a significant inverse relationship between log(sTfR) and the Hb level as would be expected in anemic patients with appropriate marrow response. Thus, in children with cancer, anemia is associated with a decreased total bone marrow erythropoietic activity which, in contrast to what has been reported in anemic cancer adults, is not related to defective EPO production.
Adolescent↗