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Biomedical subjects

C Robertson

Publications and source records attributed to C Robertson.

At least 19 recordsLinked to original sources
PubMed1998

Biologic activity of tamoxifen at low doses in healthy women.

BACKGROUND: Results of a clinical trial recently completed in the United States indicate that administration of tamoxifen (20 mg/day) to women at risk can reduce breast cancer incidence by approximately 50% but is associated with an increased risk of developing endometrial cancer and venous thromboembolic events. Since these adverse effects may be dose related, we investigated the effect of tamoxifen on several biomarkers when the drug was given at doses lower than those currently in use. METHODS: In two sequential experiments, 127 healthy hysterectomized women aged 35-70 years were randomly assigned to one of the following four treatment arms: placebo (n = 31) or tamoxifen at 20 mg/day (n = 30) (first experiment); or tamoxifen at 10 mg/day (n = 34) or tamoxifen at 10 mg/ alternate days (n = 32) (second experiment). Baseline and 2-month measurements of the following parameters were compared: 1) total cholesterol (primary end point) and other surrogate markers of cardiovascular disease, e.g., low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, and lipoprotein(a); 2) blood cell count; 3) fibrinogen; 4) antithrombin III; 5) osteocalcin; and, 6) in a subgroup of 103 women, insulin-like growth factor-I (IGF-I), a possible surrogate marker for breast cancer. RESULTS: After adjustment for the baseline values, there were reductions in circulating levels of total cholesterol and IGF-I of the same magnitude in all three tamoxifen treatment arms. A similar pattern was observed for most of the other parameters. In the placebo arm, fibrinogen level, which showed a decrease, was the only parameter exhibiting change. CONCLUSIONS: Up to a 75% reduction in the conventional dose of tamoxifen (i.e., 20 mg/day) does not affect the activity of the drug on a large number of biomarkers, most of which are surrogate markers of cardiovascular disease. This study was hypothesis generating, and larger studies are warranted to assess the efficacy of tamoxifen at low doses.

Adult↗
PubMed1998

The role of N-acetylation polymorphisms in smoking-associated bladder cancer: evidence of a gene-gene-exposure three-way interaction.

Arylamines are known bladder carcinogens and are an important constituent of tobacco smoke. The handling of arylamines in the body is complex and includes metabolism by NAT1 and NAT2, enzymes that play a role in both activation and detoxification of arylamines and their congeners. Both NAT1 and NAT2 are polymorphic, with alleles that have been shown to correlate with higher or lower enzyme activity. To explore the combined role of these genes and exposure on bladder cancer risk, we examined the NAT1 and NAT2 genotype in a case-control study of bladder cancer in which detailed exposure histories were available on all 230 cases and 203 frequency-matched controls. Using PCR-RFLP genotyping, we determined NAT2 genotype for the five most common alleles, NAT2*4, NAT2*5, NAT2*6, NAT2*7, NAT2*14 (frequently referred to as WT, M1, M2, M3, and M4, respectively). Similarly, the NAT1 genotype was determined for the four most common alleles NAT1*3, NAT1*4, and NAT1*11, and the putative high-activity allele, NAT1*10. No association between NAT2 genotype and bladder cancer risk was found whether genotype was considered alone or in combination with smoking, in either stratified or logistic regression analysis that adjusted for age, sex, and race. Stratified and logistic regression analysis both demonstrated an increased risk for individuals carrying the NAT1*10 allele among smokers. There was evidence of a gene-dosage effect, such that those who were homozygous for the NAT1*10 allele had the highest risks. There was also evidence of a statistically significant gene-environment interaction, such that bladder cancer risk depends on both NAT1 genotype and smoking exposure. Interestingly, although NAT2 genotype did not influence risk either alone or in combination with smoking exposure, there was evidence of a statistically significant gene-gene-environment three-way interaction. Bladder cancer risk from smoking exposure is particularly high in those who inherit NAT2 slow alleles in combination with one or two copies of the NAT1*10 allele. A biological mechanism for this finding is suggested.

Acetylation↗
PubMed1998

Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study.

BACKGROUND: Tamoxifen is a candidate chemopreventive agent in breast cancer, although the drug may be associated with the development of endometrial cancer. Therefore we did a trial in hysterectomised women of tamoxifen as a chemopreventive. METHODS: In October, 1992, we started a double-blind placebo-controlled, randomised trial of tamoxifen in women (mainly in Italy) who did not have breast cancer and who had had a hysterectomy. Women were randomised to receive tamoxifen 20 mg per day or placebo, both orally for 5 years. The original plan was to follow the intervention phase by 5 years' follow-up. In June, 1997, the trialists and the data-monitoring committee decided to end recruitment primarily because of the number of women dropping out of the study. Recruitment ended on July 11, 1997, and the study will continue as planned. The primary endpoints are the occurrence of and deaths from breast cancer. This preliminary interim analysis is based on intention-to-treat. FINDINGS: 5408 women were randomised; participating women have a median follow-up of 46 months for major endpoints. 41 cases of breast cancer occurred so far; there have been no deaths from breast cancer. There is no difference in breast-cancer frequency between the placebo (22 cases) and tamoxifen (19) arms. There is a statistically significant reduction of breast cancer among women receiving tamoxifen who also used hormone-replacement therapy during the trial: among 390 women on such therapy and allocated to placebo, we found eight cases of breast cancer compared with one case among 362 women allocated to tamoxifen. Compared with the placebo group, there was a significantly increased risk of vascular events and hypertriglyceridaemia among women on tamoxifen. INTERPRETATION: Although this preliminary analysis has low power, in this cohort of women at low-to-normal risk of breast cancer, the postulated protective effects of tamoxifen are not yet apparent. Women using hormone-replacement therapy appear to have benefited from use of tamoxifen. There were no deaths from breast cancer recorded in women in the study. It is essential to continue follow-up to quantify the long-term risks and benefits of tamoxifen therapy.

Adult↗
PubMed1998

Age-period-cohort analysis of chronic disease rates. I: Modelling approach.

Age-Period-cohort models are widely used by epidemiologists to analyse trends in disease incidence and mortality. The interpretation of such models is fraught with difficulty in view of the exact linear dependency between the three variables. It is the purpose of this paper to review, compare and contrast some of the more common approaches to this problem based on Poisson regression and a linear model for the log rates. Also the results of using the different approaches on a single series of data on breast cancer incidence among females in Scotland from 1960-1989 are presented for comparison. Recommendations as to the merits and drawbacks of the approaches are also given in the conclusions. Models which are based upon the estimable contrasts such as local curvatures and deviations from linearity are most suitable.

Adolescent↗
PubMed1998

Age-period-cohort models of chronic disease rates. II: Graphical approaches.

In a companion article we have reviewed a number of available modelling approaches employed in estimating the influence of age, period and cohort effects on chronic disease rates. Here we review some of the graphical methods for displaying disease rates with a view to extracting information about the separate and joint effects of age, period and cohort. The more traditional displays such as line charts are compared to approaches based on smoothing and two- and three-dimensional plots which have recently been proposed. Other graphical techniques which are principally concerned with displaying interactions, such as biplots and correspondence analysis, are also considered. These techniques are illustrated with examples to compare the techniques revealing their strengths and weaknesses. It is clear that graphical approaches can be useful tools in understanding the behaviour of chronic disease time trends.

Adult↗
PubMed1998

Age at any birth and breast cancer risk.

This paper reviews previously published models of the effect of parity and age at any birth on breast cancer risk. It is shown that these models are conceptually similar and can be written within a general model. Various restrictions on the parameters of the general model yield the specific models. The models are applicable in case control studies and are illustrated using data from a case control study of breast cancer in Italy.

Age Factors↗
PubMed1998

Similar decreases in local tumor control are calculated for treatment protraction and for interruptions in the radiotherapy of carcinoma of the larynx in four centers.

PURPOSE: Data on patients with cancer of the larynx are analyzed using statistical models to estimate the effect of gaps in the treatment time on the local control of the tumor. METHODS AND MATERIALS: Patients from four centers, Edinburgh, Glasgow, Manchester, and Toronto, with carcinoma of the larynx and treated by radiotherapy were followed up and the disease-free period recorded. In all centers the end point was control of the primary tumor after irradiation alone. The local control rates at > or = 2 years, Pc, were analyzed by log linear models, and Cox proportional hazard models were used to model the disease-free period. RESULTS: T stage, nodal involvement, and site of the tumor were important determinants of the disease-free interval, as was the radiation schedule used. Elongation of the treatment time by 1 day, or a gap of 1 day, was associated with a decrease in Pc of 0.68% per day for Pc = 0.80, with a 95% confidence interval of (0.28, 1.08)%. An increase of 5 days was associated with a 3.5% reduction in Pc from 0.80 to 0.77. At Pc = 0.60 an increase of 5 days was associated with an 7.9% decrease in Pc. The time factor in the Linear Quadratic model, gamma/alpha, was estimated as 0.89 Gy/day, 95% confidence interval (0.35, 1.43) Gy/day. CONCLUSIONS: Any gaps (public holidays are the majority) in the treatment schedule have the same deleterious effect on the disease free period as an increase in the prescribed treatment time. For a schedule, where dose and fraction number are specified, any gap in treatment is potentially damaging.

Carcinoma↗
PubMed1998

Tamoxifen reduces plasma homocysteine levels in healthy women.

Treatment with tamoxifen is associated with reduced incidence of myocardial infarction. As plasma homocysteine is an independent risk factor for cardiovascular disease, we studied the effects of tamoxifen on plasma homocysteine in 66 healthy women participating in the Italian prevention trial of breast cancer who were randomized in a double-blind manner to tamoxifen 20 mg day(-1) or placebo for 5 years. They were aged between 35 and 70 years, had undergone previous hysterectomy for non-malignant conditions and had no contraindications to the use of tamoxifen. Plasma levels of total homocysteine (tHcy) were measured at randomization and after 2 and 6 months. The mean +/- s.d. plasma levels of tHcy were 7.59 +/- 1.71 micromol l(-1), 7.25 +/- 1.61 and 7.09 +/- 1.33 in the tamoxifen group and 8.07 +/- 2.06, 7.93 +/- 1.77 and 8.12 +/- 2.04 in the placebo group at 0, 2 and 6 months (P = 0.008 for the between-group difference over time). The higher the baseline tHcy level, the greater was the lowering effect of tamoxifen. No statistically significant effect of age, body mass index or smoking habit on baseline tHcy levels and its variation over time was found. In conclusion, tamoxifen (20 mg day(-1) for 6 months) decreased plasma tHcy levels in healthy women. This effect may contribute to its protective effect on myocardial infarction.

Adult↗
PubMed1998

Effect of tamoxifen and transdermal hormone replacement therapy on cardiovascular risk factors in a prevention trial. Italian Chemoprevention Group.

The combination of tamoxifen and transdermal hormone replacement therapy (HRT) may potentially reduce risks and side-effects of either agent, but an adverse interaction could attenuate their beneficial effects. We assessed the effects of their combination on cardiovascular risk factors within a prevention trial of tamoxifen. Baseline and 12-month measurements of total, low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol, platelets and white blood cells were obtained in the following four groups: tamoxifen (n = 1117), placebo (n = 1112), tamoxifen and HRT (n = 68), placebo and HRT (n = 87). The analysis was further extended to women who were on HRT at randomization but discontinued it during the 12-month intervention period (n = 33 on tamoxifen and n = 35 on placebo) and to women who were not on HRT but started it during intervention (n = 36 in both arms of the study). Compared with small changes in the placebo group, tamoxifen was associated with changes in total, LDL- and HDL-cholesterol of approximately -9%, -19% and +0.2% in continuous HRT users compared with -9%, -14% and -0.8% in never HRT users. Similarly, there was no interaction on platelet count. In contrast, the decrease in total and LDL-cholesterol levels induced by tamoxifen was blunted by two-thirds in women who started HRT while on tamoxifen (P = 0.051 for the interaction term). We conclude that the beneficial effects of tamoxifen on cardiovascular risk factors are unchanged in current HRT users, whereas they may be attenuated in women who start transdermal HRT while on tamoxifen. Whereas a trial of tamoxifen in women already on transdermal HRT is warranted, prescription of HRT during tamoxifen may attenuate its activity.

Breast Neoplasms↗
PubMed1998

A study of proactive ethics consultation for critically and terminally ill patients with extended lengths of stay.

OBJECTIVE: To assess the effect of proactive ethics consultation on documented patient care communications and on decisions regarding high-risk intensive care unit (ICU) patients. DESIGN: Prospective, controlled study. PATIENTS: Ninety-nine ICU patients treated with >96 hrs of continuous mechanical ventilation. INTERVENTIONS: Three groups were compared: a) a baseline group enrolled in the study prior to the establishment of the hospital's ethics consultation service; b) a control group where ethics consultation was at the option of the care team; and c) a treatment group where the ethics service intervened proactively after patients received >96 hrs of continuous mechanical ventilation. Patient care planning, for subjects in the proactive group, was reviewed with physicians and with the care team using a standardized set of prompting questions designed to focus discussion of key decision-making and communication issues for critically and terminally ill patients. Issues and concerns were identified and action strategies were suggested to those in charge of the patient's care. Formal ethics consultation, using a patient care conference model, was made available upon request. MEASUREMENTS AND MAIN RESULTS: Post discharge chart reviews of the three groups indicated no statistically significant differences on important demographic variables including age, gender, and acuity. Comparisons of survivors and nonsurvivors for the three groups indicated, at statistically significant levels, more frequent and documented communications, more frequent decisions to forego life-sustaining treatment, and reduced length of stay in the ICU for the proactive consultation group. CONCLUSION: Proactive ethics consultation for high-risk patient populations offers a promising approach to improving decision-making and communication and reducing length of ICU stay for dying patients.

APACHE↗
PubMed1998

Elemental content of airway surface liquid from infants with cystic fibrosis.

We tested the hypothesis that airway surface liquid (ASL) electrolyte composition is altered in infants with cystic fibrosis (CF) and that the presence of airway inflammation affects ASL composition. We measured the tracheal ASL sodium and chloride concentration and examined bronchoalveolar lavage (BAL) fluid cytology, interleukin-8 (IL-8) concentrations, and quantitative bacterial culture in 19 infants and young children with CF. Seven infants undergoing bronchoscopy for the evaluation of stridor served as non-CF controls. In addition, we measured nasal ASL sodium and chloride concentrations from 10 young adults with CF and from 10 control subjects. On the basis of the BAL findings, the infants with CF were divided into three groups: one with little evidence of pulmonary inflammation (CF-NI, n = 5); one with obvious pulmonary inflammation (CF-I, n = 7); and an intermediate group (CF-MI, n = 7). We found the ASL sodium was not different among any of the four groups (means mM +/- SE, 85 +/- 10 controls; 78 +/- 16 CF-NI; 83 +/- 9 CF-MI, 84 +/- 9 CF-I). In contrast the ASL chloride was lower in the CF-NI group when compared with control subjects (108 +/- 5 control subjects; 77 +/- 7 CF-NI, p < 0.01). In the CF-I and CF-MI groups, the ASL chloride concentrations were of intermediate values (CF-I 95 +/- 10 mM; CF-MI 96 +/- 9 mM) and not significantly different from controls. Results from the nasal ASL analysis showed no significant differences in sodium and chloride concentrations in the CF group compared with control subjects. These results suggest that the primary abnormality of ASL composition is a reduction in chloride concentration. ASL composition appears to be affected by the presence of airway inflammation.

Adolescent↗
PubMed1998

Before viability: a geographically based outcome study of infants weighing 500 grams or less at birth.

OBJECTIVE: The primary objective of this study was to determine the likelihood of long-term survival and avoidance of disabilities in a geographically based population of infants born at 20 weeks gestation or more and weighing 500 g or less at birth. STUDY DESIGN: This was a 12-year historical cohort follow-up study of all infants born in this gestational age and birth weight category in the Province of Alberta, Canada, between 1983 and 1994. Data were collected from certificates of live births or stillbirths, death certificates, hospital records, and longitudinal multidisciplinary follow-up examinations. RESULTS: One thousand one hundred ninety-three infants were of 20 weeks gestation or more, weighed 500 g or less, and were born between 1983 and 1994. Eight hundred eleven (68.0%) were stillborn and 382 (32.0%) were born alive. Among the latter, neonatal intensive care was provided in 113 (29.6%) and withheld in 269 (70.4%). The infants receiving intensive care were of heavier birth weight, later gestational age, higher antenatal risk scores, were more likely to be born in a level III center, to have received antenatal steroids, and to have been delivered by cesarean section. Of the infants receiving intensive care, 95 (84. 1%) died and 18 (15.9%) were discharged alive, but 5 of these died after discharge because of respiratory complications. The infants discharged alive had later gestational age, were more likely to be small for gestational age, singletons, treated with antenatal steroids, and to have been delivered by cesarean section. Maternal indications were described in the majority of cesarean sections done for live-born infants. The 13 infants who were long-term survivors were followed at ages 12 and 36 months adjusted age. Four had no serious disabilities, 4 had one disability (cerebral palsy or mental retardation), and 5 had multiple disabilities (cerebral palsy plus mental retardation with blindness in 2 cases and deafness in 1 case). CONCLUSION: The majority of infants born at gestational age 20 weeks or more weighing <500 g were stillborn. Among live births, neonatal intensive care was withheld in 70% and initiated in 30%. Of the latter, 11% survived to 36 months of age, and of these, 4 infants (31%), most of whom are small for gestational age, female infants, avoided major disabilities but 9 (69%) had one or more major disabilities. Survivors are prone to rehospitalizations early in life, slow growth, feeding problems, and minor visual difficulties; rates of learning-related and behavioral problems at school age are not yet known. Implications. Parents and caregivers faced with the impending delivery of an infant in this gestational age/birth weight category should understand that survival without multiple major disabilities is possible but rare. They should be made aware of local population-based results and not just isolated reports.

Cerebral Palsy↗
PubMed1998

Risk factors for high-grade cervical intraepithelial neoplasia in patients with mild cytological dyskaryosis: human papillomavirus testing versus multivariate tree analysis of demographic data.

The objective of this study was to compare the use of molecular hybridization by hybrid capture methodology for human papillomavirus (HPV) with the use of demographic and lifestyle variables as intermediate triage in patients with cytological mild dyskaryosis. The study was designed as a prospective study using regression tree analysis of demographic data in consecutive patients who were subjected to colposcopic evaluation at the colposcopy clinic at the First Department of Obstetrics and Gynaecology, University of Milan (Milan, Italy). A total of 177 women were subjected to colposcopy because of a single routine Pap smear showing mild dyskaryosis. A structured interview, sampling for HPV testing for the detection of viral DNA by hybrid capture methodology, and colposcopic evaluation with cervical biopsies were performed for each subject. The accuracies of molecular hybridization for HPV and of the classification model based on the demographic and lifestyle variables in predicting patients with histologically high-grade cervical intraepithelial lesions were measured. The classification model based on the demographic and lifestyle variables showed comparable results with molecular hybridization for HPV (specificity, 0.75 versus 0.73; sensitivity, 0.61 versus 0.67, respectively). The use of demographic and lifestyle variables appears to be a simple and economic possibility for triaging patients with mild dyskaryotic smears in a screening program.

Adult↗
PubMed1997

Effect of parity and age at delivery on breast cancer risk in Slovenian women aged 25-54 years.

In 1988, a case-control study on breast cancer and oral contraceptives with 624 cases and 624 matched controls in the age range 25-54 years was undertaken in Slovenia. This analysis assesses the relationship between parity and breast cancer risk: the relative importance of age at first birth, age at subsequent births and total parity. We also evaluate whether a dual effect of an increased risk immediately after childbirth followed by a long-term benefit exists. Three logistic regression models were used. Age at first delivery is an important breast cancer risk factor: among parous women it was associated with a 5.3% increase/year in the odds of breast cancer. Multiparity was not shown to be an independent risk factor. Age at subsequent deliveries was associated with a 1% increase in risk for every 1 year increase of age at any birth, but this contribution to the risk was not significant. In the analysis stratified by parity the most important influence is with the age at first birth. We find no evidence of an effect on the odds of breast cancer associated with the age at the second, or later, births. We do find that there is an increased risk associated with the birth of the first child followed by a longer term protective effect. A post-menopausal woman has a reduced breast cancer risk compared with a pre-menopausal woman of the same age, adjusting for the same number of deliveries and ages at these deliveries.

Adult↗