Epidémiologie et prise en charge du cancer colorectal: une étude de population en Valais

Entre 2006 et 2009, 774 cas de cancer colorectal in situ ou invasif ont été diagnostiqués en Valais. La proportion des hommes (59%) est plus élevée que celle des femmes (41%). L'âge moyen au diagnostic est de 70 ans. 79% des tumeurs sont invasives. Le côlon est la localisation la plus fréquente (71%). 20% des cas sont de stade 0, 36% de stade I et II, 18% de stade III et 22% de stade IV. Le mode de présentation le plus fréquent est de loin la consultation pour symptômes non urgents (75%). Toutefois, 9% des patients sont pris en charge en urgence. 95% des patients traités le sont par de la chirurgie seule ou en combinaison avec d'autres traitements. 82% des patients avec un cancer colorectal invasif ont été traités dans les 30 jours. En première intention, 95% des cancers du côlon invasifs ont un traitement chirurgical alors que 53% des cancers du rectum invasifs ont un traitement chirurgical et 36% une radio-chimiothérapie. La survie du cancer colorectal invasif est de 95% à 30 jours et de 79% à 1 an. La survie est plus basse chez les personnes de 70 ans et plus (à 30 jours: 92%; à 1 an: 70%) que chez les personnes de moins de 70 ans (à 30 jours: 99%; à 1 an: 90%). Elle est également moins bonne pour les stades IV de la maladie (à 30 jours: 91%; à 1 an: 54%) que pour les stades I-II (à 30 jours: 97%; à 1 an: 91%) ou III (à 30 jours: 98%; à 1 an: 92%). Ces observations indiquent que l'épidémiologie du cancer colorectal dans la population valaisanne est similaire à ce qui est décrit dans d'autres populations en Europe, que les modalités de prise en charge sont proches de celles proposées dans les guidelines et que la survie est similaire à celle observée en Suisse et dans d'autres pays européens.

Humoral and cellular immune responses against Type I cysteine proteinase of Leishmania infantum are higher in asymptomatic than symptomatic dogs selected from a naturally infected population.

Canids are natural reservoirs of Leishmania infantum and have been promoted as experimental hosts to decipher the pathogenesis of human visceral leishmaniasis (VL). In this study, the presence of IgG antibodies as well as the presence of mononuclear leukocytes reactive to different cysteine proteinases (CPs) were examined in 13 L. infantum-infected dogs (six with symptoms, seven asymptomatic). Cysteine proteinases which belong to papain-like enzymes known as clan CA are the most studied CPs of parasite protozoa. These molecules are expressed by the intracellular stages of the parasite and could be immunogenic. We studied Type II CP (CPA) and Type I CP (CPB) with its long C-terminal extension (CTE) which could be highly immunogenic. We showed that the level of antibodies reactive to rCPA is low in both symptomatic and asymptomatic dogs. In contrast, when CPB and CTE were used as antigens, the level of total IgG (with IgG2 superior to IgG1) reached higher values in asymptomatic dogs than in dogs with VL. While the peripheral blood mononuclear cell (PBMC) reactivity was significant when cultured in the presence of freezed/thawed (F/T) lysate, it remained low in presence of CP although always higher for PBMC recovered from asymptomatic dogs. We showed the importance of CPB and CTE in particular as a target of immune response and their potential use for serodiagnosis in asymptomatic dogs.

Determining the best population-level alcohol consumption model and its impact on estimates of alcohol-attributable harms.

BACKGROUND: The goals of our study are to determine the most appropriate model for alcohol consumption as an exposure for burden of disease, to analyze the effect of the chosen alcohol consumption distribution on the estimation of the alcohol Population- Attributable Fractions (PAFs), and to characterize the chosen alcohol consumption distribution by exploring if there is a global relationship within the distribution. METHODS: To identify the best model, the Log-Normal, Gamma, and Weibull prevalence distributions were examined using data from 41 surveys from Gender, Alcohol and Culture: An International Study (GENACIS) and from the European Comparative Alcohol Study. To assess the effect of these distributions on the estimated alcohol PAFs, we calculated the alcohol PAF for diabetes, breast cancer, and pancreatitis using the three above-named distributions and using the more traditional approach based on categories. The relationship between the mean and the standard deviation from the Gamma distribution was estimated using data from 851 datasets for 66 countries from GENACIS and from the STEPwise approach to Surveillance from the World Health Organization. RESULTS: The Log-Normal distribution provided a poor fit for the survey data, with Gamma and Weibull distributions providing better fits. Additionally, our analyses showed that there were no marked differences for the alcohol PAF estimates based on the Gamma or Weibull distributions compared to PAFs based on categorical alcohol consumption estimates. The standard deviation of the alcohol distribution was highly dependent on the mean, with a unit increase in alcohol consumption associated with a unit increase in the mean of 1.258 (95% CI: 1.223 to 1.293) (R2 = 0.9207) for women and 1.171 (95% CI: 1.144 to 1.197) (R2 = 0. 9474) for men. CONCLUSIONS: Although the Gamma distribution and the Weibull distribution provided similar results, the Gamma distribution is recommended to model alcohol consumption from population surveys due to its fit, flexibility, and the ease with which it can be modified. The results showed that a large degree of variance of the standard deviation of the alcohol consumption Gamma distribution was explained by the mean alcohol consumption, allowing for alcohol consumption to be modeled through a Gamma distribution using only average consumption.

Combined impact of negative lifestyle factors on cardiovascular risk in children: a randomized prospective study.

PURPOSE: Negative lifestyle factors are known to be associated with increased cardiovascular risk (CVR) in children, but research on their combined impact on a general population of children is sparse. Therefore, we aimed to quantify the combined impact of easily assessable negative lifestyle factors on the CVR scores of randomly selected children after 4 years. METHODS: Of the 540 randomly selected 6- to 13-year-old children, 502 children participated in a baseline health assessment, and 64% were assessed again after 4 years. Measures included anthropometry, fasting blood samples, and a health assessment questionnaire. Participants scored one point for each negative lifestyle factor at baseline: overweight; physical inactivity; high media consumption; little outdoor time; skipping breakfast; and having a parent who has ever smoked, is inactive, or overweight. A CVR score at follow-up was constructed by averaging sex- and age-related z-scores of waist circumference, blood pressure, glucose, inverted high-density lipoprotein, and triglycerides. RESULTS: The age-, sex-, pubertal stage-, and social class-adjusted probabilities (95% confidence interval) for being in the highest CVR score tertile at follow-up for children who had at most one (n = 48), two (n = 64), three (n = 56), four (n = 41), or five or more (n = 14) risky lifestyle factors were 15.4% (8.9-25.3), 24.3% (17.4-32.8), 36.0% (28.6-44.2), 49.8% (38.6-61.0), and 63.5% (47.2-77.2), respectively. CONCLUSIONS: Even in childhood, an accumulation of negative lifestyle factors is associated with higher CVR scores after 4 years. These negative lifestyle factors are easy to assess in clinical practice and allow early detection and prevention of CVR in childhood.

Relationship between imatinib population pharmacokinetics and alpha-1-acid glycoprotein

Objectives: Considering the large inter-individual differences in the function of the systems involved in imatinib disposition, exposure to this drug can be expected to vary widely among patients. Among those known systems is alpha-1-acid glycoprotein (AGP), a circulating protein that strongly binds imatinib. This observational study aimed to explore the influence of plasma AGP on imatinib pharmacokinetics. Methods: A population pharmacokinetic analysis was performed using NONMEM based on 278 plasma samples from 51 oncologic patients, for whom both total imatinib and AGP plasma concentrations were measured. The influence of this biological covariate on oral clearance and volume of distribution was examined. Results: A one-compartment model with first-order absorption appropriately described the data. A hyperbolic relationship between plasma AGP levels and oral clearance, as well as volume of distribution was observed. A mechanistic approach was built up, postulating that only the unbound imatinib concentration was able to undergo first-order elimination through an unbound clearance process, and integrating the dissociation constant as a parameter in the model. This approach allowed determining an average (± SEM) free clearance of 1310 (± 172) L/h and a volume of distribution of 301 (± 23) L. By comparison, the total clearance previously determined was 14 (± 1) L/h. Free clearance was affected by body weight and pathology diagnosis. Moreover, this model provided consistent estimates of the association constant between imatinib and AGP (5.5?106 L/mol) and of the average in vivo free fraction of imatinib (1.1%). The variability observed (17% for free clearance and 66% for volume of distribution) was less than the one previously reported without considering AGP impact. AGP explained indeed about one half of the variability observed in total imatinib disposition. Conclusion: Such findings clarify in part the in vivo impact of protein binding on imatinib disposition and might raise again the question whether high levels of AGP could represent a resistance factor to imatinib. This remains however questionable, as it is not expected to affect free drug concentrations. On the other hand, would imatinib be demonstrated as a drug requiring therapeutic drug monitoring, either the measurement of free concentration or the correction of the total concentration by the actual AGP plasma levels should be considered for accurate interpretation of the results.

The association between cigarettes smoking, cannabis use and alcohol consumption in a population of young men: results of a population-based survey.

BACKGROUND: Cigarette smoking is often initiated at a young age as well as other risky behaviors such as alcohol drinking, cannabis and other illicit drugs use. Some studies suggest that cigarette smoking may have an influence on other risky behaviors but little is known about the chronology of occurrence of those different habits. The aim of this study was to assess, by young men, what were the other risky behaviors associated with cigarette smoking and the joint prevalence and chronology of occurrence of those risky behaviors. METHODS: Cross-sectional analyses of a population-based census of 3526 young men attending the recruitment for the Swiss army, aged between 17 and 25 years old (mean age: 19 years old), who filled a self reported questionnaire about their alcohol, cigarettes, cannabis and other illicit drugs habits. Actual smoking was defined as either regular smoking (¡Ý1 cigarette/day, on every day) or occasional smoking, binge drinking as six or more drinks at least twice a month, at risk drinking as 21 drinks or more per week, recent cannabis use as cannabis consumption at least once during the last month, and use of illicit drugs as consumption once or more of illicit drugs other than cannabis. Age at begin was defined as age at first use of cannabis or cigarette smoking. RESULTS: In this population of young men, the prevalence of actual smoking was 51.2% (36.5% regular smoking, 14.6% occasionnal smoking). Two third of participamnts (60.1%) declared that they ever used cannabis, 25.2% reported a recent use of cannabis. 53.8% of participants had a risky alcohol consumption considered as either binge or at risk drinking. Cigarette smoking was significantly associated with recent cannabis use (Odds Ratio (OR): 3.85, 95% Confidence Interval (CI): 3.10- 4.77), binge drinking (OR: 3.48, 95% CI: 3.03-4.00), at risk alcohol drinking (OR: 4.04, 95% CI: 3.12-5.24), and ever use of illicit drugs (OR: 4.34, 95% CI: 3.54-5.31). In a multivariate logistic regression, odds ratios for smoking were increased for cannabis users (OR 3.10,, 95% CI: 2.48-3.88), binge drinkers (OR: 1.77, 95% CI: 1.44-2.17), at risk alcohol drinkers (OR 2.26, 95% CI: 1.52-3.36) and ever users of illicit drugs (OR: 1.56, 95% CI: 1.20-2.03). The majority of young men (57.3%) initiated smoking before cannabis and mean age at onset was 13.4 years old, whereas only 11.1% began to use cannabis before smoking cigarettes and mean age at onset was slightly older (14.4 years old). 31.6% started both cannabis and tobacco at the same age (15 years old). About a third of participants (30.5%) did have a cluster of risky behaviours (smoking, at risk drinking, cannabis use) and 11.0% did cumulate smoking, drinking, cannabis and ever use of illegal drugs. More than half of the smokers (59.6%) did cumulate cannabis use and at risk alcohol drinking whereas only 18.5% of non-smokers did. CONCLUSIONS: The majority of young smokers initiated their risky behaviors by first smoking and then by other psychoactive drugs. Smokers have an increased risk to present other risky behaviors such as cannabis use, at risk alcohol consumtion and illicit drug use compared to nonsmokers. Prevention by young male adults should focus on smoking and also integrate interventions on other risky behaviors.

The Lausanne cohort Lc65+: a population-based prospective study of the manifestations, determinants and outcomes of frailty

BACKGROUND: Frailty is a relatively new geriatric concept referring to an increased vulnerability to stressors. Various definitions have been proposed, as well as a range of multidimensional instruments for its measurement. More recently, a frailty phenotype that predicts a range of adverse outcomes has been described. Understanding frailty is a particular challenge both from a clinical and a public health perspective because it may be a reversible precursor of functional dependence. The Lausanne cohort Lc65+ is a longitudinal study specifically designed to investigate the manifestations of frailty from its first signs in the youngest old, identify medical and psychosocial determinants, and describe its evolution and related outcomes. METHODS/DESIGN: The Lc65+ cohort was launched in 2004 with the random selection of 3054 eligible individuals aged 65 to 70 (birth year 1934-1938) in the non-institutionalized population of Lausanne (Switzerland). The baseline data collection was completed among 1422 participants in 2004-2005 through questionnaires, examination and performance tests. It comprised a wide range of medical and psychosocial dimensions, including a life course history of adverse events. Outcomes measures comprise subjective health, limitations in activities of daily living, mobility impairments, development of medical conditions or chronic health problems, falls, institutionalization, health services utilization, and death. Two additional random samples of 65-70 years old subjects will be surveyed in 2009 (birth year 1939-1943) and in 2014 (birth year 1944-1948). DISCUSSION: The Lc65+ study focuses on the sequence "Determinants --> Components --> Consequences" of frailty. It currently provides information on health in the youngest old and will allow comparisons to be made between the profiles of aging individuals born before, during and at the end of the Second World War.

Participation in a population-based physical activity programme as an aid for smoking cessation: a randomised trial.

OBJECTIVES: Exercise combined with nicotine therapy may help smoking cessation and minimise weight gain after quitting. Low participation in vigorous-intensity physical activity programmes precludes their population-wide applicability. In a randomised controlled trial, we tested whether a population-based moderate-intensity physical activity programme increases quit rates among sedentary smokers receiving nicotine therapy. METHODS: Participants (n=481; 57% male; mean age, 42.2 years (SD 10.1); mean cigarette consumption, 27 (SD 10.2) per day) were offered a nine-week smoking cessation programme consisting of a weekly 15-minute counselling session and the prescription of nicotine replacement therapy. In addition, participants in the physical activity group (n=229) also took part in a programme of moderate-intensity physical activity implemented at the national level, and offering nine weekly 60-minute sessions of physical activity. To ensure equal contact conditions, participants in the control group (n=252) attended weekly 60-minute health behaviour education sessions unrelated to physical activity. The primary outcome was continuous CO-verified smoking abstinence rates at 1-year follow-up. RESULTS: Continuous smoking abstinence rates were high and similar in the physical activity group and the control group at the end of the intervention (47% versus 46%, p=0.81) and at 1-year follow-up (27% versus 29%, p=0.71). The mean weight gain after one year was 4.4 kg and 6.2 kg among sustained quitters of the physical activity and control groups, respectively (p=0.06). CONCLUSION: Participation in a population-based moderate-intensity physical activity programme for 9 weeks in addition to a comprehensive smoking cessation programme did not significantly increase smoking cessation rates. A non-significant reduction in weight gain was observed among participants who quit smoking in the physical activity group. TRIAL REGISTRATION: ClinicalTrials.gov; US National Institutes for Health (available online at http://clinicaltrials.gov/; CLINICAL TRIAL REGISTRATION NUMBER: NCT00521391).

Individual reproductive success and effective population size in the greater white-toothed shrew Crocidura russula.

In order to investigate the determinants of effective population size in the socially monogamous Crocidura russula, the reproductive output of 44 individuals was estimated through genetic assignment methods. The individual variance in breeding success turned out to be surprisingly high, mostly because the males were markedly less monogamous than expected from previous behavioural data. Males paired simultaneously with up to four females and polygynous males had significantly more offspring than monogamous ones. The variance in female reproductive success also exceeded that of a Poisson distribution (though to a lesser extent), partly because females paired with multiply mated males weaned significantly more offspring. Polyandry also occurred occasionally, but only sequentially (i.e. without multiple paternity of litters). Estimates of the effective to census size ratio were ca. 0.60, which excluded the mating system as a potential explanation for the high genetic variance found in this shrew's populations. Our data suggest that gene flow from the neighbourhood (up to one-third of the total recruitment) is the most likely cause of the high levels of genetic diversity observed in this shrew's subpopulations.

Ten-year trends in overweight and obesity in the adult Portuguese population, 1995 to 2005.

ABSTRACT: BACKGROUND: There is little information regarding the trends in body mass index (BMI) and obesity in the overall Portuguese population, namely if these trends are similar according to educational level. In this study, we assessed the trends in the prevalence of overweight and obesity in the Portuguese population, overall and by educational level. METHODS: Cross-sectional national health interview surveys conducted in 1995-6 (n=38,504), 1998-9 (n=38,688) and 2005-6 (n=25,348). Data were derived from the population and housing census of 1991 and two geographically-based strata were defined. The sampling unit was the house, and all subjects living in the sampling unit were surveyed. Height and weight were self-reported; the effects of gender, age group and educational level were also assessed by self-reported structured questionnaires. Bivariate comparisons were performed using Chi-square or analysis of variance (ANOVA). Trends in BMI levels were assessed by linear regression analysis, while trends in the prevalence of obesity were assessed by logistic regression. RESULTS: Mean (+/-standard deviation) BMI increased from 25.2+/-4.0 in 1995-6 to 25.7+/-4.5 kg/m2 in 2005-6. Prevalence of overweight remained stable (36.1% in 1995-6 and 36.4% in 2005) while prevalence of obesity increased (11.5% in 1995-6 and 15.1% in 2005-6). Similar findings were observed according to age group. Mean age-adjusted BMI increase (expressed in kg/m2/year and 95% confidence interval) was 0.073 (0.062, 0.084), 0.016 (0.000, 0.031) and 0.073 (0.049, 0.098) in men with primary, secondary and university levels, respectively; the corresponding values in women were 0.085 (0.073, 0.097), 0.052 (0.035, 0.069) and 0.062 (0.038, 0.084). Relative to 1995-6, obesity rates increased by 48%, 41% and 59% in men and by 40%, 75% and 177% in women with primary, secondary and university levels, respectively. The corresponding values for overweight were 6%, 1% and 23% in men and 5%, 7% and 65% in women. CONCLUSION: Between 1995 and 2005, obesity increased while overweight remained stable in the adult Portuguese population. Although higher rates were found among lesser educated subjects, the strong increase in BMI and obesity levels in highly educated subjects is of concern.

Population pharmacokinetic analysis and pharmacogenetics of raltegravir in HIV-positive and healthy individuals.

The objectives of this study were to characterize raltegravir (RAL) population pharmacokinetics in HIV-positive (HIV(+)) and healthy individuals, identify influential factors, and search for new candidate genes involved in UDP glucuronosyltransferase (UGT)-mediated glucuronidation. The pharmacokinetic analysis was performed with NONMEM. Genetic association analysis was performed with PLINK using the relative bioavailability as the phenotype. Simulations were performed to compare once- and twice-daily regimens. A 2-compartment model with first-order absorption adequately described the data. Atazanavir, gender, and bilirubin levels influenced RAL relative bioavailability, which was 30% lower in HIV(+) than in healthy individuals. UGT1A9*3 was the only genetic variant possibly influencing RAL pharmacokinetics. The majority of RAL pharmacokinetic variability remains unexplained by genetic and nongenetic factors. Owing to the very large variability, trough drug levels might be very low under the standard dosing regimen, raising the question of a potential relevance of therapeutic drug monitoring of RAL in some situations.

Population pharmacokinetics of imatinib and the role of alpha-acid glycoprotein

AIMS: The aims of this observational study were to assess the variability in imatinib pharmacokinetics and to explore the relationship between its disposition and various biological covariates, especially plasma alpha1-acid glycoprotein concentrations. METHODS: A population pharmacokinetic analysis was performed using NONMEM based on 321 plasma samples from 59 patients with either chronic myeloid leukaemia or gastrointestinal stromal tumours. The influence of covariates on oral clearance and volume of distribution was examined. Furthermore, the in vivo intracellular pharmacokinetics of imatinib was explored in five patients. RESULTS: A one-compartment model with first-order absorption appropriately described the data, giving a mean (+/-SEM) oral clearance of 14.3 l h-1 (+/-1.0) and a volume of distribution of 347 l (+/-62). Oral clearance was influenced by body weight, age, sex and disease diagnosis. A large proportion of the interindividual variability (36% of clearance and 63% of volume of distribution) remained unexplained by these demographic covariates. Plasma alpha1-acid glycoprotein concentrations had a marked influence on total imatinib concentrations. Moreover, we observed an intra/extracellular ratio of 8, suggesting substantial uptake of the drug into the target cells. CONCLUSION: Because of the high pharmacokinetic variability of imatinib and the reported relationships between its plasma concentration and efficacy and toxicity, the usefulness of therapeutic drug monitoring as an aid to optimizing therapy should be further investigated. Ideally, such an approach should take account of either circulating alpha1-acid glycoprotein concentrations or free imatinib concentrations.