Addressing current treatment challenges in Crohn's disease in real life: A physician's survey.

BACKGROUND: In recent years several trials have addressed treatment challenges in Crohn's disease. Clinical trials however, represent a very special situation. AIMS: To perform a cross-sectional survey among gastroenterologists on the current clinical real life therapeutic approach focussing on the use of biologics. METHODS: A survey including six main questions on clinical management of loss of response, diagnostic evaluation prior to major treatment changes, preference for anti-tumour necrosis factor (TNF) agent, (de-)escalation strategies as well as a basic section regarding personal information was sent by mail to all gastroenterologists in Switzerland (n=318). RESULTS: In total, 120 questionnaires were analysed (response rate 37.7%). 90% of gastroenterologists in Switzerland use a thiopurine as the first step-up strategy (anti-TNF alone 7.5%, combination 2.5%). To address loss of response, most physicians prefer shortening the interval of anti-TNF administration followed by dose increase, switching the biologic and adding a thiopurine. In case of prolonged remission on combination therapy, the thiopurine is stopped first (52.6%) after a mean treatment duration of 15.7 months (biologic first in 41.4%). CONCLUSIONS: Everyday clinical practice in Crohn's disease patients appears to be incongruent with clinical data derived from major trials. Studies investigating reasons underlying these discrepancies are of need to optimize and harmonize treatment.

La spéciation écologique racontée au travers de l'étude de l'évolution des poissons-clowns et de quelques autres

Ecological speciation and its hallmark, adaptive radiation is a process from which most of the current biodiversity derives. As ecological opportunity allows species to colonise unoccupied niches, natural selection drives adaptive phenotypical change. In this thesis, I begin by describing how this evolutionary process acted on the evolution of the clownfishes. During its infancy, this iconic group of coral reef fishes developed a mutualism with sea anemone species. I show how this event triggered the evolutionary radiation of the group, generating species that now inhabit diverse habitats of the coral reefs. Following the appearance of the mutualism, the diversification of the clownfish was catalysed by hybridisation events which shuffled genes, allowing hybrids to reach new fitness optima. While the clownfishes appeared in the region of the coral triangle, a lineage colonised the eastern shores of Africa. I reconstructed the geographic history of the group and showed that this event lead to the rapid appearance of new species, replicating the evolutionary patterns of the original radiation. To better grasp the mechanisms of ecological speciation, I conducted analyses at the population level and identified similar evolutionary patterns than found at the clade level. I discuss how such result suggests a continuity bridging micro- and macroevolution, which so far only been theorised. In parallel to this study case, I question whether biotic and abiotic interactions can promote or restrain ecological speciation. Indeed, I show how the ecological setting of species can drastically impact on their diversification dynamics. Moreover, tradeoffs can occur between specialisation made on different ecological axes allowing species cohabitation. Overall, I show in this work that regardless of the few simple rules that explain the mechanism of ecological speciation, the unavoidable interactions with the ever changing ecological context lead diversification events to give always a different outcome. It is thus primordial to account for the ecological settings of species when discussing their evolutionary dynamics. LA SPÉCIATION ÉCOLOGIQUE RACONTÉE AU TRAVERS DE L'ÉTUDE DE L'ÉVOLUTION DES POISSONS-CLOWNS ET DE QUELQUES AUTRES Le phénomène de spéciation écologique est à l'origine de la majeure partie de la biodiversité que l'on rencontre aujourd'hui. Au fil des opportunités qu'elles rencontrent, les espèces colonisent l'espace écologique laissant la sélection naturelle forger leur phénotype moyen. Malgré l'omniprésence de ce phénomène dans la nature, beaucoup de questions qui lui sont relatives restent à élucider. C'est afin de mieux comprendre ce mécanisme que j'étudie les poissons-clowns, célèbres habitants des récifs coralliens. Dans ce travail, je démontré que le développement du comportement mutualiste liant les poissons-clowns aux anémones de mer fut l'événement qui déclencha leur diversification. Suite à ce premier événement, j'illustre comment l'hybridation entre lignées primordiales a remodelé la diversité génétique du groupe et catalysé leur radiation évolutive. Je poursuis en reconstruisant l'expansion géographique des poissons-clowns au cours du temps depuis le triangle de corail, leur lieu d'origine, jusqu'aux côtes d'Afrique de l'Ouest. Afin d'affiner ces analyses générales sur le groupe, je continue en étudiant plus finement des populations d'une seule espèce de poisson-clown. Cette fine résolution me permet de comprendre plus précisément quels sont les facteurs écologiques qui permettent aux poissons-clowns de se différencier. Les résultats de ces analyses suggèrent qu'il est important de comprendre les liens entre le contexte écologique et la diversification des espèces. J'étudie cette question dans la seconde partie de ce travail en montrant que l'hétérogénéité du paysage ou les liens entretenus avec un partenaire mutualiste influencent fortement la dynamique évolutive des espèces. Finalement, j'illustre les compromis que chaque espèce réalise en se spécialisant ou non dans ses interactions avec l'environnent. Plus généralement, je souligne dans ce travail l'influence du contexte écologique sur le résultat de la spéciation écologique. Ce sont ces interactions entre les organismes et leur environnent qui sont à l'origine de l'incroyable diversité de la vie. Il est donc primordial de les prendre en compte lors de l'étude de l'évolution des espèces.

Prévalence des thromboses veineuses mésentériques chez les patients atteints de maladie inflammatoire de l'intestin

Objectifs: Décrire la prévalence des thromboses veineuses mésentériques (TVM) chez des patients atteints de maladie inflammatoire de l'intestin (MICI). Matériels et méthodes: 161 patients (90 femmes, âge moyen 46ans) porteurs de MICI suivis dans la cohorte prospective suisse (SWISS IBD COHORT) et ayant eu une tomodensitomètrie abdominale ont été inclus (Crohn n=119 (74%), RCUH n=42 (26%)). Une analyse en consensus des branches mésentériques supérieures et inférieures a été faite à la recherche des signes d'obstruction aiguë (caillot intra-luminal) ou chroniques (rétrécissement/occlusion et collatérales veineuses). Une corrélation entre TVM et signes radiologiques classiques a été réalisée. Résultats: La TVM était présente chez 43 patients (26%) sous forme aiguë (n=2), chronique (n=36) ou les 2 (n=5). La prévalence est identique entre maladie de Crohn et RCUH (28 vs 27%) bien que les segments touchés soient différents (iléon vs rectosigmoïde). Chez 11/43 patients, la TVM est acquise car absente sur des examens antérieurs. L'existence d'une TVM était plus fréquemment associée à la présence d'une ascite (60% vs 24%) et d'une atteinte pariétale digestive (96% vs 73%). Conclusion: Les TVM son beaucoup plus fréquentes que décrites dans la litérature et sont aussi fréquentes dans la maladie de Crohn que dans la RCUH.

Comparative population genetic structure in a plant-pollinator/seed predator system.

Comparative analyses of spatial genetic structure of populations of plants and the insects they interact with provide an indication of how gene flow, natural selection and genetic drift may jointly influence the distribution of genetic variation and potential for local co-adaptation for interacting species. Here, we analysed the spatial scale of genetic structure within and among nine populations of an interacting species pair, the white campion Silene latifolia and the moth Hadena bicruris, along a latitudinal gradient across Northern/Central Europe. This dioecious, short-lived perennial plant inhabits patchy, often disturbed environments. The moth H. bicruris acts both as its pollinator and specialist seed predator that reproduces by laying eggs in S. latifolia flowers. We used nine microsatellite markers for S. latifolia and eight newly developed markers for H. bicruris. We found high levels of inbreeding in most populations of both plant and pollinator/seed predator. Among populations, significant genetic structure was observed for S. latifolia but not for its pollinator/seed predator, suggesting that despite migration among populations of H. bicruris, pollen is not, or only rarely, carried over between populations, thus maintaining genetic structure among plant populations. There was a weak positive correlation between genetic distances of S. latifolia and H. bicruris. These results indicate that while significant structure of S. latifolia populations creates the potential for differentiation at traits relevant for the interaction with the pollinator/seed predator, substantial gene flow in H. bicruris may counteract this process in at least some populations.

In vitro selection of bacteria with potential for use as probiotics in marine shrimp culture

The objective of this work was to isolate strains of lactic acid bacteria with probiotic potential from the digestive tract of marine shrimp (Litopenaeus vannamei), and to carry out in vitro selection based on multiple characters. The ideotype (ideal proposed strain) was defined by the highest averages for the traits maximum growth velocity, final count of viable cells, and inhibition halo against nine freshwater and marine pathogens, and by the lowest averages for the traits duplication time and resistance of strains to NaCl (1.5 and 3%), pH (6, 8, and 9), and biliary salts (5%). Mahalanobis distance (D²) was estimated among the evaluated strains, and the best ones were those with the shortest distances to the ideotype. Ten bacterial strains were isolated and biochemically identified as Lactobacillus plantarum (3), L. brevis (3), Weissella confusa (2), Lactococcus lactis (1), and L. delbrueckii (1). Lactobacillus plantarum strains showed a wide spectrum of action and the largest inhibition halos against pathogens, both Gram-positive and negative, high growth rate, and tolerance to all evaluated parameters. In relation to ideotype, L. plantarum showed the lowest Mahalanobis (D²) distance, followed by the strains of W. confusa, L. brevis, L. lactis, and L. delbrueckii. Among the analyzed bacterial strains, those of Lactobacillus plantarum have the greatest potential for use as a probiotic for marine shrimp.

Laparoscopy in the era of enhanced recovery.

Laparoscopy is one of the cornerstones in the surgical revolution and transformed outcome and recovery for various surgical procedures. Even if these changes were widely accepted for basic interventions, like appendectomies and cholecystectomies, laparoscopy still remains challenged for more advanced operations in many aspects. Despite these discussion, there is an overwhelming acceptance in the surgical community that laparoscopy did transform the recovery for several abdominal procedures. The importance of improved peri-operative patient management and its influence on outcome started to become a focus of attention 20 years ago and is now increasingly spreading, as shown by the incoming volume of data on this topic. The enhanced recovery after surgery (ERAS) concept incorporates simple measures of general management, and requires multidisciplinary collaboration from hospital staff as well as the patient and the relatives. Several studies have demonstrated a significant decrease in postoperative complication rate, length of hospital stay and reduced overall cost. The key elements of success are fluid restriction, a functioning epidural and preoperative carbohydrate intake. With the expansion of laparoscopic techniques, ERAS increasingly incorporates laparoscopic patients, especially in colorectal surgery. However, the precise impact of laparoscopy on ERAS is still not clearly defined. Increasing evidence suggests that laparoscopy itself is an additional ERAS item that should be considered as routine where feasible in order to obtain the best surgical outcomes.

Fistulizing Crohn's disease.

Fistulas are common in Crohn's disease. A population-based study has shown a cumulative risk of 33% after 10 years and 50% after 20 years. Perianal fistulas were the most common (54%). Medical therapy is the main option for perianal fistula once abscesses, if present, have been drained, and should include antibiotics (both ciprofloxacin and metronidazole) and immunomodulators. Infliximab should be reserved for refractory patients. Surgery is often necessary for internal fistulas.

How to Improve the Use of Proton Pump Inhibitors

Introduction: Proton pump inhibitors (PPI) are one of the most prescribed medications in the world with proven efficacy. However, several studies showed that their use often doesn't respect indications, leading to over-consumption, thus exposing patients to drug interactions and adverse events (for example pneumonias). Interruption of PPIs can induce a rebound phenomenon. This generates costs for health systems.Methods: This is a prospective interventional study performed in two hospitals: La Chaux-de-Fonds (CDF, cases) and Neucha^tel (NE, control) during two six-month periods, comparing use of PPIs before and after intervention. We elaborated recommendations (PPI doses and treatment duration) based on recent medical literature that we summarized on A6 cards and gave out to all prescribing doctors in the hospital of CDF and held a 30-minute information session for the departments of surgery, medicine and anesthesiology in March 2010. Doctors were asked to apply our recommendations as often as possible, leaving space for their own assessment. No information was given to the doctors of the control hospital. The number of PPI tablets that the pharmacy sent to each careunit in both hospitals was counted and adjusted to the number of patientdays from April to September 2009 (before intervention) and April to September 2010 (after intervention). The number of other antacids that were used in both hospitals was counted during the same periods. General practitioners (GP) in the region around CDF received an explanation letter to avoid re-introduction, after discharge from the hospital, of PPI treatment stopped during the stay. The number of gastro-duodenal ulcers and upper digestive hemorrhages was counted from April to December 2009 and the same period in 2010 in both hospitals.Results: In 2010, in the hospital of CDF, the use of PPIs per 100 patient-days decreased by 36% in the surgical and medical departments compared to 2009. In the control hospital the use of PPIs per 100 patient-days increased by 10% in the surgical department and decreased by 5% in the medical department during the same periods. The decrease from 2009 to 2010 of PPI utilization in CDF comparing to NE is statistically significant: p<0.0001. Use of other antacids didn't change, ulcers or digestive hemorrhages decreased slightly from 2009 to 2010 in both hospitals. Conclusions: The study showed that with a very low-cost intervention, it is possible to decrease considerably the use of PPIs in a hospital, without taking any risk for gastro-intestinal complications.

Molecular mechanisms of follicular associated epithelium differentiation

Les muqueuses respiratoires, genitales et digestives sont continuellement exposées aux antigènes de l?alimentation, à la flore intestinale et aux pathogènes. Cela implique une activité immunologique intense et finement régulée dans ces tissus. On admet que la modulation de ces réponses immunitaires muqueuses s?effectue dans des organes sentinels spécifiques appelés o-MALT (organized mucosal associated lymphoid tissues). Ces processus de modulation et la biologie de ces sites immuno-inducteurs sont peu connus. Ceci est pourtant d?une grande relevance si l?on veut faire un design rationnel de drogues et de vaccins muqueux. Dans l?intestin grèle, ces organes sont composés de follicules multiples et sont appelés plaques de Peyer. Ils sont constitués de follicules enrichis en cellules B comprenant ou non un centre germinatif, de regions interfolliculaires comprenant des cellules T, et d?une région en d ome riche en cellules dendritiques, cellules B naives et cellules T CD4+, surmontée par un epithelium specialisé, le FAE (epithelium associé aux follicules). Le FAE contient des cellules M spécialisées dans le transport de macromolécules et micro-organismes de la lumière intestinale au tissu lymphoide sous-jacent. Ce transport des antigènes est une condition obligatoire pour induire une réponse immunitaire. Les cellules du FAE, outre les cellules M, expriment un programme de différenciation distinct de celui des cellules associées aux villosités. Ceci est characterisé par une baisse des fonctions digestives et de défenses, et l?expression constitutive des chimiokines: CCL20 et CCL25. Le but de l?étude présentée ici est de rechercher les facteurs cellulaires et/ou moléculaire responsables de cette différenciation. Certaines études ont démontré l?importance du contact entre le compartiment mésenchymateux et l?épithelium pour la morphogenèse de ce dernier. En particulier, les molécules de la matrice extracellulaire peuvent activer des gènes clefs qui, à leur tour, vont controler l?adhésion et la differenciation cellulaire. Dans l?intestin, les cellules mésenchymateuses différencient en myofibroblastes qui participent à l?élaboration de la matrice extracellulaire. Dans cette étude, nous avons décrit les différences d?expression de molécules de la matrices sous le FAE et les villosités. Nous avons également montré une absence de myofibroblastes sous le FAE. Suite à plusieurs évidences expérimentales, certains ont proposé une influence des composés présents dans la lumière sur la différenciation et/ou la maturation des plaques de Peyer. La chimiokine CCL20, capable de recruter des cellules initiatrices de la réponse immunitaire, constitue notre seul marqueur positif de FAE. Nous avons pu montrer que la flagelline, un composé du flagelle bactérien, était capable d?induire l?expression de CCL20 in vitro et in vivo. Cet effet n?est pas limité aux cellules du FAE mais est observé sur l?ensemble de l?épithelium intestinal. Molecular mechanisms of FAE differenciation. La signalement induit par la lymphotoxine ß est critique pour l?organogenèse des plaques de Peyer, car des souris déficientes pour cette molécules ou son récepteur n?ont ni plaque de Peyer, ni la plupart des ganglions lymphatiques. Nous avons obtenus plusieurs évidences que la lymphotoxine ß était impliquée dans la régulation du gène CCL20 in vitro et in vivo.<br/><br/>Mucosal surfaces of the respiratory, genital and digestive systems are exposed to food antigens, normal bacterial flora and oral pathogens. This justifies an intense and tuned immunological activity in mucosal tissues. The modulation of immune responses in the mucosa is thought to occur in specific sentinel sites, the organized mucosa associated lymphoid tissues (o-MALT). This immune modulation and the biology of these immune-inductive sites are poorly understood but highly important and relevant in the case of drugs and vaccines design. In the small intestine, these organs (gut associated lymphoid tissue : GALT) consists of single or multiple lymphoid follicles, the so-called Peyer?s patches (PP), with typical B cell-enriched follicles and germinal centers, inter-follicular T cell areas, and a dome region enriched in dendritic cells, naive B cells, and CD4+ T cells under a specialized follicle associated epithelium (FAE). To trigger protective immunity, antigens have to cross the mucosal epithelial barrier. This is achieved by the specialized epithelial M cells of the FAE that are able to take up and transport macromolecules and microorganisms from the environment into the underlying organized lymphoid tissue. The ontogeny of M cells remains controversial: some data are in favor of a distinct cell lineage, while others provide evidence for the conversion of differentiated enterocytes into M cells. In this study we mapped the proliferative, M cells and apoptotic compartments along the FAE. Enterocytes acquire transient M cell features as they leave the crypt and regain enterocyte properties as they move towards the apoptotic compartment at the apex of the FAE, favouring the hypothesis of a plastic phenotype. The follicle-associated epithelium (FAE) is found exclusively over lymphoid follicles in mucosal tissues, including Peyer?s patches. The enterocytes over Peyer?s patches express a distinct phenotype when compared to the villi enterocytes, characterized by the down regulation of digestive and defense functions and the constitutive expression of chemokines, i.e. CCL20 and CCL25. The purpose of this study was to investigate and identify the potential cells and/or molecules instructing FAE differentiation. Contact between the epithelial and the mesenchymal cell compartment is required for gut morphogenesis. Extracellular matrix molecules (ECM) can activate key regulatory genes which in turn control cell adhesion and differentiation. In the gut, mesenchymal cells differentiate into myofibroblats that participate to the elaboration of ECM. We have described a differential expression of extracellular matrix components under the FAE, correlating with the absence of subepithelial myofibroblats. Molecular mechanisms of FAE differenciation. Different studies proposed an influence of the luminal compartment in the differentiation and/or the maturation of PP. CCL20, a chemokine able to recruit cells that initiate adaptive immunity constitutes our first positive FAE molecular marker. We have shown that CCL20 gene expression is inducible in vitro and in vivo in intestinal epithelium by flagellin, a component of bacterial flagella. This effect was not restricted to the FAE. Lymphotoxin ß (LTß) signaling is critical for PPs organogenesis as LT deficient mice as well as LTß-receptor-/- mice lack PPs and most of the lymph nodes (LN). The continuous signaling via LTßR-expressing cells appears necessary for the maintenance throughout the life of PP architecture. We obtained in vitro and in vivo evidence that LTß signalling is involved in CCL20 gene expression.

Imatinib plasma concentrations variability in hemato-oncologic patients

Abstract Imatinib (Glivec~ has transformed the treatment and prognosis of chronic myeloid leukaemia (CML) and of gastrointestinal stromal tumor (GIST). However, the treatment must be taken indefinitely and is not devoid of inconvenience and toxicity. Moreover, resistance or escape from disease control occurs. Considering the large interindividual differences in the function of the enzymatic and transport systems involved in imatinib disposition, exposure to this drug can be expected to vary widely among patients. Among those known systems is a cytochrome P450 (CYI'3A4) that metabolizes imatinib, the multidrug transporter P-glycoprotein (P-gp; product of the MDR1 gene) that expels imatinib out of cells, and al-acid glycoprotein (AGP), a circulating protein binding imatinib in the plasma. The aim of this observational study was to explore the influence of these covariates on imatinib pharmacokinetics (PK), to assess the interindividual variability of the PK parameters of the drug, and to evaluate whether imatinib use would benefit from a therapeutic drug monitoring (TDM) program. A total of 321 plasma concentrations were measured in 59 patients receiving imatinib, using a validated chromatographic method developed for this study (HPLC-LTV). The results were analyzed by non-linear mixed effect modeling (NONMEM). A one-compartment pharmacokinetic model with first-order absorption appropriately described the data, and a large interindividual variability was observed. The MDK> polymorphism 3435C>T and the CYP3A4 activity appeared to modulate the disposition of imatinib, albeit not significantly. 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. This approach allowed determining an average free clearance (CL,~ of 13101/h and a volume of distribution (Vd) of 301 1. By comparison, the total clearance determined was 141/h (i.e. 233 ml/min). Free clearance was affected by body weight and pathology diagnosis. The estimated variability of imatinib disposition (17% for CLu and 66% for Vd) decreased globally about one half with the model incorporating the AGP impact. Moreover, some associations were observed between PK parameters of the free imatinib concentration and its efficacy and toxicity. Finally, the functional influence of P-gp activity has been demonstrated in vitro in cell cultures. These elements are arguments to further investigate the possible usefulness of a TDM program for imatinib. It may help in individualizing the dosing regimen before overt disease progression or development of treatment toxicity, thus improving both the long-term therapeutic effectiveness and tolerability of this drug. Résumé L'imatinib (Glivec ®) a révolutionné le traitement et le pronostic de la leucémie myéloïde chronique (LMC) et des tumeurs stromales d'origine digestive (GIST). Il s'agit toutefois d'un traitement non dénué d'inconvénients et de toxicité, et qui doit être pris indéfiniment. Par ailleurs, une résistance, ou des échappements au traitement, sont également rencontrés. Le devenir de ce médicament dans l'organisme dépend de systèmes enzymatiques et de transport connus pour présenter de grandes différences interindividuelles, et l'on peut s'attendre à ce que l'exposition à ce médicament varie largement d'un patient à l'autre. Parmi ces systèmes, on note un cytochrome P450 (le CYP3A4) métabolisant l'imatinib, la P-glycoprotéine (P-gp ;codée par le gène MDR1), un transporteur d'efflux expulsant le médicament hors des cellules, et l'atglycoprotéine acide (AAG), une protéine circulante sur laquelle se fixe l'imatinib dans le plasma. L'objectif de la présente étude clinique a été de déterminer l'influence de ces covariats sur la pharmacocinétique (PK) de l'imatinib, d'établir la variabilité interindividuelle des paramètres PK du médicament, et d'évaluer dans quelle mesure l'imatinib pouvait bénéficier d'un programme de suivi thérapeutique (TDM). En utilisant une méthode chromatographique développée et validée à cet effet (HPLC-UV), un total de 321 concentrations plasmatiques a été dosé chez 59 patients recevant de l'imatinib. Les résultats ont été analysés par modélisation non linéaire à effets mixtes (NONMEM). Un modèle pharmacocinétique à un compartiment avec absorption de premier ordre a permis de décrire les données, et une grande variabilité interindividuelle a été observée. Le polymorphisme du gène MDK1 3435C>T et l'activité du CYP3A4 ont montré une influence, toutefois non significative, sur le devenir de l'imatinib. Une relation hyperbolique entre les taux plasmatiques d'AAG et la clairance, comme le volume de distribution, a été observée. Une approche mécanistique a donc été élaborée, postulant que seule la concentration libre subissait une élimination du premier ordre. Cette approche a permis de déterminer une clairance libre moyenne (CLlibre) de 13101/h et un volume de distribution (Vd) de 301 l. Par comparaison, la clairance totale était de 141/h (c.à.d. 233 ml/min). La CLlibre est affectée par le poids corporel et le type de pathologie. La variabilité interindividuelle estimée pour le devenir de l'imatinib (17% sur CLlibre et 66% sur Vd) diminuait globalement de moitié avec le modèle incorporant l'impact de l'AAG. De plus, une certaine association entre les paramètres PK de la concentration d'imatinib libre et l'efficacité et la toxicité a été observée. Finalement, l'influence fonctionnelle de l'activité de la P-gp a été démontrée in nitro dans des cultures cellulaires. Ces divers éléments constituent des arguments pour étudier davantage l'utilité potentielle d'un programme de TDM appliqué à l'imatinib. Un tel suivi pourrait aider à l'individualisation des régimes posologiques avant la progression manifeste de la maladie ou l'apparition de toxicité, améliorant tant l'efficacité que la tolérabilité de ce médicament. Résumé large public L'imatinib (un médicament commercialisé sous le nom de Glivec ®) a révolutionné le traitement et le pronostic de deux types de cancers, l'un d'origine sanguine (leucémie) et l'autre d'origine digestive. Il s'agit toutefois d'un traitement non dénué d'inconvénients et de toxicité, et qui doit être pris indéfiniment. De plus, des résistances ou des échappements au traitement sont également rencontrés. Le devenir de ce médicament dans le corps humain (dont l'étude relève de la discipline appelée pharmacocinétique) dépend de systèmes connus pour présenter de grandes différences entre les individus, et l'on peut s'attendre à ce que l'exposition à ce médicament varie largement d'un patient à l'autre. Parmi ces systèmes, l'un est responsable de la dégradation du médicament dans le foie (métabolisme), l'autre de l'expulsion du médicament hors des cellules cibles, alors que le dernier consiste en une protéine (dénommée AAG) qui transporte l'imatinib dans le sang. L'objectif de notre étude a été de déterminer l'influence de ces différents systèmes sur le comportement pharmacocinétique de l'imatinib chez les patients, et d'étudier dans quelle mesure le devenir de ce médicament dans l'organisme variait d'un patient à l'autre. Enfin, cette étude avait pour but d'évaluer à quel point la surveillance des concentrations d'imatinib présentes dans le sang pourrait améliorer le traitement des patients cancéreux. Une telle surveillance permet en fait de connaître l'exposition effective de l'organisme au médicament (concept abrégé par le terme anglais TDM, pour Therapeutic Drag Monitoring. Ce projet de recherche a d'abord nécessité la mise au point d'une méthode d'analyse pour la mesure des quantités (ou concentrations) d'imatinib présentes dans le sang. Cela nous a permis d'effectuer régulièrement des mesures chez 59 patients. Il nous a ainsi été possible de décrire le devenir du médicament dans le corps à l'aide de modèles mathématiques. Nous avons notamment pu déterminer chez ces patients la vitesse à laquelle l'imatinib est éliminé du sang et l'étendue de sa distribution dans l'organisme. Nous avons également observé chez les patients que les concentrations sanguines d'imatinib étaient très variables d'un individu à l'autre pour une même dose de médicament ingérée. Nous avons pu aussi mettre en évidence que les concentrations de la protéine AAG, sur laquelle l'imatinib se lie dans le sang, avait une grande influence sur la vitesse à laquelle le médicament est éliminé de l'organisme. Ensuite, en tenant compte des concentrations sanguines d'imatinib et de cette protéine, nous avons également pu calculer les quantités de médicament non liées à cette protéine (= libres), qui sont seules susceptibles d'avoir une activité anticancéreuse. Enfin, il a été possible d'établir qu'il existait une certaine relation entre ces concentrations, l'effet thérapeutique et la toxicité du traitement. Tous ces éléments constituent des arguments pour approfondir encore l'étude de l'utilité d'un programme de TDM appliqué à l'imatinib. Comme chaque patient est différent, un tel suivi pourrait aider à l'ajustement des doses du médicament avant la progression manifeste de la maladie ou l'apparition de toxicité, améliorant ainsi tant son efficacité que son innocuité.

Patients' preferences on information and involvement in decision-making in gastrointestinal surgery

Contexte et but de l'étude: La relation médecin-patient a subi d'importants changements et l'actuelle émancipation des patients a conduit à un véritable partenariat dans la prise de décisions thérapeutiques. Notre étude a pour but de déterminer les préférences des patients pour différents aspects de la prise de décisions au cours d'un traitement et de ses potentielles complications, de même que la quantité et le type d'information souhaitée avant une intervention chirurgicale digestive. Patients et méthodes : Il s'agit d'une étude prospective non-randomisée basée sur un questionnaire donné lors de la consultation préopératoire à 254 patients consécutifs prévus pour une chirurgie gastro-intestinale élective. Résultats : Pour les potentielles complications chirurgicales et la possibilité d'un séjour aux soins intensifs, 64% des patients souhaitent participer activement aux décisions médicales, et respectivement 89% et 60% des patients aimeraient discuter d'une éventuelle réanimation cardio-pulmonaire et de limitations au traitement. Respectivement 73%, 77% et 47% des patients ont souhaité une information très détaillée, une infoimation pour une possible hospitalisation en soins intensifs ou une éventuelle réanimation cardiaque. Les patients âgés ou avec un niveau de formation bas étaient significativement moins intéressés à une prise de décision partagée (p=0.003 et 0.015) et à une information complète (p=0.03 et 0.05), De plus, l'implication des familles dans les prises de décision n'était favorisée que si le patient est en coma (74%), et significativement moins importante chez les personnes âgées et de sexe masculin (p=0.04 et 0.03 respectivement). Ni le type de chirurgie prévue (majeure ou mineure) ni la sévérité de la pathologie (cancer ou non) ne furent des facteurs statistiquement significatifs pour un désir plus élevé de partager la prise de décision, pour plus d'information ou pour impliquer d'avantage la famille. Conclusions : Notre étude démontre que la majorité des patients chirurgicaux souhaitent recevoir une information préopératoire complète concernant leur maladie et le traitement planifié. Ils considèrent également comme crucial d'être impliqués dans les prises de décisions thérapeutiques pour le traitement et pour les possibles complications. Le rôle de la famille est limité aux situations ou le patient n'est plus en mesure de participer aux décisions.

Survival after surgical drainage of malignant pericardial effusion.

OBJECTIVES: Management of malignant pericardial effusion (PE) is complex. Cardiac surgeons are not necessarily familiar with or are challenged by the many underlying etiologies. Analyzing risk factors for mortality may help to estimate the benefit of surgery in high-risk patients. METHODS: Patients undergoing a surgical pericardiotomy for malignant PE, between 2001 and 2011, were included. The influence of tumor type, disease extension, intra-pericardial tumor infiltration on early mortality and long-term survival as well as freedom from symptoms after drainage, and the use of sclerosing agents on PE recurrence rates was analyzed. RESULTS: PE drainage was performed on 46 patients 12 ± 30 months after tumor diagnosis. Malignant diseases were lung cancers (50 %), breast cancers (15 %), lymphoma and leukemia (13 %), cancers of the digestive tract (13 %), and others (9 %). 80 % of patients were symptomatic and symptom relief was achieved in 65 %. Nobody died during surgery. Recurrence rate was 4 %. Early in-hospital mortality was 22 %. After 1 year, 29 % of patients were alive. Eleven patients (24 %) had a complete tumor regression. Metastatic spread (p < 0.001), pericardial infiltration (p = 0.02), and intra-pericardial Bleomycin (p = 0.01) injection were associated with increased mortality. Hematological malignancies had a better prognosis for survival. CONCLUSION: Surgical pericardiotomy is safe, associated with a low recurrence rate and symptom relief in the majority of dyspneic patients. Intra-pericardial Bleomycin may reduce recurrent effusion but does not ameliorate survival. Long-term survival rate was low with an increased mortality in cases of metastatic spreading, pericardial infiltration, and as the tumor of origin: breast cancers. Leukemic and lymphatic tumors have better prognosis.

Médecine d'urgence [Emergency medicine: updates 2013].

New evidences published this year are susceptible to change the management of several medical emergencies. Combined antiplatelet therapy might be beneficial for the management of TIA or minor stroke and rapid blood pressure lowering might improve the outcome in patients with intracerebral hemorrhage. A restrictive red cell transfusion strategy is indicated in case of upper digestive bleeding and coagulation factors concentrates are superior to fresh frozen plasma for urgent warfarin reversal. Prolonged systemic steroid therapy is not warranted in case of acute exacerbation of BPCO, and iterative physiotherapy is not beneficial after acute whiplash. Finally, family presence during cardiopulmonary resuscitation may reduce post-traumatic stress disorder among relatives.

Spectrum of digoxin-induced ocular toxicity: a case report and literature review.

BACKGROUND: Digoxin intoxication results in predominantly digestive, cardiac and neurological symptoms. This case is outstanding in that the intoxication occurred in a nonagenarian and induced severe, extensively documented visual symptoms as well as dysphagia and proprioceptive illusions. Moreover, it went undiagnosed for a whole month despite close medical follow-up, illustrating the difficulty in recognizing drug-induced effects in a polymorbid patient. CASE PRESENTATION: Digoxin 0.25 mg qd for atrial fibrillation was prescribed to a 91-year-old woman with an estimated creatinine clearance of 18 ml/min. Over the following 2-3 weeks she developed nausea, vomiting and dysphagia, snowy and blurry vision, photopsia, dyschromatopsia, aggravated pre-existing formed visual hallucinations and proprioceptive illusions. She saw her family doctor twice and visited the eye clinic once until, 1 month after starting digoxin, she was admitted to the emergency room. Intoxication was confirmed by a serum digoxin level of 5.7 ng/ml (reference range 0.8-2 ng/ml). After stopping digoxin, general symptoms resolved in a few days, but visual complaints persisted. Examination by the ophthalmologist revealed decreased visual acuity in both eyes, 4/10 in the right eye (OD) and 5/10 in the left eye (OS), decreased color vision as demonstrated by a score of 1/13 in both eyes (OU) on Ishihara pseudoisochromatic plates, OS cataract, and dry age-related macular degeneration (ARMD). Computerized static perimetry showed non-specific diffuse alterations suggestive of either bilateral retinopathy or optic neuropathy. Full-field electroretinography (ERG) disclosed moderate diffuse rod and cone dysfunction and multifocal ERG revealed central loss of function OU. Visual symptoms progressively improved over the next 2 months, but multifocal ERG did not. The patient was finally discharged home after a 5 week hospital stay. CONCLUSION: This case is a reminder of a complication of digoxin treatment to be considered by any treating physician. If digoxin is prescribed in a vulnerable patient, close monitoring is mandatory. In general, when facing a new health problem in a polymorbid patient, it is crucial to elicit a complete history, with all recent drug changes and detailed complaints, and to include a drug adverse reaction in the differential diagnosis.

Fruit and vegetables and cancer risk : a review of southern European studies

High intakes of fruit and vegetables may reduce the risk of cancer at several sites. Evidence has been derived mainly from case-control studies. We reviewed the relationship between consumption of vegetables and fruit and the risk of several common cancers in a network of Italian and Swiss case-control studies including over 10 000 cases of fourteen different cancers and about 17 000 controls. Data were suggestive of a protective role of vegetable intake on the risk of several common epithelial cancers. OR for the highest compared with the lowest levels of consumption ranged from 0·2 (larynx, oral cavity and pharynx) to 0·9 (prostate). Inverse associations were found for both raw and cooked vegetables, although for upper digestive tract cancers the former were somewhat stronger. Similar inverse associations were found for cruciferous vegetables. Frequent consumption of allium vegetables was also associated with reduced risk of several cancers. Fruit was a favourable correlate of the risk of several cancers, particularly of the upper digestive tract, with associations generally weaker than those reported for vegetables. A reduced risk of cancers of the digestive tract and larynx was found for high consumption of citrus fruit. Suggestive protections against several forms of cancer, mainly digestive tract cancers, were found for high consumption of apples and tomatoes. High intakes of fibres, flavonoids and proanthocyanidins were inversely related to various forms of cancer. In conclusion, data from our series of case-control studies suggested a favourable role of high intakes of fruit and vegetables in the risk of many common cancers, particularly of the digestive tract. This adds evidence to the indication that aspects of the Mediterranean diet may have a favourable impact not only on CVD, but also on several common (epithelial) cancers, particularly of the digestive tract.