Empirical antifungal therapy in neutropaenic cancer patients with persistent fever

Invasive fungal infections are frequent and severe complications in leukaemic patients with prolonged neutropaenia. Empirical antifungal therapy has become the standard of care in patients with persistent fever despite treatment with broad-spectrum antibiotics. For decades amphotericin B deoxycholate has been the sole option for empirical antifungal therapy. Recently, several new antifungal agents became available. The choice of the most appropriate drug should be guided by efficacy and safety criteria. The recommendations from the First European Conference on Infections in Leukaemia (ECIL-1) on empirical antifungal therapy in neutropaenic cancer patients with persistent fever have been developed by an expert panel after assessment of clinical practices in Europe and evidence-based review of the literature. Many antifungal regimens can now be recommended for empirical therapy in neutropaenic cancer patients. However, persistent fever lacks specificity for initiation of therapy. Development of empirical and pre-emptive strategies using new clinical parameters, laboratory markers and imaging techniques for early diagnosis of invasive mycoses are needed.

Assessment of a sheep animal model to optimize photodynamic therapy in the oesophagus

Background and Objectives: Precursor lesions of oesophagus adenocarcinoma constitute a clinical dilemma. Photodynamic therapy (PDT) is an effective treatment for this indication, but it is difficult to optimise without an appropriate animal model. For this reason, we assessed the sheep model for PDT in the oesophagus with the photosensitiser meta-(tetra-hydroxyphenyl) chlorin (mTHPC). Materials and Methods: Twelve sheep underwent intravenous mTHPC injection, blood sampling and fluorescence measurements. mTHPC's pharmacokinetics was measured in vivo and in plasma by fluorescence spectroscopy. Biopsies of sheep oesophagus were compared to corresponding human tissue, and the mTHPC's biodistribution was studied under fluorescence microscopy. Finally, the sheep oesophageal mucosa was irradiated, 4 days after mTHPC's injection. Results: Histologically, the sheep and human oesophagus were closely comparable, with the exception of additional fatty tissue in the sheep oesophagus. mTHPC's pharmacokinetics in sheep and human plasmas were similar, with a maximum of concentration in the sheep 10 hours after i.v. injection. mTHPC's pharmacokinetics in vivo reached its maximum after 30-50 hours, then decreased to background levels, as in humans under similar conditions. Two days after injection, mTHPC was mainly distributed in the lamina propria, followed by a penetration into the epithelium. The sheep and human tissue sensitivity to mTHPC PDT was similar. Conclusion: In conclusion, this model showed many similarities with humans as to mTHPC's plasma and tissue pharmacokinetics, and for tissue PDT response, making it suitable to optimise oesophagus PDT. Lasers Surg. Med. 41:643-652,2009. (C) 2009Wiley-Liss,Inc.

Violences sexistes dans le couple et expériences des femmes par rapport à la justice en Espagne

A l'occasion de la Journée internationale des droits des femmes 2013, l'association le Relais de Sénart, association féministe qui accueille, accompagne, et héberge les femmes victimes de violences conjugales, l'Institut de Recherche Interdisciplinaire sur les enjeux Sociaux (Iris), la Fédération Nationale Solidarité Femmes et le Centre Hubertine Auclert se sont associés pour organiser une journée d'étude sur les enjeux scientifiques, politiques et institutionnels soulevés par les violences envers les femmes depuis les années 1970. Il s'est agi de permettre aux associations de bénéficier d'un autre regard sur leur travail et leurs outils ; et de faire en sorte que la recherche en sciences sociales puisse se nourrir du point de vue des professionnel-le-s. Le partenariat scientifique et associatif a ainsi visé à explorer la manière dont les associations s'approprient, ou non, les outils issus du champ académique, et réciproquement.

Is intracerebral hemorrhage a time-dependent phenomenon after successful combined intravenous and intra-arterial therapy?

BACKGROUND AND PURPOSE: Onset-to-reperfusion time (ORT) has recently emerged as an essential prognostic factor in acute ischemic stroke therapy. Although favorable outcome is associated with reduced ORT, it remains unclear whether intracranial bleeding depends on ORT. We therefore sought to determine whether ORT influenced the risk and volume of intracerebral hemorrhage (ICH) after combined intravenous and intra-arterial therapy. METHODS: Based on our prospective registry, we included 157 consecutive acute ischemic stroke patients successfully recanalized with combined intravenous and intra-arterial therapy between April 2007 and October 2011. Primary outcome was any ICH within 24 hours posttreatment. Secondary outcomes included occurrence of symptomatic ICH (sICH) and ICH volume measured with the ABC/2. RESULTS: Any ICH occurred in 26% of the study sample (n=33). sICH occurred in 5.5% (n=7). Median ICH volume was 0.8 mL. ORT was increased in patients with ICH (median=260 minutes; interquartile range=230-306) compared with patients without ICH (median=226 minutes; interquartile range=200-281; P=0.008). In the setting of sICH, ORT reached a median of 300 minutes (interquartile range=276-401; P=0.004). The difference remained significant after adjustment for potential confounding factors (adjusted P=0.045 for ICH; adjusted P=0.002 for sICH). There was no correlation between ICH volume and ORT (r=0.16; P=0.33). CONCLUSIONS: ORT influences the rate but not the volume of ICH and appears to be a critical predictor of symptomatic hemorrhage after successful combined intravenous and intra-arterial therapy. To minimize the risk of bleeding, revascularization should be achieved within 4.5 hours of stroke onset.

Oral chloramphenicol therapy for multiple liver abscesses in hyperimmunoglobulinemia E syndrome.

In a patient with Hyper-IgE-syndrome multiple liver abscesses developed in spite of prophylactic treatment with trimethoprim and sulfamethoxazol. Ultrasound confirmed the clinical diagnosis and percutaneous needle aspiration under ultrasonographic guidance and culture of the aspirated pus allowed specific antibiotic treatment by oral chloramphenicol alone without surgical drainage. The isolated Staph.aureus strain was resistant to trimethoprim and sulfamethoxazol.

Extremity exposure in nuclear medicine therapy with 90Y-labelled substances - Results of the ORAMED project

90Y-labelled radiopharmaceuticals offer promising prospects for radionuclide therapies of tumours, e.g. radioimmunotherapies (RIT), (EANM, 2007), peptide receptor radiotherapies (PRRT), (Otte et al., 1998), and selective internal radiotherapies (SIRT), (Salem and Thurston, 2006). 90Y, an almost pure high-energy beta radiation emitter (Eβ,max = 2.28 MeV), is a favourable radionuclide for therapeutic purposes. However, when preparing and performing these therapies, high activities of 90Y (>1 GBq) are to be manipulated and technicians, physicians and nurses may receive high skin exposures to the hands. If radiation protection standards are low, the exposure of staff can exceed the annual skin dose limit of 500 mSv. Within a particular work package (WP4) of the ORAMED project, comprehensive measurements in nuclear medicine departments of several hospitals in 6 European countries were carried out. The study focussed on 90Y-labelled substances such as Zevalin® and DOTATOC to achieve a representative database on staff exposure. This paper summarises the most important results and conclusions for individual monitoring of skin exposure of staff.

Genomic copy number aberrations in glioblastoma, response to therapy and molecular machanisms

Résumé : Le glioblastome (GBM, WHO grade IV) est la tumeur cérébrale primaire la plus fréquente et la plus maligne, son pronostic reste très réservé et sa réponse aux différents traitements limitée. Récemment, une étude clinique randomisée (EORTC 26981/NCIC CE.3) a démontré que le traitement combiné de temozolomide et radiothérapie (RT/TMZ) est le meilleur dans les cas de GBM nouvellement diagnostiqués [1]. Cependant, seul un sous-groupe de patients bénéficie du traitement RT/TMZ et même parmi eux, leur survie reste très limitée. Pour tenter de mieux comprendre les réponses au traitement RT/TMZ, la biologie du GBM, identifier d'autres facteurs de résistance et découvrir de nouvelles cibles aux traitements, nous avons conduit une analyse moléculaire étendue à 73 patients inclus dans cette étude clinique. Nous avons complété les résultats moléculaires déjà obtenus par un profil génomique du nombre de copies par Array Comparative Genomic Hybridization. Afin d'atteindre nos objectifs, nous avons analysé en parallèle les données cliniques des patients et leurs profils moléculaires. Nos résultats confirment des analyses connues dans le domaine des aberrations du nombre de copies (CNA) et de profils du glioblastome. Nous avons observé une bonne corrélation entre le CNA génomique et l'expression de l'ARN messager dans le glioblastome et identifié un nouveau modèle de CNA du chromosome 7 pouvant présenter un intérêt clinique. Nous avons aussi observé par l'analyse du CNA que moins de 10% des glioblastomes conservent leurs mécanismes de suppression de tumeurs p53 et Rb1. Nous avons aussi observé que l'amplification du CDK4 peut constituer un facteur supplémentaire de résistance au traitement RT/TMZ, cette observation nécessite confirmation sur un plus grand nombre d'analyses. Nous avons montré que dans notre analyse des profils moléculaires et cliniques, il n'est pas possible de différencier le GBM à composante oligodendrogliale (GBM-O) du glioblastome. En superposant les profils moléculaires et les modèles expérimentaux in vitro, nous avons identifié WIF-1 comme un gène suppresseur de tumeur probable et une activation du signal WNT dans la pathologie du glioblastome. Ces observations pourraient servir à une meilleure compréhension de cette maladie dans le futur. Abstract : Glioblastoma, (GBM, WHO grade IV) is the most malignant and most frequent primary brain tumor with a very poor prognosis and response to therapy. A recent randomized clinical trial (EORTC26981/NCIC CE.3) established RT/TMZ as the 1St effective chemo-radiation therapy in newly diagnosed GBM [1]. However only a genetic subgroup of patients benefit from RT/TMZ and even in this subgroup overall survival remains very dismal. To explain the observed response to RT/TMZ, have a better understanding of GBM biology, identify other resistance factors and discover new drugable targets a comprehensive molecular analysis was performed in 73 of these GBM trial cohort. We complemented the available molecular data with a genomic copy number profiling by Array Comparative Genomic Hybridization. We proceeded to align the molecular profiles and the Clinical data, to meet our project objectives. Our data confirm known GBM Copy Number Aberrations and profiles. We observed a good correlation of genomic CN and mRNA expression in GBM, and identified new interesting CNA pattern for chromosome 7 with a potential clinical value. We also observed that by copy number aberration data alone, less than 10% of GBM have an intact p53 and Rb1 tumor .suppressor pathways. We equally observed that CDK4 amplification might constitute an additional RT/TMZ resistant factor, an observation that will need confirmation in a larger data set. We show that the molecular and clinical profiles in our data set, does not support the identification of GBM-O as a new entity in GBM. By combining the molecular profiles and in vitro model experiments we identify WIF1 as a potential GBM TSG and an activated WNT signaling as a pathologic event in GBM worth incorporation in attempts to better understand and impact outcome in this disease.

Le couple peint et son spectateur : esthétique de la réception et peinture figurative

Cette thèse s'intéresse à la manière dont la peinture représente le couple, et à la manière dont le spectateur reçoit et interprète cette représentation, les deux aspects du processus étant admis étroitement solidaires l'un de l'autre. Le corpus obéit au principe d'une traversée thématique sélective sur une période qui va de 1880 à la fin du 20e siècle ; il rassemble des oeuvres de peintres de nationalités diverses (Manet, Vuillard, Bonnard, Vallotton, Munch, Schiele, Kirchner, Beckmann, Hopper et Freud, pour citer les principaux). La perspective méthodologique, définie dans l'introduction du travail, est centrée sur la réception des oeuvres, sous l'angle phénoménologique et herméneutique prioritairement. La première partie développe une approche en lien avec la littérature, où le motif du couple est omniprésent, à partir de l'hypothèse selon laquelle cette parenté intervient dans la réception du thème en peinture ; ce dont résulte fréquemment un déploiement du potentiel narratif de l'image, dont la notion de scénario permet de rendre compte. La deuxième partie se concentre sur le discours pictural en tant que tel, sur les moyens dont la peinture dispose pour faire sens en préparant la lecture à venir, et donc corollairement sur les spécificités de la réception picturale pour la catégorie considérée, soit la peinture de genre. L'attention est portée sur la réception en tant que processus, perceptif et réflexif à la fois, par lequel le spectateur trouve accès à l'oeuvre et développe avec elle une forme de dialogue. La troisième partie explore l'idée élémentaire suivante : représenter un couple, c'est toujours exposer une certaine conception de la relation entre l'homme et la femme. A travers les images du couple créées par quelques peintres majeurs de la première moitié du 20e siècle, on peut suivre l'émergence comme telle de la question du rapport entre les sexes, dont les gender studies ont fait leur objet central. Enfin, une quatrième partie a pour but d'approfondir la question du rapport que nous entretenons avec les représentations figuratives et les modalités de l'implication du spectateur. Y sont envisagés le pouvoir et le fonctionnement référentiels des oeuvres picturales, pour tenter de clarifier le statut des différents modes de compréhension et d'analyse dont nous disposons à leur égard.

A model of cellular dosimetry for macroscopic tumors in radiopharmaceutical therapy.

PURPOSE: In the radiopharmaceutical therapy approach to the fight against cancer, in particular when it comes to translating laboratory results to the clinical setting, modeling has served as an invaluable tool for guidance and for understanding the processes operating at the cellular level and how these relate to macroscopic observables. Tumor control probability (TCP) is the dosimetric end point quantity of choice which relates to experimental and clinical data: it requires knowledge of individual cellular absorbed doses since it depends on the assessment of the treatment's ability to kill each and every cell. Macroscopic tumors, seen in both clinical and experimental studies, contain too many cells to be modeled individually in Monte Carlo simulation; yet, in particular for low ratios of decays to cells, a cell-based model that does not smooth away statistical considerations associated with low activity is a necessity. The authors present here an adaptation of the simple sphere-based model from which cellular level dosimetry for macroscopic tumors and their end point quantities, such as TCP, may be extrapolated more reliably. METHODS: Ten homogenous spheres representing tumors of different sizes were constructed in GEANT4. The radionuclide 131I was randomly allowed to decay for each model size and for seven different ratios of number of decays to number of cells, N(r): 1000, 500, 200, 100, 50, 20, and 10 decays per cell. The deposited energy was collected in radial bins and divided by the bin mass to obtain the average bin absorbed dose. To simulate a cellular model, the number of cells present in each bin was calculated and an absorbed dose attributed to each cell equal to the bin average absorbed dose with a randomly determined adjustment based on a Gaussian probability distribution with a width equal to the statistical uncertainty consistent with the ratio of decays to cells, i.e., equal to Nr-1/2. From dose volume histograms the surviving fraction of cells, equivalent uniform dose (EUD), and TCP for the different scenarios were calculated. Comparably sized spherical models containing individual spherical cells (15 microm diameter) in hexagonal lattices were constructed, and Monte Carlo simulations were executed for all the same previous scenarios. The dosimetric quantities were calculated and compared to the adjusted simple sphere model results. The model was then applied to the Bortezomib-induced enzyme-targeted radiotherapy (BETR) strategy of targeting Epstein-Barr virus (EBV)-expressing cancers. RESULTS: The TCP values were comparable to within 2% between the adjusted simple sphere and full cellular models. Additionally, models were generated for a nonuniform distribution of activity, and results were compared between the adjusted spherical and cellular models with similar comparability. The TCP values from the experimental macroscopic tumor results were consistent with the experimental observations for BETR-treated 1 g EBV-expressing lymphoma tumors in mice. CONCLUSIONS: The adjusted spherical model presented here provides more accurate TCP values than simple spheres, on par with full cellular Monte Carlo simulations while maintaining the simplicity of the simple sphere model. This model provides a basis for complementing and understanding laboratory and clinical results pertaining to radiopharmaceutical therapy.