Le prince Joachim, 6e fils du Kaiser : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 57563

Presence of an oligodendroglioma-like component in newly diagnosed glioblastoma identifies a pathogenetically heterogeneous subgroup and lacks prognostic value: central pathology review of the EORTC_26981/NCIC_CE.3 trial.

Glioblastoma (GBM) is a morphologically heterogeneous tumor type with a median survival of only 15 months in clinical trial populations. However, survival varies greatly among patients. As part of a central pathology review, we addressed the question if patients with GBM displaying distinct morphologic features respond differently to combined chemo-radiotherapy with temozolomide. Morphologic features were systematically recorded for 360 cases with particular focus on the presence of an oligodendroglioma-like component and respective correlations with outcome and relevant molecular markers. GBM with an oligodendroglioma-like component (GBM-O) represented 15% of all confirmed GBM (52/339) and was not associated with a more favorable outcome. GBM-O encompassed a pathogenetically heterogeneous group, significantly enriched for IDH1 mutations (19 vs. 3%, p = 0.003) and EGFR amplifications (71 vs. 48%, p = 0.04) compared with other GBM, while co-deletion of 1p/19q was found in only one case and the MGMT methylation frequency was alike (47 vs. 46%). Expression profiles classified most of the GBM-O into two subtypes, 36% (5/14 evaluable) as proneural and 43% as classical GBM. The detection of pseudo-palisading necrosis (PPN) was associated with benefit from chemotherapy (p = 0.0002), while no such effect was present in the absence of PPN (p = 0.86). In the adjusted interaction model including clinical prognostic factors and MGMT status, PPN was borderline nonsignificant (p = 0.063). Taken together, recognition of an oligodendroglioma-like component in an otherwise classic GBM identifies a pathogenetically mixed group without prognostic significance. However, the presence of PPN may indicate biological features of clinical relevance for further improvement of therapy.

High incidence of childhood hemolytic uremic syndrome in Switzerland is associated with indicators of livestock farming intensity

Background: Hemolytic-uremic syndrome (HUS) is a multisystem disorder associated with significant morbidity and mortality. Typically, HUS is preceded by an episode of (bloody) diarrhea mostly due to Shiga-toxin (Stx) producing Escherichia coli (STEC). The main reservoir for STEC is the intestine of healthy ruminants, mostly cattle, and recent studies have revealed an association between indicators of livestock density and human STEC infection or HUS, respectively. Nationwide data on HUS in Switzerland have been established through the Swiss Pediatric Surveillance Unit (SPSU) [Schifferli et al. Eur J Pediatr. 2010; 169:591-8]. Aims: Analysis of age-specific incidence rate of childhood HUS and possible association of Shiga-toxin associated HUS (Stx-HUS) with indicators of livestock farming intensity. Methods: Epidemiological and ecological analysis based on the SPSU data (1997-2003) and the database of the Swiss Federal Statistical Office (data on population and agriculture). Results: One hundred-fourteen cases were registered, 88% were ≤5 years old. The overall annual incidence rate was 1.42 (0.60-1.91) and 4.23 (1.76-6.19) per 100000 children ≤5 and ≤16 years, respectively (P = 0.005). Stx-HUS was more frequent compared to cases not associated with STEC (P = 0.002). The incidence rate for Stx-HUS was 3.85 (1.76-5.65) in children ≤5, compared to 0.27 (0.00-0.54) per 100'000 children 5-16 years (P = 0.002), respectively. The incidence rate of cases not associated with STEC infection did not significantly vary with age (P = 0.107). Compared to data from Scotland, Canada, Ireland, Germany, England, Australia, Italy, and Austria the annual incidence rate of HUS in young children is highest in Switzerland. Ecological analysis revealed strong association between the incidence rate of Stx-HUS and indicators of rural occupation (agricultural labourer / population, P = 0.030), farming intensity (livestock breeding farms / population, P = 0.027) and cattle density (cattle / cultivated area, P = 0.013). Conclusions: Alike in other countries, HUS in Switzerland is mostly associated with STEC infection and affects predominantly young children. However, the incidence rate is higher compared to countries abroad and is significantly correlated with indicators of livestock farming intensity. The present data support the impact of direct and indirect contact with animals or fecal contaminants in transmission of STEC to humans.

Mediastinal lymph node clearance after docetaxel-cisplatin neoadjuvant chemotherapy is prognostic of survival in patients with stage IIIA pN2 non-small-cell lung cancer: a multicenter phase II trial.

PURPOSE: A multicenter, phase II trial investigated the efficacy and toxicity of neoadjuvant docetaxel-cisplatin in locally advanced non-small-cell lung cancer (NSCLC) and examined prognostic factors for patients not benefiting from surgery. PATIENTS AND METHODS: Ninety patients with previously untreated, potentially operable stage IIIA (mediastinoscopically pN2) NSCLC received three cycles of docetaxel 85 mg/m2 day 1 plus cisplatin 40 mg/m2 days 1 and 2, with subsequent surgical resection. RESULTS: Administered dose-intensities were docetaxel 85 mg/m2/3 weeks (range, 53 to 96) and cisplatin 95 mg/m2/3 weeks (range, 0 to 104). The 265 cycles were well tolerated, and the overall response rate was 66% (95% confidence interval [CI], 55% to 75%). Seventy-five patients underwent tumor resection with positive resection margin and involvement of the uppermost mediastinal lymph node in 16% and 35% of patients, respectively (perioperative mortality, 3%; morbidity, 17%). Pathologic complete response occurred in 19% of patients with tumor resection. In patients with tumor resection, downstaging to N0-1 at surgery was prognostic and significantly prolonged event-free survival (EFS) and overall survival (OS; P =.0001). At median follow-up of 32 months, the median EFS and OS were 14.8 months (range, 2.4 to 53.4) and 33 months (range, 2.4 to 53.4), respectively. Local relapse occurred in 27% of patients with tumor resection, with distant metastases in 37%. Multivariate analyses identified mediastinal clearance (hazard ratio, 0.22; P =.0003) and complete resection (hazard ratio, 0.26; P =.0006) as strongly prognostic for increased survival. CONCLUSION: Neoadjuvant docetaxel-cisplatin is effective and tolerable in stage IIIA pN2 NSCLC. Resection is recommended only for patients with mediastinal downstaging after chemotherapy.

Delayed diagnosis of acute ischemic stroke in children - a registry-based study in Switzerland.

QUESTIONS UNDER STUDY/PRINCIPLES: After arterial ischemic stroke (AIS) an early diagnosis helps preserve treatment options that are no longer available later. Paediatric AIS is difficult to diagnose and often the time to diagnosis exceeds the time window of 6 hours defined for thrombolysis in adults. We investigated the delay from the onset of symptoms to AIS diagnosis in children and potential contributing factors. METHODS: We included children with AIS below 16 years from the population-based Swiss Neuropaediatric Stroke Registry (2000-2006). We evaluated the time between initial medical evaluation for stroke signs/symptoms and diagnosis, risk factors, co-morbidities and imaging findings. RESULTS: A total of 91 children (61 boys), with a median age of 5.3 years (range: 0.2-16.2), were included. The time to diagnosis (by neuro-imaging) was <6 hours in 32 (35%), 6-12 hours in 23 (25%), 12-24 hours in 15 (16%) and >24 hours in 21 (23%) children. Of 74 children not hospitalised when the stroke occurred, 42% had adequate outpatient management. Delays in diagnosis were attributed to: parents/caregivers (n = 20), physicians of first referral (n = 5) and tertiary care hospitals (n = 8). A co-morbidity hindered timely diagnosis in eight children. No other factors were associated with delay to diagnosis. A total of 17 children were inpatients at AIS onset. CONCLUSIONS: One-third of children with AIS were diagnosed within six hours. Diagnostic delay was predominately caused by insufficient recognition of stroke symptoms. Increased public and expert awareness and immediate access to diagnostic imaging are essential. The ability of parents/caregivers and health professionals to recognise stroke symptoms in a child needs to be improved.

Patterns of calcium-binding proteins support parallel and hierarchical organization of human auditory areas.

The human primary auditory cortex (AI) is surrounded by several other auditory areas, which can be identified by cyto-, myelo- and chemoarchitectonic criteria. We report here on the pattern of calcium-binding protein immunoreactivity within these areas. The supratemporal regions of four normal human brains (eight hemispheres) were processed histologically, and serial sections were stained for parvalbumin, calretinin or calbindin. Each calcium-binding protein yielded a specific pattern of labelling, which differed between auditory areas. In AI, defined as area TC [see C. von Economo and L. Horn (1930) Z. Ges. Neurol. Psychiatr.,130, 678-757], parvalbumin labelling was dark in layer IV; several parvalbumin-positive multipolar neurons were distributed in layers III and IV. Calbindin yielded dark labelling in layers I-III and V; it revealed numerous multipolar and pyramidal neurons in layers II and III. Calretinin labelling was lighter than that of parvalbumin or calbindin in AI; calretinin-positive bipolar and bitufted neurons were present in supragranular layers. In non-primary auditory areas, the intensity of labelling tended to become progressively lighter while moving away from AI, with qualitative differences between the cytoarchitectonically defined areas. In analogy to non-human primates, our results suggest differences in intrinsic organization between auditory areas that are compatible with parallel and hierarchical processing of auditory information.

Genetic and maternal contributions to offspring viability under different environmental conditions in various salmonids

Summary : Due to anthropogenic impacts and natural fluctuations, fish usually have to cope with constantly changing and often hostile environments. Whereas adult fish have various possibilities to counteract unfavourable environmental conditions, embryos have much fewer options. Besides by their developing immune system, they are protected by the egg envelopes and several immune substances provided by their mothers. In addition to this, they may also adjust their hatching timing in reaction to various risks. However, individuals may vary in their defensive potential. This variation may be either based on their genetics and/or on differential maternal investments and may be dependent on the experienced stress. Nevertheless, in fish, the impact of such parental contributions on embryo and/or juvenile viability is still poorly investigated. The main objective of this thesis was to investigate the importance of paternal (i.e. genetic) and maternal (i.e. genetic + egg investment) contributions to offspring viability under different environmental conditions and at different life stages. In order to investigate this, we used gametes of various salmonids for in vitro fertilisation experiments based on full-factorial breeding designs. The individual studies are summarised in the following chapters: In the first chapter, we tested the effectiveness of the embryonic immune system in Lake whitefish (Coregonus palaea). Namely, we investigated paternal and maternal contributions to the embryos' tolerance to different kinds of pathogen exposure. Additionally, we tested whether an early sub-léthal exposure has a positive or a negative effect on an embryo's susceptibility to later pathogen exposures with the same pathogen. We found that pre-challenged embryos were more susceptible to future challenges. Moreover, pathogen susceptibility was dependent on maternal investments and/or the embryos' own genetics, depending on the challenge level. Chapter 2 summarises a similar study with brown trout (Salmo trutta). In addition to the previously described investigations, we analysed if genetic effects on offspring viability are mediated either by parental MHC genotypes or relatedness based on neutral microsatellite markers, and we tested if males signal their genetic quality either by their body size or their melanin-based skin colouration. We found that embryo survival was lower at higher stress levels and dependent on the embryos' genetics. Addirionally, parents with similar and/or, very common MHC genotypes had higher offspring viabilities. Finally, darker males produced more viable offspring. In the first two chapters we investigated the embryos' defensive potential based on their immune system, i.e. their pathogen tolerance. In chapter 3 we investigate whether hatching timing of Lake whitefìsh (C. palaea) is dependent on parental contributions and/or on pathogen pressure, and whether there are parental-environmental interactions. We found that whitefish embryos hatch earlier under increasing pathogen pressure. Moreover, hatching timing was affected by embryo genetics and/or maternally provided resources, but the magnitude of the effect was dependent on the pathogen. pressure. We also found a significant paternal-environmental interaction, indicating that the hatching efficiency of a certain sib group is dependent on the pathogen environment. Chapter 4 describes an analogous study with brown trout (S. trutta), with similar findings. In the former chapters, we only looked at offspring performance during the embryonic period, and only under semi-natural conditions. In chapter 5 we now test the performance and viability of embryonic and juvenile brown trout (S. trutta) under natural conditions. To measure embryo viability, we put them in brood boxes, buried them in the gravel of a natural river, and analysed survival after several months. To investigate juvenile survival and performance, wé reared embryos under different stress levels in the laboratory and subsequently released the resulting hatchlings in to a closed river section. Juvenile size and survival was then determined one year later. Additionally, we investigated if sires differ in their genetic quality, determined by embryo and juvenile survival as well as juvenile size, and if they signal their quality by either body size or melanin-based body darkness. We found hat juvenile size was dependent on genetic effects and on maternal investment, whereas this was neither the case for embryo nor for juvenile survival. Additionally, we found that offspring of darker males grew larger, and larger juveniles had also an increased survival. Finally, we found acarry-over effect of the early non-lethal challenge: exposing embryos to higher stress levels resulted in smaller juveniles. To evaluate the long-term performance of differently treated groups, mark-recapture studies are inevitable. For this purpose, effective mass-marking techniques are essential. In chapter 6 we tested the suitability of the fluorescent pigment spray marking method for the mass marking of European graylings (Thymallus thymallus), with very promising results. Our in vitro fertilisation studies on whitefish may reveal new insights on potential genetic benefits of mate choice, but the mating system of whitefish under natural conditions is still poorly investigated. In order to study this, we installed underwater cameras at the spawning place of a Coregonus suidteri population, recorded the whole mating period and subsequently analysed the recordings. Confirmations of previous findings as well as exciting new observations are listed and discussed in chapter 7. Dus aux impacts anthropogéniques et aux fluctuations naturelles, les poissons doivent faire face à des environnements en perpétuel changement. Ces changements font que les poissons doivent s'adapter à de nouvelles situations, souvent hostiles pour eux. Les adultes ont différentes possibilités d'échapper à un environnement peu favorable, ce n'est par contre pas le cas des embryons. Les embryons sont protégés d'une part par leur système immunitaire en développement, d'autre part, par la coquille de l'eeuf et différentes substances immunitaires fournies par leur mère. De plus, ils sont capables d'influencer leur propre date d'éclosion en réponse à différents facteurs de stress. Malgré tout, les individus varient dans leur capacité à se défendre. Cette variation peut être basé sur des facteurs génétiques et/ou sur des facteurs maternels, et est dépendante du stress subi. Néanmoins, chez les poissons, l'impact de telles contributions parentales sur la survie d'embryons et/ou juvéniles est peu étudié. L'objectif principal de cette thèse a été d'approfondir les connaissances sur l'importance de la contribution paternelle (c.a.d. génétique) et maternelle (c.a.d. génétique + investissement dans l'oeuf) sur la survie des jeunes dans différentes conditions expérimentales et stades de vie. Pour faire ces analyses, nous avons utilisé des gamètes de divers salmonidés issus de croisements 'full-factorial'. Les différentes expériences sont résumées dans les chapitres suivants: Dans le premier chapitre, nous avons testé l'efficacité du système immunitaire des embryons chez les corégones (Coregonus palea). Plus précisément nous avons étudié la contribution paternelle et maternelle à la tolérance des embryons à différents niveaux de stress pathogène. Nous avons aussi testé, si une première exposition non létale à un pathogène avait un effet positif ou négatif sur la susceptibilité d'un embryon a une deuxième exposition au même pathogène. Nous avons trouvé que des embryons qui avaient été exposés une première fois étaient plus sensibles au pathogène par la suite. Mais aussi que la sensibilité au pathogène était dépendante de l'investissement de la mère et/ou des gènes de l'embryon, dépendamment du niveau de stress. Le deuxième chapitre résume une étude similaire avec des truites (Salmo truffa). Nous avons examiné, si la survie des jeunes variait sous différentes intensités de stress, et si la variance observée était due aux gènes des parents. Nous avons aussi analysé si les effets génétiques sur la survie des juvéniles étaient dus au MHC (Major Histocompatibility Complex) ou au degré de parenté des parents. De plus, nous avons analysé si les mâles signalaient leur qualité génétique par la taille du corps ou par leur coloration noire, due à la mélanine. On a trouvé que la survie des embryons était plus basse quand le niveau de stress était plus haut mais que la variation restait dépendante de la génétique des embryons. De plus, les parents avec des MHC similaires et/ou communs avaient des embryons avec une meilleure survie. Par contre, des parents avec un degré de parenté plus haut produisent des embryons avec une survie plus mauvaise. Finalement nous avons montré que les mâles plus foncés ont des embryons qui survivent mieux, mais que la taille des mâles n'a pas d'influence sur la survie de ces mêmes embryons. Dans les deux premiers chapitres, nous avons étudié le potentiel de défense des embryons basé sur leur système immunitaire, c.a.d. leur tolérance aux pathogènes. Dans le troisième chapitre, nous nous intéressons à la date d'éclosion des corégones (C. palea), pour voir si elle est influencée par les parents ou par la pression des pathogènes, et si il y a une interaction entre ces deux facteurs. Nous avons trouvé que les jeunes naissent plus rapidement lorsque la pression en pathogènes augmente. La date d'éclosion est influencée par la génétique des embryons et/ou l'investissement des parents, mais c'est la magnitude des effets qui est dépendante de la pression du pathogène. Nous avons aussi trouvé une interaction entre l'effet paternel et l'environnement, ce qui indique que la rapidité d'éclosion de certains croisements est dépendante des pathogènes dans l'environnement. Le chapitre 4 décrit une étude analogue avec de truites (S. truffa), avec des résultats sitzimilaires. Dans les précédents chapitres nous nous sommes uniquement concentrés sur les performances des jeunes durant leur stade embryonnaire, et seulement dans des conditions semi naturelles. Dans le chapitre 5 nous testons la performance et la viabilité des embryons et de juvéniles de truites (S. truffa) dans des conditions naturelles. Nous avons trouvé que la taille des juvéniles était dépendante d'effets génétiques et de l'investissement maternel, mais ceci n'était ni les cas pour les survie des embryons et des juvéniles. De plus, nous avons trouvé que les jeunes des mâles plus foncés devenaient plus grands et que les grands ont un meilleur taux de survie. Finalement nous avons trouvé un 'carry-over effect' d'une première exposition non létale à un pathogène: exposer des embryons à des plus hauts niveaux de stress donnait des juvéniles plus petits. Pour évaluer la performance à long terme de groupes traités dé manières différentes, une méthode de marquage-recapture est inévitable. Pour cette raison, des techniques de marquage en masse sont nécessaires. Dans le chapitre 6, nous avons testé l'efficacité de la technique `fluorescent pigment spray marking' pour le marquage en masse de l'Ombre commun (Thymallus thymallus), avec des résultats très prometteurs. Les études de fertilisations in vitro avec les corégones nous donnent une idée du potentiel bénéfice génétique que représente la sélection d'un bon partenaire, même si le système d'accouplement des corégones en milieu naturel reste peu connu. Pour combler cette lacune, nous avons installé des caméras sous-marines autour de la frayère d'une population de corégones (C. suidteri), nous avons enregistré toute la période de reproduction et nous avons analysé les données par la suite. Ainsi, nous avons été capables de confirmer bien des résultats trouvés précédemment, mais aussi de faire de nouvelles observations. Ces résultats sont reportés dans le septième chapitre, où elles sont comparées avec des observations antérieures.

The weaker points of fish acute toxicity tests and how tests on embryos can solve some issues.

Fish acute toxicity tests play an important role in environmental risk assessment and hazard classification because they allow for first estimates of the relative toxicity of various chemicals in various species. However, such tests need to be carefully interpreted. Here we shortly summarize the main issues which are linked to the genetics and the condition of the test animals, the standardized test situations, the uncertainty about whether a given test species can be seen as representative to a given fish fauna, the often missing knowledge about possible interaction effects, especially with micropathogens, and statistical problems like small sample sizes and, in some cases, pseudoreplication. We suggest that multi-factorial embryo tests on ecologically relevant species solve many of these issues, and we shortly explain how such tests could be done to avoid the weaker points of fish acute toxicity tests.

Acute pulmonary embolectomy.

Acute pulmonary embolism (PE) is a common condition frequently associated with a high mortality worldwide. It can be classified into non-massive, sub-massive and massive, based on the degree of haemodynamic compromise. Surgical pulmonary embolectomy, despite having been in existence for over 100 years, is generally regarded as an option of last resort, with expectedly high mortality rates. Recent advances in diagnosis and recognition of key qualitative predictors of mortality, such as right ventricular stress on echocardiography, have enabled the re-exploration of surgical pulmonary embolectomy for use in patients prior to the development of significant circulatory collapse, with promising results. We aim to review the literature and discuss the indications, perioperative workup and outcomes of surgical pulmonary embolectomy in the management of acute PE.

Cetuximab In Combination With Docetaxel In Patients (Pts) With Metastatic Castration Resistant (Mcrpc) And Docetaxel-Refractory Prostate Cancer: Final Analysis Of The Multicenter Phase Ii Trial Sakk 08/07

There is no registered treatment (ttr) for pts with mCRPC who have progressive disease during or shortly after docetaxel (doc). EGFR overexpression increases in prostate cancer during the course of the disease. We investigated efficacy and safety of the combination of the monoclonal EGFR antibody cetuximab (cet) and doc in pts with mCRPC who are doc-refractory. Methods: Pts with mCRPC progressing during or < 90 days after at least 12 weeks of doc were included. Ttr consisted of the same doc regimen as prior to progression (35mg/m2 d1,8,15 q4w or 75mg/m2 q3w) in combination with cet (400mg/m2 d1, then 250mg/m2 weekly). Primary endpoint was progression free survival (PFS) at 12 weeks defined as absence of PSA progression or progression of metastases (mets). Secondary endpoints included toxicity, PFS at 24 weeks, PSA response, response of measureable disease and overall survival. 35 pts were needed in a Simon's two stage optimal design with a power of 90% and a significance level of 5% in order to test PFS rate at 12 weeks of £10% vs ?30%. Results: 35 evaluable pts were enrolled at 15 Swiss centers between 7/08 and 9/09. Median follow up was 14.8 months. Confirmed PFS at 12 weeks was 34% (95%CI 19-52%), PFS at 24 weeks was 20% and overall survival was 12.0 months (95%CI 7.1 -15.6). 20% (7/35) had a confirmed decline in PSA ? 50% and 31% (11/35) had a confirmed PSA decline ? 30%. Of pts with measurable disease (n=24) PR, SD and PD at week 12 was 4%, 54% and 25%, respectively (17% not evaluable). 3/9 (33%) pts with PDduring last doc ttr before inclusion reached the primary endpoint compared to 7/18 (39%) with PR or SD to last doc. 54% of evaluable pts experienced grade 3 and 6% grade 4 toxicity. Discussion: The result of the primary endpoint was promising in this first trial to test cet in combination with doc in pts with docetaxel-refractory mCRPC. Because this goal was achieved in such a highly pretreated pts population it appears that inhibition of the EGFR pathway may play a more important and persistent role in the treatment of prostate cancer than perceived so far. Further research is therefore warranted. Disclosure: R. Cathomas: - Membership on advisory board for sanofi aventis (suisse) and Merck. S. Gillessen: - Membership in advisory board for Sanofi Aventis. All other authors have declared no conflicts of interest.