Trimodal therapy for invasive bladder cancer: is it really equal to radical cystectomy?

PURPOSE OF REVIEW: Trimodal therapy (TMT) is considered the most effective bladder-sparing approach for muscle-invasive urothelial carcinoma of the bladder (MIBC) and an alternative to radical cystectomy. The purpose of this article was to review and summarize the current knowledge on the equivalence of TMT and radical cystectomy based on the recent literature. RECENT FINDINGS: TMT consists of a maximal transuretral resection of the bladder, followed by a concurrent radiotherapy and chemotherapy, limiting salvage radical cystectomy to nonresponder tumors or muscle-invasive recurrence. In large population studies, less than 6% of the patients with nonmetastatic MIBC receive a chemoradiation therapy and this rate is stable. A growing body of evidence exists that TMT provides good oncologic outcomes with low morbidity when compared with radical cystectomy. TMT requires, however, a close follow-up because of the high risk of local recurrence and salvage radical cystectomy in up to 30% of the patients. Salvage radical cystectomy can be performed with adequate results but does not offer the same opportunity of reconstruction and functional outcomes than primary radical cystectomy. SUMMARY: Although radical cystectomy is still the treatment of reference for most of the patients with localized MIBC, TMT represents a reasonable alternative in highly selected patients. Any firm conclusion on the equivalence or superiority of one treatment to the other is still limited by the lack of randomized controlled trials and the heterogeneity of the available literature. Future studies and multidisciplinary approach are mandatory to optimize the patient selection and regimen of TMT.

Operational sex ratio, sexual conflict and the intensity of sexual selection.

Modern sexual selection theory indicates that reproductive costs rather than the operational sex ratio predict the intensity of sexual selection. We investigated sexual selection in the polygynandrous common lizard Lacerta vivipara. This species shows male aggression, causing high mating costs for females when adult sex ratios (ASR) are male-biased. We manipulated ASR in 12 experimental populations and quantified the intensity of sexual selection based on the relationship between reproductive success and body size. In sharp contrast to classical sexual selection theory predictions, positive directional sexual selection on male size was stronger and positive directional selection on female size weaker in female-biased populations than in male-biased populations. Thus, consistent with modern theory, directional sexual selection on male size was weaker in populations with higher female mating costs. This suggests that the costs of breeding, but not the operational sex ratio, correctly predicted the strength of sexual selection.

Determinants of male fitness: disentangling intra- and inter-sexual selection.

Both intra- and inter-sexual selection may crucially determine a male's fitness. Their interplay, which has rarely been experimentally investigated, determines a male's optimal reproductive strategy and thus is of fundamental importance to the understanding of a male's behaviour. Here we investigated the relative importance of intra- and inter-sexual selection for male fitness in the common lizard. We investigated which male traits predict a male's access to reproduction allowing for both selective pressures and comparing it with a staged mating experiment excluding all types of intra-sexual selection. We found that qualitatively better males were more likely to reproduce and that sexual selection was two times stronger when allowing for both selective pressures, suggesting that inter- and intra-sexual selection determines male fitness and confirming the existence of multi-factorial sexual selection. Consequently, to optimize fitness, males should trade their investment between the traits, which are important for inter- and intra-sexual selection.

Pharmacogenetic and clinical study on adverse effects induced by psychotropic drugs

Second-generation antipsychotics (SGAs) have become the first-line antipsychotic treatment for psychotic disorders due to their better overall tolerance compared to classical antipsychotics. However, metabolic side effects such as weight gain are frequently described during treatment with SGAs and/or other psychotropic drugs including some antidepressants and mood stabilizers, which may also result in poor adherence to treatment. The aim of this work was to investigate different methods to predict common side effects, in particular weight gain during treatment with weight gain inducing psychotropic drugs. Firstly, clinical data were used to determine the potential predictive power of a one month weight gain on weight increase after three and 12 months of treatment (n=351 patients). A fast and strong weight gain of >5% after a period of one month (>5%WG) was found to be the best predictor for an important weight gain at three (>15%) and 12 months (>20%). Similar analyses in an independent cohort of psychiatric adolescents (n=42), showed that a comparable >4% weight gain at one month is the best predictor for an important weight gain at three months (>15%). Secondly, we aimed to determine whether an extensive analysis of genes could be used, in addition to clinical factors, to predict patients at risk for >5%WG or for type 2 diabetes (T2D). Adding genetic markers to clinical variables to predict >5%WG increased significantly the area under the curve (AUC) of the analysis (AUCfinai:0.92, AUCdmicai:0.75, pcO.OOOl, n=248). Conversely, genetic risk scores were found to be associated with T2D (OR: 2.5, p=0.03, n=285) but without a significant increase of AUC'when compared to the prediction based to clinical factors alone. Finally, therapeutic drug monitoring was used to predict extrapyramidal symptoms during risperidone treatment (n=150). Active moiety (sum of risperidone and of its active metabolite 9- hydroxyrisperidone plasma concentrations) of >40 ng/ml should be targeted only in case of insufficient response. These results highlight different approaches for personalizing psychotropic treatments in order to reduce related side effects. Further research is needed, in particular on the identification of genetic markers, to improve the implementation of these results into clinical practice. Résumé Les antipsychotiques atypiques (APA) sont devenus le traitement antipsychotique de première intention pour le traitement des psychoses, grâce à un profil d'effets secondaires plus favorables comparé aux antipsychotiques typiques. Néanmoins, d'autres effets indésirables d'ordre métabolique (ex. prise pondérale) sont observés sous APA, stabilisateurs de l'humeur et/ou certains antidépresseurs, pouvant aussi limiter l'adhérence au traitement. L'objectif de ce travail est d'explorer différentes méthodes permettant de prédire des effets secondaires courants, en particulier la prise de poids durant un traitement avec des psychotropes pouvant induire un tel effet. Dans une première partie, des données cliniques ont été évaluées pour leurs potentiels prédictifs d'une prise de poids à un mois sur une prise de poids à trois et 12 mois de traitement (n=351 patients). Une prise de poids rapide et forte >5% à un mois (PP>5%) s'est avérée être le meilleur prédicteur pour une prise pondérale importante à trois (>15%) et 12 (>20%) mois de traitement. Des analyses similaires dans une cohorte pédiatrique (n=42) ont indiqué une prise de poids >4% à un mois comme le meilleur prédicteur pour une prise pondérale importante (>15%) à trois mois de traitement. Dans une deuxième partie, des marqueurs génétiques, en complément aux données cliniques, ont été analysés pour leur contribution potentielle à la prédiction d'une PP>5% et au dépistage du diabète de type 2 (DT2). L'ajout de variants génétiques aux données cliniques afin de prédire une PP>5% a augmenté significativement l'aire sous la courbe (ASC) de l'analyse (ASCflnai:0.92, ASCC|inique:0.75, p<0.0001, n=248). Concernant le DT2, un score génétique est associé au DT2 (OR: 2.5, p=0.03, n=285), néanmoins aucune augmentation significative de l'ASC n'a été observée par rapport à l'analyse avec les données cliniques seules. Finalement, des mesures de concentrations plasmatiques de médicaments ont été utilisées pour prédire la survenue de symptômes extrapyramidaux sous rispéridone (n=150). Cette analyse nous a permis d'établir qu'une concentration plasmatique de rispéridone associée à son métabolite actif >40 ng/ml ne devrait être recherchée qu'en cas de réponse clinique insuffisante. Ces différents résultats soulignent différentes approches pour personnaliser la prescription de psychotropes afin de réduire la survenue d'effets secondaires. Des études supplémentaires sont néanmoins nécessaires, en particulier sur l'identification de marqueurs génétiques, afin d'améliorer l'implémentation de ces résultats en pratique clinique. Résumé large publique Les antipsychotiques atypiques et autres traitements psychotropes sont couramment utilisés pour traiter les symptômes liés à la schizophrénie et aux troubles de l'humeur. Comme pour tout médicament, des effets secondaires sont observés. L'objectif de ce travail est d'explorer différentes méthodes qui permettraient de prédire la survenue de certains effets indésirables, en particulier une prise de poids et la survenue d'un diabète. Dans une première partie, nous avons évalué l'effet d'une prise de poids précoce sur une prise de poids au long terme sous traitement psychotrope. Les analyses ont mis en évidence dans une population psychiatrique qu'une prise de poids à un mois >5% par rapport au poids initial permettait de prédire une prise pondérale importante après trois (>15%) et 12 (>20%) mois de traitement. Un résultat semblable a. été observé dans un autre groupe de patients exclusivement pédiatriques. Dans une deuxième partie, nous avons évalué la contribution potentielle de marqueurs génétiques à la prédiction d'une prise pondérale de >5% après un mois de traitement ainsi que dans la survenue d'un diabète de type 2. Pour la prise de poids, la combinaison des données génétiques aux données cliniques a permis d'augmenter de 17% la précision de la prédiction, en passant de 70% à 87%. Concernant la survenue d'un diabète, les données génétiques n'ont pas amélioré la prédiction. Finalement, nous avons analysé la relation possible entre les concentrations sanguines d'un antipsychotique atypique couramment utilisé, la rispéridone, et la survenue d'effets secondaires (ici les tremblements). Il est ressorti de cette étude qu'une concentration plasmatique du médicament supérieure à 40 ng/ml ne devrait être dépassée qu'en cas de réponse thérapeutique insuffisante, au risque de voir augmenter la survenue d'effets secondaires du type tremblements. Ces résultats démontrent la possibilité de prédire avec une bonne précision la survenue de certains effets secondaires. Cependant, en particulier dans le domaine de la génétique, d'autres études sont nécessaires afin de confirmer les résultats obtenus dans nos analyses. Une fois cette étape franchie, il serait possible d'utiliser ces outils dans la pratique clinique. A terme, cela pourrait permettre au prescripteur de sélectionner les traitements les mieux adaptés aux profils spécifiques de chaque patient.

Identification of imaging selection patterns in acute ischemic stroke patients and the influence on treatment and clinical trial enrollment decision making.

BACKGROUND AND PURPOSE: For the STroke Imaging Research (STIR) and VISTA-Imaging Investigators The purpose of this study was to collect precise information on the typical imaging decisions given specific clinical acute stroke scenarios. Stroke centers worldwide were surveyed regarding typical imaging used to work up representative acute stroke patients, make treatment decisions, and willingness to enroll in clinical trials. METHODS: STroke Imaging Research and Virtual International Stroke Trials Archive-Imaging circulated an online survey of clinical case vignettes through its website, the websites of national professional societies from multiple countries as well as through email distribution lists from STroke Imaging Research and participating societies. Survey responders were asked to select the typical imaging work-up for each clinical vignette presented. Actual images were not presented to the survey responders. Instead, the survey then displayed several types of imaging findings offered by the imaging strategy, and the responders selected the appropriate therapy and whether to enroll into a clinical trial considering time from onset, clinical presentation, and imaging findings. A follow-up survey focusing on 6 h from onset was conducted after the release of the positive endovascular trials. RESULTS: We received 548 responses from 35 countries including 282 individual centers; 78% of the centers originating from Australia, Brazil, France, Germany, Spain, United Kingdom, and United States. The specific onset windows presented influenced the type of imaging work-up selected more than the clinical scenario. Magnetic Resonance Imaging usage (27-28%) was substantial, in particular for wake-up stroke. Following the release of the positive trials, selection of perfusion imaging significantly increased for imaging strategy. CONCLUSIONS: Usage of vascular or perfusion imaging by Computed Tomography or Magnetic Resonance Imaging beyond just parenchymal imaging was the primary work-up (62-87%) across all clinical vignettes and time windows. Perfusion imaging with Computed Tomography or Magnetic Resonance Imaging was associated with increased probability of enrollment into clinical trials for 0-3 h. Following the release of the positive endovascular trials, selection of endovascular only treatment for 6 h increased across all clinical vignettes.

Maladaptive emotion regulation strategies and stress sensitivity mediate the relation between adverse life events and attenuated positive psychotic symptoms.

INTRODUCTION: There is now solid evidence for a relation between adverse life events (ALE) and psychotic symptoms in patients with psychosis and in the general population. A recent study has shown that this relation may be partially mediated by stress sensitivity, suggesting the influence of other factors. The aim of this study was to assess the mediation effect of emotion regulation strategies and stress sensitivity in the relation between ALE and attenuated positive psychotic symptoms (APPS) in the general population. METHODS: Hundred and twelve healthy volunteers were evaluated with measures of APPS, emotion regulation strategies, ALE and stress sensitivity. RESULTS: Results demonstrated that the relation between ALE, hallucination and delusion proneness was completely mediated by maladaptive emotion regulation strategies, but not by stress sensitivity. However, in addition to maladaptive emotion regulation strategies, stress sensitivity demonstrated a mediation effect between ALE and attenuated positive psychotic positive symptoms when positive psychotic symptoms were grouped together. CONCLUSIONS: There are probably several possible trajectories leading to the formation of positive psychotic symptoms and the results of the present study reveal that one such trajectory may involve the maladaptive regulation of negative emotions alongside a certain general vulnerability after experiencing ALE.

Genomics of clinal variation in Drosophila: disentangling the interactions of selection and demography.

Clines in phenotypes and genotype frequencies across environmental gradients are commonly taken as evidence for spatially varying selection. Classical examples include the latitudinal clines in various species of Drosophila, which often occur in parallel fashion on multiple continents. Today, genomewide analysis of such clinal systems provides a fantastic opportunity for unravelling the genetics of adaptation, yet major challenges remain. A well-known but often neglected problem is that demographic processes can also generate clinality, independent of or coincident with selection. A closely related issue is how to identify true genic targets of clinal selection. In this issue of Molecular Ecology, three studies illustrate these challenges and how they might be met. Bergland et al. report evidence suggesting that the well-known parallel latitudinal clines in North American and Australian D. melanogaster are confounded by admixture from Africa and Europe, highlighting the importance of distinguishing demographic from adaptive clines. In a companion study, Machado et al. provide the first genomic comparison of latitudinal differentiation in D. melanogaster and its sister species D. simulans. While D. simulans is less clinal than D. melanogaster, a significant fraction of clinal genes is shared between both species, suggesting the existence of convergent adaptation to clinaly varying selection pressures. Finally, by drawing on several independent sources of evidence, Bo?ičević et al. identify a functional network of eight clinal genes that are likely involved in cold adaptation. Together, these studies remind us that clinality does not necessarily imply selection and that separating adaptive signal from demographic noise requires great effort and care.

Condition-dependence, pleiotropy and the handicap principle of sexual selection in melanin-based colouration.

The signalling function of melanin-based colouration is debated. Sexual selection theory states that ornaments should be costly to produce, maintain, wear or display to signal quality honestly to potential mates or competitors. An increasing number of studies supports the hypothesis that the degree of melanism covaries with aspects of body condition (e.g. body mass or immunity), which has contributed to change the initial perception that melanin-based colour ornaments entail no costs. Indeed, the expression of many (but not all) melanin-based colour traits is weakly sensitive to the environment but strongly heritable suggesting that these colour traits are relatively cheap to produce and maintain, thus raising the question of how such colour traits could signal quality honestly. Here I review the production, maintenance and wearing/displaying costs that can generate a correlation between melanin-based colouration and body condition, and consider other evolutionary mechanisms that can also lead to covariation between colour and body condition. Because genes controlling melanic traits can affect numerous phenotypic traits, pleiotropy could also explain a linkage between body condition and colouration. Pleiotropy may result in differently coloured individuals signalling different aspects of quality that are maintained by frequency-dependent selection or local adaptation. Colouration may therefore not signal absolute quality to potential mates or competitors (e.g. dark males may not achieve a higher fitness than pale males); otherwise genetic variation would be rapidly depleted by directional selection. As a consequence, selection on heritable melanin-based colouration may not always be directional, but mate choice may be conditional to environmental conditions (i.e. context-dependent sexual selection). Despite the interest of evolutionary biologists in the adaptive value of melanin-based colouration, its actual role in sexual selection is still poorly understood.