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First-line chemotherapy with selective internal radiation therapy for intrahepatic cholangiocarcinoma: The French ACABi GERCOR PRONOBIL cohort
No full textInternational audienceBackground and Aims: Selective internal radiation therapy (SIRT) is a promising option for liver-only unresectable intrahepatic cholangiocarcinoma (iCCA). The Real-SIRTCCA study retrospectively assessed the benefit of adding SIRT to chemotherapy in this setting within the French nationwide observational cohort ACABi-GERCOR-PRONOBIL. Methods: Inclusion criteria were advanced iCCA with limited or no extrahepatic disease, treated with first-line gemcitabine plus platinum chemotherapy +/- concurrent SIRT. All patients treated with chemotherapy and concurrent SIRT were included. To ensure groups' similarity, a rigorous selection was applied to the chemo-only group, with exclusion of patients with liver involvement >50% and extrahepatic metastases. The primary outcome was progression-free survival (PFS). Secondary outcomes were overall survival (OS), objective response rate (ORR) and tumor resection rate. Propensity score and inverse probability of treatment weighting (IPTW) propensity approaches were used to address confounding factors between groups. Results: Between July 2007 and December 2023, 277 patients met the Real-SIRTCCA inclusion criteria, with 88 in the chemoSIRT group and 189 in chemo-only group. Chemo-SIRT was associated with longer PFS (median = 10.8 vs. 5.5 months, hazard ratio [HR] 0.54, 95% CI 0.41-0.71, p <0.0001), a trend for longer OS (median = 22.5 vs. 15.1 months, HR 0.76, 95% CI 0.571.01), higher ORR (58.3% vs. 28.5%, odds ratio [OR] 3.51, 95% CI 2.03-6.09, p <0.0001), and resection rate (18.7% vs. 8.8%, p = 0.0279) compared to chemo-alone. After IPTW, the superiority of chemo-SIRT was confirmed with better PFS (HR 0.55, 95% CI 0.45-0.66, p <0,0001), OS (HR 0.70, 95% CI 0.58-0.85, p = 0.0004), ORR (OR 3.17, 95% CI 2.18-4.49, p <0.0001) and resection rate (OR 2.94, 95% CI 1.71-5.03, p <0.0001). Conclusions: Adding SIRT to first-line chemotherapy significantly improved survival outcomes, ORR, and secondary tumor resection rates in locally advanced iCCA. Prospective randomized data are needed to confirm these results. Clinical trial number: NCT04935853. (c) 2024 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
In spinis collige rosas. Mélanges offerts à Jean-François Maillard par ses collègues et amis
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Reverberations of Rodomonte in and around _Othello_
No full textInternational audienceThis chapter takes a broadly intertextual approach to supplementing the Italian histoires tragiques by Giraldi Cinzio and Matteo Bandello long recognised as sources for the basic intrigue of Shakespeare’s _Othello_. Central to this exploration is the depiction in Ariosto’s _Orlando Furioso_ of the confrontation between the lustful Moor Rodomonte and his beautiful Christian captive, Isabella – a confrontation which results in her death in defence of her chastity and his consequent repentance. The versions of this episode presented in the translation of Ariosto by John Harington (1591) and the dramatisation of Nicolas de Montreux (_Isabelle_, c. 1584) are discussed as especially illuminating the dynamic between Othello and Desdemona. Contemporary audiences might have further related this dynamic to a number of narratives involving sexualised power-relations between a “barbaric” and a “fair” warrior. Such analogues range from the biblical encounter of Judith and Holofernes to Marie de Gournay’s story (in _Le proumenoir de Monsieur de Montaigne_, 1594) of a Persian princess pursued to her death by the Thracian Othalcus, whose name strangely anticipates that of Shakespeare’s protagonist. The cumulative effect of such intertexts is to highlight the English dramatist’s synthetic blending of histoire tragique, romance fable and martyrdom legend so as to produce a heavily overdetermined – and conspicuously unstable – protagonist whose tragic destruction of Desdemona is inextricable from his own.Ce chapitre aborde la pièce shakespearienne de manière largement intertextuelle, afin de supplémenter les histoires tragiques italiennes par Giraldi Cinzio et Matteo Bandello reconnues depuis longtemps comme sources de l’intrigue de base. Au centre de cette exploration se trouve l’épisode de l’Orlando Furioso de l’Arioste où s’affrontent le Maure lascive Rodomonte et sa belle captive chrétienne Isabella, affrontement dont l’issue est la morte de cette dernière pour défendre sa chasteté et la repentance de son agresseur. Les versions de cet épisode trouvées dans la traduction de John Harington (1591), ainsi que dans sa dramatisation par Nicolas de Montreux (Isabelle, vers 1584), s’avèrent particulièrement révélatrices à l’égard de la dynamique entre Othello et Desdémone, avec laquelle le public contemporain aurait pu également mettre en rapport encore des narratifs présentant des jeux de pouvoir sexualisés entre un guerrier « barbare » et une belle antagoniste (« fair warrior »). De tels analogues couvrent une large gamme à partir de l’histoire biblique de Judith et d’Holoferne, et allant jusqu’à l’intrigue du _Proumenoir de Monsieur de Montaigne_ de Marie de Gournay (1594), où une princesse persane se trouve en Thrace poursuivie à sa mort par le barbare Othalcus, dont le nom anticipe étrangement celui du protagoniste shakespearien.L’effet cumulatif de tels intertextes est de mettre en lumière la fusion effectuée par le dramaturge entre les genres de l’histoire tragique, de la fable romanesque et de la légende du martyre pour produire un protagoniste tragique surdéterminé – donc notamment instable – dont la destruction de Desdémone est indissociable de la sienne
Metastability in the stochastic nearest-neighbor Kuramoto model of coupled phase oscillators
No full textInternational audienceThe Kuramoto model (KM) of n coupled phase-oscillators is analyzed in this work. The KM on a Cayley graph possesses a family of steady state solutions called twisted states. Topologically distinct twisted states are distinguished by the winding number q \in Z. It is known that for the KM on the nearest-neighbor graph, a q-twisted state is stable if |q| < n/4. In the presence of small noise, the KM exhibits metastable transitions between q-twisted states. Specifically, a typical trajectory remains in the basin of attraction of a given q-twisted state for an exponentially long time, but eventually transitions to the vicinity of another such state. In the course of this transition, it passes in close proximity of a saddle of Morse index 1, called a relevant saddle. In this work, we provide an exhaustive analysis of metastable transitions in the stochastic KM with nearest-neighbor coupling.We start by analyzing the equilibria and their stability. First, we identify all equilibria in this model. Using the discrete Fourier transform and eigenvalue estimates for rank-1 perturbations of symmetric matrices, we classify the equilibria by their Morse indices. In particular, we identify all stable equilibria and all relevant saddles involved in the metastable transitions. Further, we use Freidlin-Wentzell theory and the potential-theoretic approach to metastability to establish the metastable hierarchy and sharp estimates of Eyring-Kramers type for the transition times. The former determines the precise order, in which the metastable transitions occur, while the latter characterizes the times between successive transitions. The theoretical estimates are complemented by numerical simulations and a careful numerical verification of the transition times. Finally, we discuss the implications of this work for the KM with other coupling types including nonlocal coupling and the continuum limit as n tends to infinity
Reliability of online visual and proprioceptive feedback: impact on learning and sensorimotor coding
No full textInternational audienceMultisensory integration is essential for learning and sensorimotor coding, facilitating learners' adaptation to environmental changes. Recent findings confirm that introducing unreliability into visual feedback enhances the use of motor coding, probably because proprioceptive cues are given greater weight. The present study was designed to test this hypothesis and, more generally, to explore the impact of visual versus proprioceptive cue reliability on learning processes. Participants performed a 12-target pointing sequence 100 times with different combinations of visual and proprioceptive feedback: reliable versus unreliable. Retention tests and intermanual transfer tests were administered 24 hours later. Results showed that learning and sensorimotor coding were both affected by the different combinations of visual and proprioceptive cue reliability. Fully reliable feedback allowed for the best retention, while fully unreliable feedback resulted in the worst retention. Visual reliability alone mediated the level of visuospatial coding performance in visuospatial transfer, regardless of the level of proprioceptive reliability, and conversely, reliable proprioception combined with unreliable vision provided the optimum sensory environment for motor coding in the motor transfer test.Overall, our study highlighted the essential role of both visual cue reliability and proprioceptive cue reliability -and their interactions-in motor learning and its generalization
Caenorhabditis elegans, un modèle utilisé pour le criblage de microbiotes fromagers à effet santé
No full textInternational audienceLes fromages sont des aliments fermentés et une source de micro-organismes lorsque nous les consommons. En effet, les fromages, et en particulier ceux au lait cru, sont connus pour leur grande biodiversité microbienne au sein de laquelle des micro-organismes bénéfiques pour la santé humaine sont présents. Après consommation, ils peuvent s'installer dans notre organisme et avoir un effet. Nous utilisons le modèle in vivo Caenorhabditis elegans pour rechercher les effets santé liés à la consommation de micro-organismes fromagers. C. elegans est un eucaryote invertébré rond à peau lisse et mesure environ 1 mm à l'âge adulte. Il vit dans le sol et principalement dans la végétation en décomposition où il se nourrit de micro-organismes (bactéries, levures). En laboratoire, il se nourrit exclusivement de la bactérie Escherichia coli OP50 et sa culture se fait en boîtes de Petri. Son anatomie très simple et facilement observable du fait de son corps transparent, en fait un modèle de choix pour l'étude de microorganismes ayant de potentiels effets sur la santé.</div
Réduction des modèles EDP d’évolution du cancer structurée en phénotype: une approche généralisée de la dynamique des moments
No full textIntratumour phenotypic heterogeneity is nowadays understood to play a critical role in disease progression and treatment failure. Accordingly, there has been increasing interest in the development of mathematical models capable of capturing its role in cancer cell adaptation. This can be systematically achieved by means of models comprising phenotype-structured nonlocal partial differential equations, tracking the evolution of the phenotypic density distribution of the cell population, which may be compared to gene and protein expression distributions obtained experimentally. Nevertheless, given the high analytical and computational cost of solving these models, much is to be gained from reducing them to systems of ordinary differential equations for the moments of the distribution. We propose a generalised method of model-reduction, relying on the use of a moment generating function, Taylor series expansion and truncation closure, to reduce a nonlocal reaction-advection-diffusion equation, with general phenotypic drift and proliferation rate functions, to a system of moment equations up to arbitrary order. Our method extends previous results in the literature, which we address via two examples, by removing any a priori assumption on the shape of the distribution, and provides a flexible framework for mathematical modellers to account for the role of phenotypic heterogeneity in cancer adaptive dynamics, in a simpler mathematical framework
Recurrent <i>GRHL</i> fusions in a subset of sebaceoma: microscopic and molecular characterisation of eight cases
No full textInternational audienceAimsSebaceous neoplasms constitute a group of adnexal tumours, including sebaceous adenoma, sebaceoma and sebaceous carcinoma. Although mismatch repair deficiency may be observed, the nature of the genetic alterations contributing to the development of most of these tumours is still unknown. In the present study, we describe the clinical, microscopic, and molecular features of eight sebaceomas with GRHL gene rearrangement.Methods and resultsAmong these sebaceomas, four occurred in women and four in men; the median age was 63 years (range = 29–89). The tumours were located in the head and neck area in all cases. Microscopic examination revealed a well-demarcated lesion located in the dermis with focal extension into the subcutaneous tissue (three cases). The neoplasms displayed macronodular (eight cases), cribriform (seven cases) and organoid (six cases) growth patterns, occurring in combination. The tumours were mainly composed of immature basophilic cells associated with scattered mature sebocytes. Numerous small infundibular cysts were present in seven cases. Mitotic activity was low (none/one to four mitoses/mm2). Immunohistochemistry showed positivity for androgen receptor and p63. Preserved expression of MLH1, PMS2, MSH2 and MSH6 was observed in all cases. RNA-sequencing revealed RCOR1::GRHL2 (three cases), BCL6::GRHL1 (two cases), a BCOR::GRHL2 (one case), RCOR1::GRHL1 (one case) and TLE1::GRHL1 (one case) fusion transcript. Methylation analysis demonstrated that GRHL-fused sebaceomas form an independent cluster and highlight the proximity of such tumours with poromas with folliculo-sebaceous differentiation.ConclusionsIn conclusion, we report recurrent fusions of the GRHL genes in a distinctive subset of sebaceomas harbouring infundibulocystic differentiation, a frequent organoid growth pattern and lack of mismatch repair deficiency
L’agentivité interrogée : du coaching à la pair-aidance
No full textInternational audienceAu sein du paradigme de l’accompagnement, le pouvoir d’agir est une notion centrale, tout comme celle d’ empowerment , présente dans le champ de l’éducation thérapeutique. Ce texte propose d’interroger une autre notion : l’agentivité et ses formes au cours de la vie adulte. La notion permet de se déprendre des logiques recentrées sur le volontaire et le développement de soi ; elle comporte une dimension transversale à l’ensemble des figures, fonctions et logiques d’accompagnement en éducation, formation et santé. Cette étude est conduite à partir d’une interrogation croisée entre deux figures pensées comme antagoniques dans leurs logiques au sein du paradigme de l’accompagnement des adultes : la pair-aidance en santé et le coaching