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Real-world comparison of the effectiveness of tofacitinib and ustekinumab in patients with ulcerative colitis: the TORUS study
No full textInternational audienceBackground & aims: We compared the effectiveness of tofacitinib and ustekinumab in patients with ulcerative colitis (UC) previously exposed to at least one anti-tumor necrosis factor (TNF) agent.Methods: In this multicenter real-world evidence study, we consecutively included patients with UC ≥18 years old, previously exposed to anti-TNF therapy, with partial Mayo score >2 and, starting tofacitinib or ustekinumab. All the comparisons were performed using propensity score analyses.Results: Overall, 124 and 165 patients were included in the tofacitinib and ustekinumab groups, respectively. Symptomatic remission, off corticosteroids (partial Mayo score ≤2) was achieved at week 16 in 37.8% and 35.8%, among the tofacitinib and ustekinumab groups, respectively (adjusted odds ratio [OR], 1.09; 95% confidence interval [CI], 0.60-2.00; P = .75), with higher tofacitinib effectiveness in patients with prior exposure to ≥3 biologics (46.7% vs 23.1%; adjusted OR, 2.92; 95% CI, 1.02-8.39; P = .047). Primary failure to any biologic (OR, 2.88; 95% CI, 1.20-6.98) and prior exposure to ≥3 advanced therapies (OR, 2.45; 95% CI, 1.03-5.82), but not disease severity, were associated with ustekinumab failure. We did not find any significant difference between tofacitinib and ustekinumab regarding clinical remission per modified Mayo score (17.0% vs 11.7%; adjusted OR, 1.55; 95% CI, 0.65-3.68; P = .32) and histological and endoscopic improvement (4.4% vs 7.8%; adjusted OR, 0.54; 95% CI, 0.16-1.86; P = .32). After a median follow-up of 11.8 months (interquartile range, 6.1-20.5 months), we did not observe any difference regarding the risk of UC relapse-related drug discontinuation (adjusted hazard ratio, 1.44; 95% CI, 0.94-2.21; P = .10), and the risk of secondary loss of response among patients achieving CFREM at week 16 (adjusted hazard ratio, 1.88; 95% CI, 0.57-6.19; P = .30).Conclusion: Tofacitinib and ustekinumab are similarly effective to induce and maintain corticosteroid-free remission after anti-TNF failure in UC. However, tofacitinib could be favored in case of multiple therapeutic failures (≥3 biologics) and primary failure to any biologic
[Vestibulopathies and adult cancers: A literature review].
No full textInternational audienceContext: Therapeutics used in cancer treatment can cause vestibular ototoxicity, which is particularly challenging to detect due to the frequent occurrence of nausea and vomiting in patients experiencing significant fatigue and stress. An appropriate diagnosis enables optimal symptom correction, reduces the risk of falls, and improves quality of life.Materials and methods: Following a concise overview of the anatomy, physiology, and principles of vestibular exploration, a narrative review of the primary vestibulopathies encountered in cancer patients is conducted. This review details their exploration and the anti-cancer treatments responsible for vestibular ototoxicity.Key findings: Vestibular ototoxicity from systemic treatments typically presents as chronic bilateral vestibulopathy. Vestibular functional tests differentiate between central and peripheral lesions, quantify the damage, and guide imaging assessments. Platinum salts are the main agents causing cochlear ototoxicity, although their toxicity mechanisms on the vestibular system remain unclear. Cases of vestibular ototoxicity have been described with immune checkpoint inhibitors. Radiotherapy and direct tumor invasion can also cause vestibular damage. All vestibular alterations increase the risk of falls, particularly in the elderly. A vestibular assessment by an otolaryngologist is indicated; treatment usually involves vestibular rehabilitation.Conclusion: Collaboration between oncologists and otolaryngologists is crucial for evaluating vestibular function during cancer treatments with potential ototoxicity
A low gluten diet adversely affects the gut microbiota of healthy adult
No full textInternational audienceIncreasing number of apparently healthy individuals is adhering to a gluten-free lifestyle without any underlying medical indication, although the evidence for the health benefits in these individuals remains unclear. A low- or free-gluten diet has already been shown to alter the gut microbiota, however the nature of this modification seems to be inconsistent between the studies. Since the symbiotic partnership with the commensal gut microbiota is crucial for the host’s health, we investigated the conferred changes to gut microbiota composition and metabolites upon switching to low-gluten diet, in order to define whether they could potentially benefit to healthy people.Forty healthy volunteers consuming gluten in their usual diet (HGD, high- gluten diet), were included in a randomised control trial consisting of two successive 8-week dietary intervention periods on low-gluten diet (LGD). After each 8-week period, gut microbiota composition was assessed by 16S rRNA gene sequencing, molecular quantification by qPCR and cultural approach, while its metabolic capacity was evaluated through measuring faecal fermentative metabolites by 1H NMR.A prolonged period of LGD of 16 weeks reduced gut microbiota richness, and decreased the relative abundance of bacterial species with potential previously reported health benefits such as Akkermansia muciniphila and Bifidobacterium sp. A decrease in certain plant cell wall polysaccharides-degrading species was also observed. While there was no major modification affecting the main short chain fatty acid profiles, the concentration of the intermediate metabolite, ethanol, was increased in faecal samples in LGD.In conclusion, a 16-week LGD significantly altered both composition and metabolic production of the gut microbiota in healthy individuals, towards a more dysbiotic profile previously linked to adverse effects on the host’s health. Therefore, the evaluation of more long-term LGD impact is warrante
Etude épidémiologique sur le risque des faibles doses de RX en cardiologie interventionnelle pédiatrique, cohorte française Coccinelle dans le cadre du projet européen HARMONIC
No full textInternational audienc
Study of the release kinetics of dalbavancin from bone allografts
No full textInternational audienceBone infections are common and difficult to treat, and secondary bone defects, which are often observed, may require a bone allograft. In this case, the surgeon will add antibiotics (usually vancomycin) in direct contact with the bone graft during the procedure, in order to allow in-situ release after implantation in the operating site. Dalbavancin is a novel antibiotic indicated for treating acute bacterial infections resistant to vancomycin. Its modified chemical structure grants it an increased half-life that could modify its release kinetics from the bone allograft. The aim of this study was to determine the release kinetics of dalbavancin from bone grafts after they were immersed in a dalbavancin solution. The study was conducted using a Design of Experiments (DoE) protocol. Decellularized and delipidated allograft bone cubes were preliminarily characterized and put into contact with dalbavancin solutions. The parameters that were studied where the allograft mass, initial dalbavancin concentration and contact time. The samples were then transferred into the release media, which was sampled over time and dalbavancin was quantified using a high pressure liquid chromatography with diode array detector method that was developed for the occasion. Our results showed that on average, dalbavancin was fully released after 5 min for the lower mass bone grafts, but after 60 min for the high mass and high concentration conditions. Contact time had no impact, thus indicating a fast loading process of dalbavancin into the allograft. Although our study revealed the possible benefits of using dalbavancin in bone grafting, an in-vivo study is required to confirm our hypotheses
PhenolQuest: a new reference FFQ for a more precise and comparable assessment of (poly)phenol intake in Europe
No full textInternational audience(Poly)phenols represent a large class of bioactive compounds present in our diet. An increasing number of epidemiological, clinical and pre-clinical studies are demonstrating the beneficial effects of (poly)phenols on various health parameters, parlicularly in relation to the prevention of cardiometabolic diseases. However, fully understanding their potential in preventive nutrition requires significant improvements in the assessment of individuals' exposure to a variety of (poly)phenols. One of the current limitations is the use of standard Food Frequency Questionnaires (FFQs) that are not specifically designed for that purpose and as a consequence lack precision and accuracy for the assessment of (poly)phenol intake. We developed the FFQ PhenolQuest, specially designed to assess with a high level of details the dietary intake of 120 (poly)phenols belonging to all main families, in populations following a European-style diet. It includes 188 foods with a number of additional variations (n = 75). Special effort was made to optimize the questionnaire's design and usability. In particular, the consumption frequency options were expanded compared to the standard FFQ and tailored to the different food groups. An application test conducted on a French population panel of 110 subjects demonstrated PhenolQuest's ability to capture the diversity of (poly)phenol source consumption patterns. PhenolQuest is shared in integrality for free use and further validation by the community. This article presents the challenges and strategies used for its development, as well as its scope of use
Identification of serum proteins associated with response of triple-negative breast cancer to neoadjuvant chemotherapy: preliminary results from the INSTIGO trial
No full textInternational audienceBackground: Triple-negative breast cancer (TNBC) is a breast cancer subtype with the highest recurrence rates, for which response to neoadjuvant chemotherapy (NACT) is a critical prognostic factor. Liquid biopsy (LB) is an emerging approach in the personalization of TNBC management; among the numerous circulating molecules assessable by LB, serum proteins are gaining interest, owing to their multiple roles in cancer progression and anti-cancer immune response. Here we report findings of interim analyses in the INSTIGO trial, which aims to discover circulating protein biomarkers of TNBC response to NACT.Patients and methods: Blood samples were collected at diagnosis and at the time of post-NACT surgery from 30 non-metastatic TNBC patients. NACT consisted of standard carboplatin-paclitaxel and epirubicin-cyclophosphamide regimens. A panel of 21 proteins was quantified in serum using high-sensitivity multiplex immunoassays (Luminex MAP® technology).Results: Among the 24 analysable patients, 13 had pathological complete response (pCR) and 11 were without pCR. In the pCR group, mean CX3CL1, angiopoietin-2 (ANGPOI-2), CD40 and PD-L1 levels increased significantly after NACT (p < 0.001, p < 0.001, p = 0.006, and p = 0.02, respectively). In the non-pCR group, mean CXCL5 level tended to decrease after treatment (p = 0.06). When the difference in protein levels between the end and the start of NACT was measured for each patient (Δ of a given protein), ΔCX3CL1, ΔCXCL5 and ΔANGPOI-2 differed significantly between pCR and non-pCR patients (p = 0.003, p = 0.04, p = 0.04, respectively). The baseline concentrations of CCL5, IL8, TIE2, CX3CL1 and CXCL5 tended to be associated with response to NACT, with higher levels observed among the non-pCR patients; however, statistical significance was not reached.Conclusion: Our findings highlight the potential of circulating proteins to be biomarkers of TNBC response to NACT. Pre/post-NACT changes in CX3CL1, CXCL5, CD40, ANGPOI-2 and PD-L1 levels suggest their relevance for assessing NACT efficacy. These results will be validated at completion of the INSTIGO trial.Trial registration: ClinicalTrials.gov, identifier NCT04438681
Exploration des liens entre le profil lipidomique circulant et l'obésité sarcopénique dans la cohorte OBESAR
No full textInternational audienceIntroduction et but de l’étudeL'obésité sarcopénique (OS) est cliniquement reconnue définie par une diminutionde masse et de fonction musculaire, associée à une éladiposité corporelle. Elle estassociée à de nombreuses comorbidités, ce qui en fait une préoccupation de santépublique majeure. Son développement est lié à plusieurs altérations métaboliquestelles que la résistance à l'insuline et la lipotoxicité. Dans la population de patientsobèses, l'OS est souvent sous-diagnostiquée. Ainsi, une meilleure compréhensiondes mécanismes sous-jacents précoces et l'identification des individus obèses àrisque de développer une sarcopénie sont cruciales. Cette étude visait à évaluerles modifications de la signature lipidomique circulante associée à l'OS et àdéterminer si des espèces lipidiques circulantes pourraient être identifiées commebiomarqueurs.Matériel et méthodesUn profil lipidomique circulant complet a été obtenu par LC-MS/MS chez despatients de la cohorte OBESAR (âge: 54,8±6,3 ans ; IMC: 44±6 kg/m² ; poids:114,7±17 kg). Le profil a été comparé à l'aide d'une ANOVA entre 3 groupes depatients stratifiés selon la sévérité de la SO en utilisant un index phénotypique deSO (SOPi) avec des niveaux catégorisés comme faible, moyen et élevé. Cet indexa été calculé à l'aide d'une formule qui intègre la force de préhension, la massemaigre appendiculaire et la masse grasse corporelle. Un test t a par aileurs étéréalisé pour comparer les SOPi bas et élevés, et un modèle de régression logistiquebinaire a été appliqué pour classer les patients dans les 2 groupes. Enfin, lacorrélation entre les niveaux de lipides plasmatiques et le SOPi a été évaluée parun test de Pearson. Par la suite, un modèle de régression linéaire multivariée a étéobtenu pour les lipides présentant une corrélation significative.Résultats et analyse statistiqueDans un groupe de 130 patientes, 53 espèces lipidiques présentaient des niveauxcirculants significativement différents entre les groupes à SOPi bas, moyen etélevé. Le modèle de régression logistique binaire a démontré un niveau desensibilité de 82 % dans la classification des patientes à SOPi faible et élevé àl'aide de 5 molécules et le niveau total de LPE. Parmi tous les lipides testés pour lacorrélation linéaire avec le SOPi, 3 espèces contenant des acides graspolyinsaturés ont été utilisées pour construire un modèle de régression linéaire quis'est avéré significativement inversement lié au SOPi (P<0,05).ConclusionCes résultats démontrent des altérations du profil lipidomique plasmatique dans unepopulation de patientes souffrant d'obésité sévère. Un sous-ensemble d'espèceslipidiques contenant des acides gras polyinsaturés est corrélé avec les critères del'obésité sarcopénique. Ainsi, ces métabolites lipidiques pourraient être utiles pouridentifier les patients à haut risque d'OS ou pour mieux cibler des interventionsnutritionnelles ou pharmacologiques chez ces patientes
The challenge to identify sensitive safety biomarkers of peripheral neurotoxicity in the rat: A collaborative effort across industry and academia (IMI NeuroDeRisk project)
No full textInternational audiencePeripheral nervous system (PNS) toxicity assessment in non-clinical safety studies is challenging and relies mostly on histopathological assessment. The present work aims to identify blood-based biomarkers that could detect peripheral neuropathy in rats upon exposure to neurotoxic compounds. Three anticancer agents (oxaliplatin, cisplatin, paclitaxel) and a developmental compound (NVS-1) were assessed in male rats (Wistar Han). Clinical and/or functional endpoints (i.e., electronic Von Frey, Cold Plate, and Paw Pressure tests) and blood biomarkers (i.e., neurofilament light chain (NfL), neurofilament heavy chain (NF-H), microtubule-associated protein Tau (Tau), neuron specific enolase (NSE), vascular endothelial growth factor A (VEGFA), and glial fibrillary acidic protein (GFAP)) were assessed. Drug exposure and histopathological evaluations were conducted on selected nervous tissues. Oxaliplatin, cisplatin and paclitaxel treatment resulted in a significant decrease of nociceptive thresholds. Clinical signs suggestive of PNS toxicity were observed with NVS-1. NfL was consistently increased in the NVS-1 study and correlated with moderate microscopic findings in dorsal root ganglia (DRG). Only minimal microscopic findings were observed in oxaliplatin-treated animals, whereas no treatment-related microscopic findings were observed in animals treated with cisplatin and paclitaxel. For all compounds, exposure was confirmed in the PNS tissues. Clinical and functional changes were observed with all the compounds evaluated. NfL levels in plasma proved to be the most sensitive indicator of PNS toxicities, capturing moderate nervous degeneration in DRG. A combined approach that includes both functional assessments and biomarker measurements offers a more comprehensive evaluation than histopathological analysis alone when monitoring drug-induced neurotoxicity in rat models