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Immunologie de la fécondation, de l’implantation et de la grossesse : Interactions clés et perspectives thérapeutiques
No full textInternational audienceThe immunology of fertilization, implantation and pregnancy is based on a complex balance between maternal immune tolerance and a controlled inflammatory response. Adaptation of the maternal immune system is essential for the survival of the semi-allogenic foetus, and any imbalance can lead to complications such as implantation failure, early pregnancy loss and obstetric pathologies. Several cell types, including uterine Natural Killer (NKu) cells, macrophages and dendritic cells, play a key role in regulating the maternal-fetal interface. Similarly, the balance between pro- and anti-inflammatory cytokines, as well as the expression of specific HLA molecules, determines the success of gestation. Immunological disorders, such as those observed in endometriosis, adenomyosis and chronic endometritis, alter endometrial receptivity and increase the risk of reproductive failure. In addition, abnormalities in NK cell activation and cytokine profile have been implicated in repeated implantation failure and recurrent pregnancy loss. Although immunomodulatory treatments such as corticosteroids, intravenous immunoglobulins and intralipids are being explored to improve pregnancy outcomes, their efficacy has yet to be confirmed by large-scale studies.L’immunologie de la fécondation, de l’implantation et de la grossesse repose sur un équilibre complexe entre tolérance immunitaire maternelle et réponse inflammatoire contrôlée. L’adaptation du système immunitaire maternel est essentielle pour permettre la survie du fœtus semi-allogène, tout déséquilibre pouvant conduire à des complications de la grossesse telles que l’échec d’implantation, les pertes de grossesse précoces et certaines pathologies obstétricales. Plusieurs types cellulaires, notamment les cellules Natural Killer utérines (NKu), les macrophages et les cellules dendritiques, jouent un rôle clé dans la régulation de l’interface materno-fœtale. De même, l’équilibre entre les cytokines pro- et anti-inflammatoires, ainsi que l’expression de molécules HLA spécifiques, conditionnent la réussite de la gestation. Des troubles immunologiques, comme ceux observés dans l’endométriose, l’adénomyose et l’endométrite chronique, altèrent la réceptivité endométriale et augmentent le risque d’échec reproductif. Par ailleurs, des anomalies de l’activation des cellules NK et du profil cytokinique ont été impliquées dans les échecs d’implantation répétés et les pertes récurrentes de grossesses. Bien que les traitements immunomodulateurs tels que les corticoïdes, les immunoglobulines intraveineuses et les intralipides soient explorés pour améliorer les issues de grossesse, leur efficacité reste à confirmer par des études de grande ampleur
Head and neck radiotherapy after reconstructive flap surgery: Results of the multicentric XFLAP1 study
No full textInternational audienceBackground and purpose:Postoperative target delineation after reconstructive surgery in head and neck cancer (HNC) is heterogeneous; whether to include the flap or focus on the native tissue–flap junction is debated. We quantified patterns of relapse relative to flaps and summarized practice, toxicity and function.Materials and methods:in the retrospective XFLAP1 cohort (2018–2023), patients with HNC underwent tumor resection with flap reconstruction and postoperative radiotherapy (PORT) ± concurrent chemotherapy. Competing-risks (Fine-Gray) estimated locoregional relapse (LRR) and metastases; overall survival (OS) used Kaplan-Meier. Flaps were contoured a posteriori on planning CTs, when available.Results:Of 355 patients across eight centres, free flaps were used in 239 (67%) and regional pedicled flaps in 69 (33%). The entire flap body was encompassed in the CTVs in 66% of plans; median flap-body dose was 65.3 Gy and pedicle Dmax 67.5 Gy for the delineated flaps (N = 153). Median follow-up was 32.9 months, 120/355 (34%) patients relapsed, including 68 (19%) LRR and 71 (20%) metastases. Median time to LRR was 7.35 months; only 3 (1%) of relapses arose within the flap body. Two-year cumulative incidence was 15.8% for LRR and 16.7% for metastases; two-year OS was 74.6%. On multivariable analysis, pN2–3 predicted metastases; LRR, metastases, and ECOG ≥ 1 were associated with worse OS.Conclusions:relapses in the flap-body epicentre were rare; most local failures involved the native tissue–flap junction or non-flap sites. These data support junction-focused CTVs with reduced emphasis of the flap body to limit morbidity, pending prospective validation
DOP016 Monitoring serum αvβ6 antibodies during induction vedolizumab therapy is a strong and drug-selective predictor of sustained clinical remission in UC at one year
No full textDigital Oral PresentationInternational audienceBackground Antibodies against the integrin αvβ6 has been detected in the serum from inflammatory bowel disease (IBD) patients treated with vedolizumab (VDZ). We aimed to assess the impact of serum αvβ6 antibodies on the pharmacokinetics and the effectiveness of VDZ in IBD. Methods Real-world data were collected from two multicentric, prospective, observational studies, one including patients with IBD treated with VDZ the (VEDOPREDIRESP) and the second one including UC patients treated with intensified golimumab (GOLILOR). Serum αvβ6, antibodies titers were measured prior starting VDZ therapy (baseline) and at week (w)6 (ELISA assay). All clinical datasets and laboratory results were blinded to disease outcomes. Predictors for sustained clinical remission were assessed using univariate tests and multivariate logistic regression. Results During VEDOPREDIRESP, 115 IBD patients (UC, n = 67) were included. At the end of follow-up (W52), 49% of IBD patients (54% for UC) achieved clinical remission. At baseline, abnormal serum αvβ6 antibodies titers (>9.1µg/mL based on the median titers + 3 SD from controls) were significantly more frequent in UC than in CD patients (94% vs 19%, respectively; p < 0.001) and the median titers were significantly higher in UC patients (271 µg/mL (38-884) vs 5.2 µg/mL (2.5-10); p < 0.001). Using a ROC curve analysis, the best threshold value to distinguish UC from CD was 15µg/mL (AUROC : 0.95; Sen : 0.92, Spe : 0.95). In UC, the median serum αvβ6 antibodies titers from patients starting VDZ significantly drop over time between W0 and W6 (243 vs 190 µg/mL, respectively; p = 0.04). During induction regimen with VDZ in UC patients, a reduction of the αvβ6 antibodies titers of more than 30% between W0 and W6 predicted further sustained clinical remission at W52 (AUROC: 0.79; Se: 0.78, Sp : 0.80) (Fig 1). Using multivariate analysis, the only independent factor associated with clinical remission was the reduction of the αvβ6 antibodies titers of more than 30% between W0 and W6 (0R : 5.36, IC95 : 1.12- 8.54; p :0.04). In contrast to VDZ, when using an independent cohort of UC patients treated with golimumab, the median αvβ6 antibodies titers did not differ over time between responders and non-responders to drug intensification. Conclusion Serum αvβ6 antibodies are novel accurate markers to discriminate UC from CD. In UC patients, monitoring serum αvβ6 antibodies titers during induction with VDZ is a strong and drug specific predictor associated with sustained clinical remission at one year and might be of paramount interest to guide clinician’s decision. Conflict of interest: Roblin, Xavier: MSD, Abbvie, Amgen, Celltrion, Galapagos, Janssen, Takeda, Ferring, Theradiag, Lilly, Pfizer Nancey, Stéphane: Abbvie, Janssen, Pfizer, Celltrion, Takeda, Amgen Fresenius Kabi, Sandoz, Lilly XR: MSD, Abbvie, Amgen, Biogen, Celltrion, Galapagos, Janssen, Takeda, Ferring, Theradiag, Lilly Mechi, Fatma: Fumery, Mathurin: Grant: Pfizer Personal Fees: Abbvie, Janssen, Takeda, MSD, Biogen, Amgen, Sandoz, Fresenius, Gilead, Celgene, Galapagos, Mylan, Tillots, Ferring, Pfizer, Hospira, CTMA, Boehringer, Lilly, Arena Non-financial Support: Abbvie, Janssen, Takeda, MSD, Galapagos, Ferring, Pfizer Hebuterne, Xavier: Xavier Hébuterne reports clinical research funding from AbbVie, Abivax, Alphasigma, Arena Pharmaceuticals, Celgene, Eli Lilly, Enterome, Gilead, Janssen, InDex Pharmaceuticals, Pfizer, Roche, Salix, Sangamo, Takeda, Theravance, serving on advisory boards for AbbVie, Abivax, Arena Pharmaceuticals, Gilead, Janssen, Pfizer, Roche, Takeda, and participating in lectures and educational activities for AbbVie, Amgen, Baxter, Fresenius Kabi, Janssen, MSD, Mylan, Nutricia, Pfizer, Tillots, and Takeda. Altwegg, Romain: Abbvie, Celltrion, Janssen, Takeda, MSD, Pfizer Barrau, Mathilde: Abbvie, Celltrion, Takeda, Janssen, Pfizer Paul, Stephane: MSD, Takeda, Abbvie, Amgen, Theradiag, Janssen, Celltrio
Serum procalcitonin: A novel tumor biomarker for diagnosis and disease monitoring in fibrolamellar hepatocellular carcinoma
No full textInternational audienceIntroductionFibrolamellar carcinoma (FLC) is a rare primary liver cancer that predominantly affects young patients with normal known serum tumor biomarkers. An observation of an elevated procalcitonin (PCT) in one patient prompted us to investigate PCT as a biomarker in a larger cohort of FLC.MethodsWe measured serum PCT levels in 34 samples from 18 patients with FLC and in 64 patients with hepatocellular carcinoma (HCC), 24 with cholangiocarcinoma (CCA), and 20 with cirrhosis. Using RNA sequencing, we analyzed CALCA expression, encoding PCT, in 27 FLC tumors, 331 HCC tumors, 39 CCA tumors, 71 hepatoblastomas, 34 hepatocellular adenomas, and 55 non-tumor livers. Spatial transcriptomics was performed on three FLC and PCT immunohistochemistry on 13 FLC and 34 other primary or secondary liver cancers.ResultsIn 8 FLC from the European cohort, median serum PCT was significantly elevated (55.2 μg/l) compared to patients with HCC (0.14 μg/l), CCA (0.16 μg/l), and cirrhosis (0.11 μg/l; P=0.0005). It was validated in a U.S. cohort of 10 FLC patients compared to HCC and CCA (P=0.0002). Across these cohorts, elevated serum PCT was observed in 83% of FLC cases versus 3% of HCC and CCA (P<0.0001). In four patients, changes in serum PCT levels correlated with radiologic response according to RECIST 1.1. RNA sequencing demonstrated significant overexpression of CALCA in FLC compared to other primary liver tumors (P<0.0001), and spatial transcriptomics localized CALCA expression specifically to tumor cells. Immunohistochemistry confirmed PCT overexpression in 77% of FLC but not in other liver cancers.ConclusionProcalcitonin is a sensitive and specific serum biomarker for FLC among primary liver cancers, with potential utility in diagnosis and monitoring of treatment response.Impact and implicationsThis study is justified by the lack of reliable serum biomarkers for fibrolamellar carcinoma and demonstrates that procalcitonin is specifically overexpressed by FLC tumor cells and detectable in the blood of the patients with FLC. These findings are important for clinicians and researchers, as they identify a readily available biomarker that may facilitate diagnosis, improve disease monitoring, and support clinical trial design in a rare cancer that predominantly affects young patients. In clinical practice, serum PCT measurement could be incorporated as a non-invasive adjunct to imaging for the diagnosis and longitudinal assessment of FLC, although prospective studies in larger and more diverse cohorts are needed to refine diagnostic cut-offs and confirm specificity
Enhancing Fetal Brain Imaging: ALPS-FMEG Technique Achieves Accurate Signal Extraction by Mitigating Movement Artifacts
No full textInternational audiencePurpose Fetal magnetoencephalography (fMEG) enables non-invasive monitoring of fetal brain function with high temporal resolution. However, how can we isolate low signal-to-noise ratio signals of the developing brain when disruptive artifacts arise from maternal and fetal movements? Addressing this challenge is critical for understanding brain development. We present Advanced Localization and Processing of fMEG Signals based on Maternal and Gross fetal body Movement Exclusion (ALPS-FMEG), a MATLAB-based framework that improves fetal brain signals by removing fetal and maternal movement artifacts. Methods ALPS-FMEG integrates Independent Component Analysis for separation and reconstruction of fetal brain, fetal and maternal cardiac signal components in sensor space, Empirical Mode Decomposition for noise reduction, and a movement artifact detection-and-exclusion technique based on actogramCOG associated with heart rate patterns. This novel integration modifies the actogramCOG approach by pre-interpolating R waves for enhanced robustness and combines it with HRV-based logic gates, representing a first in fMEG processing to achieve artifact-free signals while preserving physiological latencies. Results ALPS-FMEG was applied to 50 fMEG datasets from 28 to 39 weeks of gestation, enhancing signal quality. For group analysis, 45 datasets were retained after excluding recordings with auditory event-related field (fAEF) latencies < 70 ms. In these, it significantly improved signal-to-noise ratio and fAEF amplitudes ( p < 0.0001), with preserved latencies. fAEF latency showed a significant negative correlation with gestational age ( p < 0.001). Conclusion ALPS-FMEG improves fetal brain signal extraction by addressing movement artifacts. This method supports robust fetal brain analysis and may be adaptable to future fMEG systems, including optically pumped magnetometers, enhancing prenatal neurophysiology and clinical research, though manual steps currently limit scalability and could be addressed via automation for broader practical use
Association between physical activity with disease activity and functional disability in patients with inflammatory bowel disease
No full textInternational audienceBackground and aims: The impact of Physical activity (PA) on the activity of inflammatory bowel disease (IBD) remains unclear.Patients and methods: A descriptive cross-sectional study included consecutive patients with Crohn's disease (CD), ulcerative colitis (UC). PA was assessed using the short International Physical Activity Questionnaire. PA was classified as low, medium or high PA. PA was also assessed according to WHO recommendations. IBD activity was evaluated using PRO-2, while IBD-related disability was assessed with the IBD-disk questionnaire.Results: Among a total of 2514 patients (1715 CD), only 28.8% met the WHO recommendations on PA (49.8% had low PA, 35.2% had medium PA, and 15.0% had high PA). Medium and high PA levels were associated with a higher rate of patient-reported clinical remission in patients with CD (OR 1.30 [1.08-1.57] for medium PA, and 1.33 [1.03-1.72] for high PA vs. low PA; p-trend=0.02) but not in those with UC. Higher PA levels were associated with less IBD-related disability in both CD, and UC.Conclusion: In a large cohort of IBD patients, moderate and high PA was associated with higher rates of clinical remission in patients with CD and lower IBD-related disability in both CD and UC patients
Digestive and bariatric surgery, digestive endoscopy and interventional radiology
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Crowdsourced biodiversity monitoring fills gaps in global plant trait mapping
No full textInternational audiencePlant functional traits are fundamental to ecosystem dynamics and Earth system processes, but their global characterization is limited by available field surveys and trait measurements. Recent expansions in biodiversity data aggregation—including vegetation surveys, citizen science observations, and trait measurements—offer new opportunities to overcome these constraints. Here we demonstrate that combining these diverse data sources with high-resolution Earth observation data enables accurate modeling of key plant traits at up to 1 km 2 resolution. Our approach achieves correlations up to 0.63 (15 of 31 traits exceeding 0.50) and improved spatial transferability, effectively bridging gaps in under-sampled regions. By capturing a broad range of traits with high spatial coverage, these maps can enhance understanding of plant community properties and ecosystem functioning, while serving as tools for modeling global biogeochemical processes and informing conservation efforts. Our framework highlights the power of crowdsourced biodiversity data in addressing longstanding extrapolation challenges in global plant trait modeling, with continued advancements in data collection and remote sensing poised to further refine trait-based understanding of the biosphere
TEM OR ESD IN EARLY RECTAL TUMORS: A CLINICAL & COST-EFFECTIVENESS ANALYSIS
No full textInternational audienceBACKGROUND & AIMSFor the local excision of early rectal tumors (ERTs), the relative effectiveness of endoscopic submucosal dissection (ESD) vs. transanal endoscopic microsurgery (TEM) is subject to debate. The comparisons are limited to retrospective, single-center studies lacking a health economic assessment.METHODSA cost-effectiveness analysis was conducted alongside a non-randomized, two-arm, comparative, multicenter study. The main inclusion criterion was an ERT (adenomas, in situ and usT1N0 carcinomas) that could be resected with ESD or TEM, depending on the center. The primary effectiveness criterion was complete resection. A healthcare system perspective and a one-year horizon were adopted for the cost evaluation. The results of the analysis were adjusted for baseline covariates: age, sex, body mass index, ASA score, histology, and previous pelvic surgery.RESULTS213 ESD and 117 TEM procedures were analyzed. At one year and with a willingness-to-pay of €2500 for complete resection, the incremental net monetary benefit of ESD was significant (€1797 (95%CI, €861–€3,032), p<0.001). ESD was more cost-effective for decision thresholds ranging from €0 to €6,000. In terms of secondary outcomes, the en-bloc excision rate favored ESD (99%, vs. 92.5%, p<0.01). There were no significant between-group differences in overall and major morbidity. At 3 years, a cost-utility analysis did not reveal between-group differences in health-related quality of life, and the overall survival rates were similar. However, the disease-free survival rate was higher after ESD (94.3%, vs. 84.6% for TEM; adjusted HR=3.55 (95%CI, 1.64–7.75), p<0.001).CONCLUSIONFor ERT, ESD was more cost-effective and offered higher-quality excision and lower recurrence rates than TEM. (ClinicalTrials.gov: NCT02885142)
Motion as a language: transformer-based classification of antimicrobial peptide conformational dynamics
No full textInternational audienceAntimicrobial peptides (AMPs) represent a promising alternative to traditional antibiotics against which many bacteria are rapidly gaining resistance. Today, databases containing tens of thousands of AMPs, along with their properties and biological activities, can be screened to select lead candidates for a given application. The conformational plasticity of AMPs has been proven crucial for the recognition of their targets. However, the volume, complexity and recalcitrance to classification of conformational data, obtained from e.g. molecular dynamics (MD) simulations, prevents it from being included in databases, let alone used as a criterion for the screening of AMPs. This work applies the transformer neural network architecture (which powers large language models such as ChatGPT) to the detection of temporal and spatial context in time series of AMP conformations from MD simulations. It shows how the representation of AMP conformational space learnt by the network can be leveraged for the unsupervised classification of AMP plasticity, which can subsequently be used alongside conventional properties for the screening of databases. Thus, it reveals how deep learning can pave the way toward restoring conformational dynamics to its legitimate importance within drug design pipelines