Cavéoline-1 prédictive de la métastase et de la rechute locorégionale des cancers des voies aérodigestives supérieures

This translational research project on head and neck cancers has identified caveolin-1 (Cav1) as a prognostic biomarker for the evolution of a primary tumor of these cancers. Indeed, an overexpression of this protein favors a locoregional relapse whereas a deficiency of Cav1 engages the tumor towards a metastatic process. Moreover, we have highlighted the involvement of the Cav1 / EREG / YAP axis in the resistance to treatment (cetuximab and radiotherapy). Finally, we identified epiregulin (EREG) as the key protein in cetuximab resistance. Thus, a deficiency of EREG sensitizes cells to cetuximab by activation of ferroptosis and the association of this target therapy with the RSL3 molecule or metformin drastically restricts cell survival by accentuating this programmed cell death. These last results could be confirmed thanks to a complex 3D model recapitulating the intra- and inter-tumoral heterogeneity, namely the tumoroid model established from surgical parts of patients with head and neck cancer.Ce projet de recherche translationnelle sur les cancers des voies aérodigestives supérieures (VADS) a permis d’identifier la cavéoline-1 (Cav1) comme un biomarqueur pronostique de l’évolution d’une tumeur primitive des VADS. En effet, une surexpression de cette protéine favorise une rechute locorégionale alors qu’un déficit de Cav1 engage la tumeur vers un processus métastatique. De plus, nous avons mis en évidence l’implication de l’axe Cav1 / EREG / YAP dans la résistance au traitement (cétuximab et radiothérapie). Enfin, nous avons identifié l’épireguline (EREG) comme la protéine clé de la résistance au cétuximab. Ainsi, un déficit d’EREG sensibilise les cellules au cétuximab par activation de la ferroptose et l’association de cette thérapie ciblée à la molécule de RSL3 ou à la metformine restreint drastiquement la survie cellulaire en accentuant cette mort cellulaire programmée. Ces derniers résultats ont pu être confirmés grâce à un modèle 3D complexe récapitulant l’hétérogénéité intra- et inter-tumorale, à savoir le modèle tumoroïde établi à partir de pièces opératoires de patients atteints d’un cancer des VADS

Caveolin-1 predictive of metastasis and locoregional relapse of head and neck squamous cell carcinoma

Ce projet de recherche translationnelle sur les cancers des voies aérodigestives supérieures (VADS) a permis d’identifier la cavéoline-1 (Cav1) comme un biomarqueur pronostique de l’évolution d’une tumeur primitive des VADS. En effet, une surexpression de cette protéine favorise une rechute locorégionale alors qu’un déficit de Cav1 engage la tumeur vers un processus métastatique. De plus, nous avons mis en évidence l’implication de l’axe Cav1 / EREG / YAP dans la résistance au traitement (cétuximab et radiothérapie). Enfin, nous avons identifié l’épireguline (EREG) comme la protéine clé de la résistance au cétuximab. Ainsi, un déficit d’EREG sensibilise les cellules au cétuximab par activation de la ferroptose et l’association de cette thérapie ciblée à la molécule de RSL3 ou à la metformine restreint drastiquement la survie cellulaire en accentuant cette mort cellulaire programmée. Ces derniers résultats ont pu être confirmés grâce à un modèle 3D complexe récapitulant l’hétérogénéité intra- et inter-tumorale, à savoir le modèle tumoroïde établi à partir de pièces opératoires de patients atteints d’un cancer des VADS.This translational research project on head and neck cancers has identified caveolin-1 (Cav1) as a prognostic biomarker for the evolution of a primary tumor of these cancers. Indeed, an overexpression of this protein favors a locoregional relapse whereas a deficiency of Cav1 engages the tumor towards a metastatic process. Moreover, we have highlighted the involvement of the Cav1 / EREG / YAP axis in the resistance to treatment (cetuximab and radiotherapy). Finally, we identified epiregulin (EREG) as the key protein in cetuximab resistance. Thus, a deficiency of EREG sensitizes cells to cetuximab by activation of ferroptosis and the association of this target therapy with the RSL3 molecule or metformin drastically restricts cell survival by accentuating this programmed cell death. These last results could be confirmed thanks to a complex 3D model recapitulating the intra- and inter-tumoral heterogeneity, namely the tumoroid model established from surgical parts of patients with head and neck cancer

Caveolin-1 predictive of metastasis and locoregional relapse of head and neck squamous cell carcinoma

Ce projet de recherche translationnelle sur les cancers des voies aérodigestives supérieures (VADS) a permis d’identifier la cavéoline-1 (Cav1) comme un biomarqueur pronostique de l’évolution d’une tumeur primitive des VADS. En effet, une surexpression de cette protéine favorise une rechute locorégionale alors qu’un déficit de Cav1 engage la tumeur vers un processus métastatique. De plus, nous avons mis en évidence l’implication de l’axe Cav1 / EREG / YAP dans la résistance au traitement (cétuximab et radiothérapie). Enfin, nous avons identifié l’épireguline (EREG) comme la protéine clé de la résistance au cétuximab. Ainsi, un déficit d’EREG sensibilise les cellules au cétuximab par activation de la ferroptose et l’association de cette thérapie ciblée à la molécule de RSL3 ou à la metformine restreint drastiquement la survie cellulaire en accentuant cette mort cellulaire programmée. Ces derniers résultats ont pu être confirmés grâce à un modèle 3D complexe récapitulant l’hétérogénéité intra- et inter-tumorale, à savoir le modèle tumoroïde établi à partir de pièces opératoires de patients atteints d’un cancer des VADS.This translational research project on head and neck cancers has identified caveolin-1 (Cav1) as a prognostic biomarker for the evolution of a primary tumor of these cancers. Indeed, an overexpression of this protein favors a locoregional relapse whereas a deficiency of Cav1 engages the tumor towards a metastatic process. Moreover, we have highlighted the involvement of the Cav1 / EREG / YAP axis in the resistance to treatment (cetuximab and radiotherapy). Finally, we identified epiregulin (EREG) as the key protein in cetuximab resistance. Thus, a deficiency of EREG sensitizes cells to cetuximab by activation of ferroptosis and the association of this target therapy with the RSL3 molecule or metformin drastically restricts cell survival by accentuating this programmed cell death. These last results could be confirmed thanks to a complex 3D model recapitulating the intra- and inter-tumoral heterogeneity, namely the tumoroid model established from surgical parts of patients with head and neck cancer

Cav1/EREG/YAP Axis in the Treatment Resistance of Cav1-Expressing Head and Neck Squamous Cell Carcinoma

International audienceThe EGFR-targeting antibody cetuximab (CTX) combined with radiotherapy is the only targeted therapy that has been proven effective for the treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Recurrence arises in 50% of patients with HNSCC in the years following treatment. In clinicopathological practice, it is difficult to assign patients to classes of risk because no reliable biomarkers are available to predict the outcome of HPV-unrelated HNSCC. In the present study, we investigated the role of Caveolin-1 (Cav1) in the sensitivity of HNSCC cell lines to CTX-radiotherapy that might predict HNSCC relapse. Ctrl- and Cav-1-overexpressing HNSCC cell lines were exposed to solvent, CTX, or irradiation, or exposed to CTX before irradiation. Growth, clonogenicity, cell cycle progression, apoptosis, metabolism and signaling pathways were analyzed. Cav1 expression was analyzed in 173 tumor samples and correlated to locoregional recurrence and overall survival. We showed that Cav1-overexpressing cells demonstrate better survival capacities and remain proliferative and motile when exposed to CTX-radiotherapy. Resistance is mediated by the Cav1/EREG/YAP axis. Patients whose tumors overexpressed Cav1 experienced regional recurrence a few years after adjuvant radiotherapy ± chemotherapy. Together, our observations suggest that a high expression of Cav1 might be predictive of locoregional relapse of LA-HNSC

Causes of acute respiratory failure in patients with small-vessel vasculitis admitted to intensive care units: a multicenter retrospective study

International audienceRationale: Acute respiratory failure (ARF) in patients admitted to the intensive care unit (ICU) with known or de novo small-vessel vasculitis (Svv) may be secondary to the underlying immune disease or to other causes. Early identification of the cause of ARF is essential to initiate the most appropriate treatment in a timely fashion. Methods: A retrospective multicenter study in 10 French ICUs from January 2007 to January 2018 to assess the clinical presentation, main causes and outcome of ARF associated with Svv, and to identify variables associated with non-immune etiology of ARF in patients with known Svv. Results: During the study period, 121 patients [62 (50-75) years; 62% male; median SAPSII and SOFA scores 39 (27-52) and 6 (4-8), respectively] were analyzed. An immune cause was identified in 67 (55%), and a non-immune cause in 54 (45%) patients. ARF was associated with several causes in 43% (n = 52) of cases. The main immune cause was diffuse alveolar hemorrhage (DAH) (n = 47, 39%), whereas the main non-immune cause was pulmonary infection (n = 35, 29%). The crude 90-day and 1-year mortality were higher in patients with non-immune ARF, as compared with their counterparts (32% and 38% vs. 15% and 20%, respectively; both p = 0.03), but was marginally significantly higher after adjusted analysis in a Cox model (p = 0.053). Among patients with a known Svv (n = 70), immunosuppression [OR 9.41 (1.52-58.3); p = 0.016], and a low vasculitis activity score [0.84 (0.77-0.93)] were independently associated with a non-immune cause, after adjustment for the time from disease onset to ARF, time from respiratory symptoms to ICU admission, and severe renal failure. Conclusions: An extensive diagnosis workup is mandatory in ARF revealing or complicating Svv. Non-immune causes are involved in 43% of cases, and their short and mid-term prognosis may be poorer than those of immune ARF. Readily identified predictive factors of a non-immune cause could help avoiding unnecessary immunosuppressive therapies

High-Dose Dexamethasone and Oxygen Support Strategies in Intensive Care Unit Patients With Severe COVID-19 Acute Hypoxemic Respiratory Failure

International audienc

A Bayesian reanalysis of the Standard versus Accelerated Initiation of Renal-Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial

Background Timing of initiation of kidney-replacement therapy (KRT) in critically ill patients remains controversial. The Standard versus Accelerated Initiation of Renal-Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial compared two strategies of KRT initiation (accelerated versus standard) in critically ill patients with acute kidney injury and found neutral results for 90-day all-cause mortality. Probabilistic exploration of the trial endpoints may enable greater understanding of the trial findings. We aimed to perform a reanalysis using a Bayesian framework. Methods We performed a secondary analysis of all 2927 patients randomized in multi-national STARRT-AKI trial, performed at 168 centers in 15 countries. The primary endpoint, 90-day all-cause mortality, was evaluated using hierarchical Bayesian logistic regression. A spectrum of priors includes optimistic, neutral, and pessimistic priors, along with priors informed from earlier clinical trials. Secondary endpoints (KRT-free days and hospital-free days) were assessed using zero–one inflated beta regression. Results The posterior probability of benefit comparing an accelerated versus a standard KRT initiation strategy for the primary endpoint suggested no important difference, regardless of the prior used (absolute difference of 0.13% [95% credible interval [CrI] − 3.30%; 3.40%], − 0.39% [95% CrI − 3.46%; 3.00%], and 0.64% [95% CrI − 2.53%; 3.88%] for neutral, optimistic, and pessimistic priors, respectively). There was a very low probability that the effect size was equal or larger than a consensus-defined minimal clinically important difference. Patients allocated to the accelerated strategy had a lower number of KRT-free days (median absolute difference of − 3.55 days [95% CrI − 6.38; − 0.48]), with a probability that the accelerated strategy was associated with more KRT-free days of 0.008. Hospital-free days were similar between strategies, with the accelerated strategy having a median absolute difference of 0.48 more hospital-free days (95% CrI − 1.87; 2.72) compared with the standard strategy and the probability that the accelerated strategy had more hospital-free days was 0.66. Conclusions In a Bayesian reanalysis of the STARRT-AKI trial, we found very low probability that an accelerated strategy has clinically important benefits compared with the standard strategy. Patients receiving the accelerated strategy probably have fewer days alive and KRT-free. These findings do not support the adoption of an accelerated strategy of KRT initiation

Regional Practice Variation and Outcomes in the Standard Versus Accelerated Initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) Trial: A Post Hoc Secondary Analysis.

ObjectivesAmong patients with severe acute kidney injury (AKI) admitted to the ICU in high-income countries, regional practice variations for fluid balance (FB) management, timing, and choice of renal replacement therapy (RRT) modality may be significant.DesignSecondary post hoc analysis of the STandard vs. Accelerated initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial (ClinicalTrials.gov number NCT02568722).SettingOne hundred-fifty-three ICUs in 13 countries.PatientsAltogether 2693 critically ill patients with AKI, of whom 994 were North American, 1143 European, and 556 from Australia and New Zealand (ANZ).InterventionsNone.Measurements and main resultsTotal mean FB to a maximum of 14 days was +7199 mL in North America, +5641 mL in Europe, and +2211 mL in ANZ (p p p p p p p p = 0.007).ConclusionsAmong STARRT-AKI trial centers, significant regional practice variation exists regarding FB, timing of initiation of RRT, and initial use of continuous RRT. After adjustment, such practice variation was associated with lower ICU and hospital stay and 90-day mortality among ANZ patients compared with other regions