Les anesthésiques locaux stimulent l’apoptose des cellules de carcinome hépatocellulaire

National audienceIntroduction Le carcinome hépatocellulaire (CHC) est un cancer fréquent et agressif avec des options thérapeutiques limitées. Le principal traitement pour le CHC, à un stade précoce, est la chirurgie malgré un risque élevé de récidive (70 % après 5 ans). Des études rétrospectives ont montré que l’administration d’anesthésiques locaux (Als) lors de la chirurgie du cancer pourrait réduire la récidive du cancer. Dans des travaux précédents nous avions montré que les Als inhibaient la croissance des cellules de CHC HuH7 in vitro avec un mécanisme différent en fonction du type d’Als, la ropivacaïne induisait un blocage du cycle cellulaire en phase G2 alors que la lidocaïne n’avait pas d’effets spécifiques. Dans ce travail nous avons cherché à comprendre le(s) mécanisme(s) par lequel(s) les Als inhibent la croissance des cellules de CHC. Matériel et méthodes Afin de confirmer les résultats observés sur la lignée HuH7, une autre lignée de cellules de CHC à la croissance plus lente, la lignée cellulaire HepaRG au stade de cellules progénitrices, a été cultivée avec ou sans différentes doses de lidocaïne (10-3Molaire [M] à 10-4M) et ropivacaïne (10-3M à 10-4M). Des gènes d’intérêts (cycline A2, cycline B1, CDK1, APC, HRK, MKI67) ont été étudiés par Rt-qPCR. Des tests fonctionnels d’apoptose, basé sur l’activité caspase 3, et de sénéscence ont été réalisés pour étudier le devenir des cellules. Résultats Sur la lignée HepaRG, la ropivacaïne diminuait le taux d’ARNm de cyclines B1 (protéine clé de la progression en phase G2 du cycle cellulaire) (p < 0,05) mais n’avait pas d’effet sur cycline A2 et CDK1 (protéines impliquées dans la transition G2–M). Les Als augmentaient le taux d’ARNm de APC (p < 0,05) et de HRK (protéine pro-apoptotique) (p < 0,05) et diminuaient le taux d’ARNm de MKI67 (marqueur de prolifération cellulaire) (p < 0,05). La Lidocaïne augmentait le taux d’activité de la caspase 3 et le taux d’apoptose des cellules HepaRG aux dose de 10-3 M et 10-4M (p < 0,01), la ropivacaïne augmentait mais de façon plus modeste (p < 0,05) l’activité caspase. Aucun des Als n’avait d’action sur la sénéscence (Fig. 1). Discussion Il existe un effet et un mécanisme d’action spécifique de chaque Als sur les cellules cancéreuses de CHC : La lidocaïne induit une augmentation de l’apoptose dans les cellules de CHC in vitro ; la ropivacaïne inhibe spécifiquement la croissance des cellules CHC in vitro par blocage du cycle cellulaire. Ces résultats expérimentaux encourageants suggèrent un bénéfice à l’administration d’Als lors de la chirurgie carcinologique. Ils doivent être confirmés par des études clinique

Prevalence and impact of frailty on mortality in elderly ICU patients: a prospective, multicenter, observational study.

International audiencePURPOSE: Frailty is a recent concept used for evaluating elderly individuals. Our study determined the prevalence of frailty in intensive care unit (ICU) patients and its impact on the rate of mortality. METHODS: A multicenter, prospective, observational study performed in four ICUs in France included 196 patients aged ≥65 years hospitalized for >24 h during a 6-month study period. Frailty was determined using the frailty phenotype (FP) and the clinical frailty score (CFS). The patients were separated as follows: FP score <3 or ≥3 and CFS <5 or ≥5. RESULTS: Frailty was observed in 41 and 23% of patients on the basis of an FP score ≥3 and a CFS ≥5, respectively. At admission to the ICU, the Simplified Acute Physiology Score II (SAPS II) and Sequential Organ Failure Assessment (SOFA) scores did not differ between the frail and nonfrail patients. In the multivariate analysis, the risk factors for ICU mortality were FP score ≥3 [hazard ratio (HR), 3.3; 95% confidence interval (CI), 1.6-6.6; p < 0.001], male gender (HR, 2.4; 95% CI, 1.1-5.3; p = 0.026), cardiac arrest before admission (HR, 2.8; 95% CI, 1.1-7.4; p = 0.036), SAPS II score ≥46 (HR, 2.6; 95% CI, 1.2-5.3; p = 0.011), and brain injury before admission (HR, 3.5; 95% CI, 1.6-7.7; p = 0.002). The risk factors for 6-month mortality were a CFS ≥5 (HR, 2.4; 95% CI, 1.49-3.87; p < 0.001) and a SOFA score ≥7 (HR, 2.2; 95% CI, 1.35-3.64; p = 0.002). An increased CFS was associated with significant incremental hospital and 6-month mortalities. CONCLUSIONS: Frailty is a frequent occurrence and is independently associated with increased ICU and 6-month mortalities. Notably, the CFS predicts outcomes more effectively than the commonly used ICU illness scores

Clarifying the role of DNA methylation in tree phenotypic plasticity

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Effect of anakinra versus usual care in adults in hospital with COVID-19 and mild-to-moderate pneumonia (CORIMUNO-ANA-1): a randomised controlled trial

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Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia

International audienceImportance Severe pneumonia with hyperinflammation and elevated interleukin-6 is a common presentation of coronavirus disease 2019 (COVID-19).Objective To determine whether tocilizumab (TCZ) improves outcomes of patients hospitalized with moderate-to-severe COVID-19 pneumonia.Design, Setting, and Particpants This cohort-embedded, investigator-initiated, multicenter, open-label, bayesian randomized clinical trial investigating patients with COVID-19 and moderate or severe pneumonia requiring at least 3 L/min of oxygen but without ventilation or admission to the intensive care unit was conducted between March 31, 2020, to April 18, 2020, with follow-up through 28 days. Patients were recruited from 9 university hospitals in France. Analyses were performed on an intention-to-treat basis with no correction for multiplicity for secondary outcomes.Interventions Patients were randomly assigned to receive TCZ, 8 mg/kg, intravenously plus usual care on day 1 and on day 3 if clinically indicated (TCZ group) or to receive usual care alone (UC group). Usual care included antibiotic agents, antiviral agents, corticosteroids, vasopressor support, and anticoagulants.Main Outcomes and Measures Primary outcomes were scores higher than 5 on the World Health Organization 10-point Clinical Progression Scale (WHO-CPS) on day 4 and survival without need of ventilation (including noninvasive ventilation) at day 14. Secondary outcomes were clinical status assessed with the WHO-CPS scores at day 7 and day 14, overall survival, time to discharge, time to oxygen supply independency, biological factors such as C-reactive protein level, and adverse events.Results Of 131 patients, 64 patients were randomly assigned to the TCZ group and 67 to UC group; 1 patient in the TCZ group withdrew consent and was not included in the analysis. Of the 130 patients, 42 were women (32%), and median (interquartile range) age was 64 (57.1-74.3) years. In the TCZ group, 12 patients had a WHO-CPS score greater than 5 at day 4 vs 19 in the UC group (median posterior absolute risk difference [ARD] −9.0%; 90% credible interval [CrI], −21.0 to 3.1), with a posterior probability of negative ARD of 89.0% not achieving the 95% predefined efficacy threshold. At day 14, 12% (95% CI −28% to 4%) fewer patients needed noninvasive ventilation (NIV) or mechanical ventilation (MV) or died in the TCZ group than in the UC group (24% vs 36%, median posterior hazard ratio [HR] 0.58; 90% CrI, 0.33-1.00), with a posterior probability of HR less than 1 of 95.0%, achieving the predefined efficacy threshold. The HR for MV or death was 0.58 (90% CrI, 0.30 to 1.09). At day 28, 7 patients had died in the TCZ group and 8 in the UC group (adjusted HR, 0.92; 95% CI 0.33-2.53). Serious adverse events occurred in 20 (32%) patients in the TCZ group and 29 (43%) in the UC group (P = .21).Conclusions and Relevance In this randomized clinical trial of patients with COVID-19 and pneumonia requiring oxygen support but not admitted to the intensive care unit, TCZ did not reduce WHO-CPS scores lower than 5 at day 4 but might have reduced the risk of NIV, MV, or death by day 14. No difference on day 28 mortality was found. Further studies are necessary for confirming these preliminary results.Trial Registration ClinicalTrials.gov Identifier: NCT0433180

Sarilumab in adults hospitalised with moderate-to-severe COVID-19 pneumonia (CORIMUNO-SARI-1): An open-label randomised controlled trial

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Dolutegravir-based dual maintenance regimens combined with lamivudine/emtricitabine or rilpivirine: risk of virological failure in a real-life setting

International audienceBackground Maintenance ART with dolutegravir-based dual regimens have proved their efficacy among HIV-1-infected subjects in randomized trials. However, real-life data are scarce, with limited populations and follow-up. Objectives We assessed virological failure (VF) and resistance-associated mutations (RAMs) on dolutegravir maintenance regimens in combination with rilpivirine or with lamivudine or emtricitabine (xTC) and analysed the factors associated with VF. Methods Between 2014 and 2018, all HIV-1-infected adults included in the Dat’AIDS cohort and starting dolutegravir/rilpivirine or dolutegravir/xTC as a maintenance dolutegravir-based dual regimen were selected. VF was defined as two consecutive HIV RNA values &gt;50 copies/mL or a single value &gt;400 copies/mL. We compared cumulative genotypes before initiation of a maintenance dolutegravir-based dual regimen with genotype at VF. Results We analysed 1374 subjects (799 on dolutegravir/rilpivirine and 575 on dolutegravir/xTC) with a median follow-up of 20 months (IQR = 11–31) and 19 months (IQR = 11–31), respectively. VF occurred in 3.8% (n = 30) of dolutegravir/rilpivirine subjects and 2.6% (n = 15) of dolutegravir/xTC subjects. Among subjects receiving dolutegravir/rilpivirine, two genotypes harboured emerging RAMs at VF: E138K on NNRTI (n = 1); and E138K+K101E on NNRTI and N155H on INSTI (n = 1). Among subjects receiving dolutegravir/xTC, no new RAM was detected. The only predictive factor of VF on dolutegravir/rilpivirine was the history of failure on an NNRTI-based regimen (adjusted HR = 2.97, 95% CI = 1.28–6.93). No factor was associated with VF on dolutegravir/xTC. Conclusions In this large real-life cohort, dolutegravir/rilpivirine and dolutegravir/xTC sustained virological suppression and were associated with a low rate of VF and RAM emergence. Careful virological screening is essential before switching to dolutegravir/rilpivirine in virologically suppressed patients with a history of NNRTI therapy