Influence du bevacizumab sur la régénération hépatique après hépatectomie chez le lapin

La chirurgie curative du cancer colorectal métastatique est possible chez moins de 20% des patients atteints. La majorité de ces patients reçoivent une chimiothérapie d'induction, fréquemment à base d'un anticorps anti-VEGF : le bevacizumab. Nous avons étudié l'influence du bevacizumab, sur la régénération hépatique après hépatectomie chez le lapin. 30 lapins ont eu une hépatectomie de 28%. Ils étaient ensuite randomisés en 2 groupes, en aveugle. 1 groupe a reçu du sérum salé, l'autre groupe a eu une injection IV de bevacizumab (50 mg/Kg). Des prélèvements hépatiques ont été réalisés, après sacrifices aux 2e, 3e, 5e, 7e et 14e jours. La prolifération des hépatocytes a été étudiée par un immunomarquage au Ki-67. L'apoptose a été évaluée par l'activité enzymatique de la caspase-3. L'expression des ARNm de VEGF, HGF et I Ba a été déterminée par RT-PCR quantitative. La prolifération hépatocytaire était diminuée dans le groupe ayant reçu du bevacizumab. Le nombre d'hépatocytes marqués était diminué par rapport au groupe contrôle par un facteur 1,8 à J3 (p<0,05), 1,6 à J5 (p<0,003) et 2,1 à J14 (p<0,05). L'expression de l'ARNm du VEGF et d'HGF était équivalente dans les 2 groupes. L'expression de l'ARNm d'I Ba ne variait significativement que dans le groupe contrôle, uniquement entre J0 et J2 (p<0,005). La variation était de 179% VS 112% dans le groupe bevacizumab (p<0,05). L'activité de la caspase-3 était identique et stable dans les 2 groupes après hépatectomie. Une injection IV unique de bevacizumab en post-opératoire immédiat altère la régénération hépatique après hépatectomie à 28% chez le lapin.CLERMONT FD-BCIU-Santé (631132104) / SudocSudocFranceF

Efficacy of high-intensity focused ultrasound-assisted hepatic resection (HIFU-AR) on blood loss reduction in patients with liver metastases requiring hepatectomy: study protocol for a randomized controlled trial

International audienceAbstractBackgroundLiver resection is the only potentially curative treatment for colorectal liver metastases (LM). It is considered a safe procedure, but is often associated with blood loss during liver transection. Blood transfusions are frequently needed, but they are associated with increased morbidity and risk of recurrence. Many surgical devices have been developed to decrease blood loss. However, none of them has proven superior to the standard crushing technique. We developed a new, powerful intra-operative high-intensity focused ultrasound (HIFU) transducer which destroys tissue by coagulative necrosis. We aim to evaluate whether HIFU-assisted liver resection (HIFU-AR) results in reduced blood loss.MethodsThis is a prospective, single-centre, randomized (1:1 ratio), comparative, open-label phase II study. Patients with LM requiring a hepatectomy for ≥ 2 segments will be included. Patients with cirrhosis or sinusoidal obstruction syndrome with portal hypertension will be excluded. The primary endpoint is normalized blood loss in millilitres per square centimetre of liver section plane. Secondary endpoints are: total blood loss, transection time, transection time per square centimetre of liver area, haemostasis time, clip density on the liver section area, rate and duration of the Pringle manœuvre, rate of patients needing a blood transfusion, length of hospital stay, morbidity, patients with positive resection margin, and local recurrence. Assuming a blood loss of 7.6 ± 3.7 mL/cm2 among controls, the study will have 85% power to detect a twofold decrease of blood loss in the experimental arm, using a Wilcoxon (Mann-Whitney) rank-sum test with a 0.05 two-sided significance level. Twenty-one randomized patients per arm are required. Considering the risk of contraindications at surgery, up to eight patients may be enrolled in addition to the 42 planned, with an enrolment period of 24 months. Randomization will be stratified by surgeon.DiscussionWe previously demonstrated the safety and efficacy of intra-operative HIFU in patients operated on for LM. We also demonstrated the efficacy of HIFU-AR in a preclinical study. Participants in the HIFU-AR group of this randomized trial can expect to benefit from reduced blood loss and decreased ischemia of liver parenchyma.Trial registrationClinicaltrial.gov, NCT02728167. Registered on 22 March 2016

Performance of Repeated Measures of (1–3)-β-D-Glucan, Mannan Antigen, and Antimannan Antibodies for the Diagnosis of Invasive Candidiasis in ICU Patients: A Preplanned Ancillary Analysis of the EMPIRICUS Randomized Clinical Trial

International audienceBackground. We aimed to assess the prognostic value of repeated measurements of serum (1-3)-β-D-glucan (BDG), mannanantigen (mannan-Ag), and antimannan antibodies (antimannan-Ab) for the occurrence of invasive candidiasis (IC) in a high-risk nonimmunocompromised population. Methods. This was a preplanned ancillary analysis of the EMPIRICUS Randomized Clinical Trial, including nonimmunocompromised critically ill patients with intensive care unit-acquired sepsis, multiple Candida colonization, and multiple organ failure who were exposed to broad-spectrum antibacterial agents. BDG (>80 and >250 pg/mL), mannan-Ag (>125 pg/ mL), and antimannan-Ab (>10 AU) were collected repeatedly. We used cause-specific hazard models. Biomarkers were assessed at baseline in the whole cohort (cohort 1). Baseline covariates and/or repeated measurements and/or increased biomarkers were then studied in the subgroup of patients who were still alive at day 3 and free of IC (cohort 2). Results. Two hundred thirty-four patients were included, and 215 were still alive and free of IC at day 3. IC developed in 27 patients (11.5%), and day 28 mortality was 29.1%. Finally, BDG >80 pg/mL at inclusion was associated with an increased risk of IC (CSHR[IC], 4.67; 95% CI, 1.61-13.5) but not death (CSHR[death], 1.20; 95% CI, 0.71-2.02). Conclusions. Among high-risk patients, a first measurement of BDG >80 pg/mL was strongly associated with the occurrence of IC. Neither a cutoff of 250 pg/mL nor repeated measurements of fungal biomarkers seemed to be useful to predict the occurrence of IC. The cumulative risk of IC in the placebo group if BDG >80 pg/mL was 25.39%, which calls into question the efficacy of empirical therapy in this subgroup