Preoperative bevacizumab and surgery for colorectal liver metastases: a propensity score analysis.

PURPOSE: Bevacizumab associated with conventional chemotherapy has become standard care in the management of metastatic colorectal cancer. However, its impact on outcomes after liver resections (LRs) remains debated. The aim of this study was to evaluate the impact of neoadjuvant bevacizumab-based chemotherapy (BBC) on postoperative outcomes of LR for colorectal liver metastasis (CLM) using a validated approach. METHODS: All patients who received neoadjuvant therapy for CLMs between January 2005 and May 2011 were included. Risk factors for major complications (Clavien ≥3) were analyzed by univariate and multivariate analysis. Evaluation of BBC's impact on morbidity was conducted after a propensity score adjustment on factors identified to influence major complications (MCs). RESULTS: LR for CLMs after neoadjuvant chemotherapy was performed in 199 patients (127 men and 72 women). Major LR was performed on 111 patients (55.78%), and MCs occurred in 41 cases (20.6%). After multivariate analyses, major LR (OR 2.85; 95% CI 1.29-6.85; P = 0.013) and combined resections of both the primary tumor and CLMs (OR 7.12; 95% CI: 2.6-20.5; P < 0.001) were independent predictive factors for MCs. After a propensity score matching, 56 patients with a BBC regimen were compared to 112 patients without BBC. No difference in terms of biliary fistula occurrence (P = 0.94) or 90-day mortality (P = 0.66) was found. Both in the univariate and multivariate analyses, BBC was not associated with MCs (P = 0.95). CONCLUSION: The present study using propensity score matching demonstrated that BBC did not impair outcomes of LR for CLM.

Pretreatment with mangafodipir improves liver graft tolerance to ischemia/reperfusion injury in rat.

Ischemia/reperfusion injury occurring during liver transplantation is mainly due to the generation of reactive oxygen species (ROS) upon revascularization. Thus, delivery of antioxidant enzymes might reduce the deleterious effects of ROS and improve liver graft initial function. Mangafodipir trisodium (MnDPDP), a contrast agent currently used in magnetic resonance imaging of the liver, has been shown to be endowed with powerful antioxidant properties. We hypothesized that MnDPDP could have a protective effect against liver ischemia reperfusion injury when administrated to the donor prior to harvesting. Livers from Sprague Dawley rats pretreated or not with MnDPDP were harvested and subsequently preserved for 24 h in Celsior® solution at 4°C. Organs were then perfused ex vivo for 120 min at 37°C with Krebs Henseleit solution. In MnDPDP (5 µmol/kg) group, we observed that ATP content was significantly higher at the end of the cold preservation period relative to untreated group. After reperfusion, livers from MnDPDP-treated rats showed better tissue integrity, less hepatocellular and endothelial cell injury. This was accompanied by larger amounts of bile production and higher ATP recovery as compared to untreated livers. The protective effect of MnDPDP was associated with a significant decrease of lipid peroxidation, mitochondrial damage, and apoptosis. Interestingly, MnDPDP-pretreated livers exhibited activation of Nfr2 and HIF-1α pathways resulting in a higher catalase and HO-1 activities. MnDPDP also increased total nitric oxide (NO) production which derived from higher expression of constitutive NO synthase and lower expression of inducible NO synthase. In conclusion, our results show that donor pretreatment with MnDPDP protects the rat liver graft from cold ischemia/reperfusion injury and demonstrate for the first time the potential interest of this molecule in the field of organ preservation. Since MnDPDP is safely used in liver imaging, this preservation strategy holds great promise for translation to clinical liver transplantation.

Astroglial permissivity for neuritic outgrowth in neuron-astrocyte cocultures depends on regulation of laminin bioavailability.

The molecular determinants underlying the failure of axons to regenerate in the CNS after injury were studied in an in vitro model of astrogliosis and neuronal coculture. Mechanically lesioned neuron-astrocyte mouse cortical cocultures were treated with antisense glial fibrillary acidic protein (GFAP)-mRNA in order to inhibit the formation of gliofilaments that occurs in response to injury. This inhibition relieves the blockage of neuron migration and neuritic outgrowth observed after lesion, and migrating neurons reappeared, supported by a laminin-labeled extracellular network (permissive conditions). We then questioned the relationship between this permissivity and laminin production. Follow-up studies on the concentration of laminin indicated that, after antisense treatment, the laminin level was increased in the cocultures and was under the control of astrocyte-neuron interactions. The addition of exogenous laminin favored neuronal migration and neurite outgrowth, whereas neutralizing laminin bioavailability with antibodies recognizing the astroglial laminin resulted in an inhibition of both neuronal access to the lesion site and neurite outgrowth, suggesting an active role for laminin in the permissive process. This permissive process could be associated with modulation of extracellular matrix (ECM) molecule degradation by proteinases. Among the latter, matrix metalloproteinases (MMPs) are involved in the breakdown of the ECM component. Our investigation showed a net decrease of the matrix metalloproteinase MMP-2 expression and activity and an increase of its endogenous inhibitor TIMP-2 expression. Both proteins associated with permissivity should be involved in the laminin stabilization and cell-matrix interactions. High levels of laminin and laminin bioavailability, consequent to a reduction in astrogliosis, may be important permissive elements for neuronal migration and neurite outgrowth postlesion.