A systematic review of recent phase-II trials in refractory or recurrent osteosarcoma: Can we inform future trial design?

Background/Objective: To analyze changes in recurrent/refractory osteosarcoma phase II trials over time to inform future trials in this population with poor prognosis.// Methods: A systematic review of trials registered on trial registries between 01/01/2017–14/02/2022. Comparison of 98 trials identified between 2003 and 2016. Publication search/analysis for both periods, last update on 01/12/2022.// Results: Between 2017 and 2022, 71 phase-II trials met our selection criteria (19 osteosarcoma-specific trials, 14 solid tumor trials with and 38 trials without an osteosarcoma-specific stratum). The trial number increased over time: 13.9 versus 7 trials/year (p = 0.06). Monotherapy remained the predominant treatment (62% vs. 62%, p = 1). Targeted therapies were increasingly evaluated (66% vs. 41%, P = 0.001). Heterogeneity persisted in the trial characteristics. The inclusion criteria were measurable disease (75%), evaluable disease (14%), and surgical remission (11%). 82% of the trials included pediatric or adolescent patients. Biomarker-driven trials accounted for 25% of the total trials. The survival endpoint use (rather than response) slightly increased (40% versus 31%), but the study H1/H0 hypotheses remained heterogeneous. Single-arm designs predominated over multiarm trials (n = 7). Available efficacy data on 1361 osteosarcoma patients in 58 trials remained disappointing, even though 21% of these trials were considered positive, predominantly those evaluating multi-targeted kinase inhibitors.// Conclusion: Despite observed changes in trial design and an increased number of trials investigating new therapies, high heterogeneity remained with respect to patient selection, study design, primary endpoints, and statistical hypotheses in recently registered phase II trials for osteosarcoma. Continued optimization of trial design informed by a deeper biological understanding should strengthen the development of new therapies

Catalasic activity in fish liver: improvement of the UV to visible analytic method.

International audienceAntioxidative defenses and more especially catalasic activity (CAT) are studied in a large range of scientific research thematics. In environmental sciences, the problematic of oxidative stress is of great interest as pollutants can induce perturbations of redox homeostasis. Consequently, changes in antioxidative defenses levels in fish tissues and particularly in liver are used as potential biomarkers of pollution. In most studies, the CAT was assayed by following during 5 min the consumption of H2O2 in cytosolic buffered extracts at 240 nm (UV-method). This study proposed a development of this method in the visible, using permanganate and a 525-nm detection, which was more accurate, sensitive, and rapid. Moreover, the hepatic CAT of six different fish species [a cyclidae (Nimbochromis linni), 3 cyprinidae (Brachydanio rerio, Rutilus rutilus, Cyprinus carpio), an anguillidae (Anguilla anguilla), and a percidae (Perca fluviatilus)] was evaluated with the two protocols (UV- and KMnO4-method). The results but also the thermal optimum of the reaction and the interest of CAT as biomarker in ecotoxicology were discussed

Heavy metal contamination and hepatic toxicological responses in brown trout (Salmo trutta) from the Kerguelen Islands

The Kerguelen Islands include various species of freshwater fish such as brown trout (Salmo trutta). These trout are among the most isolated from direct anthropogenic impact worldwide. This study was designed to analyse cadmium (Cd) and copper (Cu) concentrations in the liver of Kerguelen brown trout, and to assess the possible impacts of these metals on hepatic histopathology and oxidative stress parameters (superoxide dismutase and catalase activity and glutathione levels). Trout were caught in the Château River, the Studer Lakes and the Ferme Pond, close to the scientific station of the Kerguelen Islands, corresponding to three morphotypes (river, lake and station). Kerguelen trouts’ hepatic concentrations of Cd and Cur were similar to those reported in previous studies in salmonids populations from areas under anthropological impacts. Clear hepatic disturbances (fibrosis, nuclear alteration, increased immune response, melanomacrophage centres [MMCs]) were observed in all tested trout. A similar histo-pathological trend was observed among the trout from the three morphotypes but anti-oxidative responses were higher in the trout from the “station” morphotype. Hepatic alterations and the presence of MMCs in the livers of Kerguelen brown trout may be related to the high levels of Cd and Cu measured in this fish at all sampling sites.Keywords: Brown trout; freshwater; fish; sub-Antarctic; liver; biomarkers(Published: 22 September 2015)Citation: Polar Research 2015, 34, 22784, http://dx.doi.org/10.3402/polar.v34.2278

Polychlorinated biphenyls in freshwater salmonids from the Kerguelen Islands in the Southern Ocean

International audienceThe Subantarctic Kerguelen Islands (49°S, 70°E) contain freshwater ecosystems among the most isolated in the world. Concentrations of polychlorinated biphenyls (PCBs) were assessed in the muscle of 48 brook trout and 38 brown trout caught during summer and spring 2006 in the rivers, lakes and ponds of Kerguelen. The sum of 29 PCBs averaged 404 and 358 ng g-1 lipid, and dioxin-like PCB was 19 and 69 ng g-1 lipid, in brook and brown trout, respectively. The values showed a high variability and some fish accumulated PCBs at levels similar to those of fish from impacted areas. While inter-sex differences were limited, the season and the morphotype appeared to have the most influence. Fish captured in summer had muscle PCB concentrations about three times higher than those caught in spring and the 'river' morphotype of brook trout showed the highest PCB levels

Bages-Sigean and Canet-St Nazaire lagoons (France): physico-chemical characteristics and contaminant concentrations (Cu, Cd, PCBs and PBDEs) as environmental quality of water and sediment

International audienceEnvironmental characteristics in water and sediments of two contrasted coastal Mediterranean lagoons, Bages-Sigean and Canet-St Nazaire, were measured over a three season survey. The urban pollution (treatment plant discharges) is very important in Canet-St Nazaire lagoon reflecting untreated sewages, while in Bages-Sigean, the northern part appears more impacted due to larger anthropogenic inputs. Dissolved Cd concentrations are on the whole similar in both lagoons, whereas Cu concentrations are by far higher in lagoon Canet-St Nazaire. Cu concentrations appear to be highly dependent on dissolved organic carbon whereas salinity seems to control Cd variations. Concerning the sediments, the confined northern part of lagoon Bages-Sigean shows organic carbon and total nitrogen enrichment whereas lipid concentrations are much higher in the Canet-St Nazaire lagoon. Cu complexation seems to be strongly related to organic matter as evidenced by the two significant positive relationships, on one hand between Cu and organic carbon, and on the other hand, between Cu and lipids. On the contrary, Cd concentrations appear to be mainly controlled by carbonates. PCBs and PBDEs were detected only in sediments and show relatively low concentrations compared to similar lagoon environments. Regarding the sediment quality guidelines, Cd, Cu and PCBs in both lagoons did not exceed any Probable Effect Concentration (PEC)

A systematic review of recent phase-II trials in refractory or recurrent osteosarcoma: Can we inform future trial design?

International audienceBackground/Objective: To analyze changes in recurrent/refractory osteosarcoma phase II trials over time to inform future trials in this population with poor prognosis.Methods: A systematic review of trials registered on trial registries between 01/01/2017–14/02/2022. Comparison of 98 trials identified between 2003 and 2016. Publication search/analysis for both periods, last update on 01/12/2022.Results: Between 2017 and 2022, 71 phase-II trials met our selection criteria (19 osteosarcoma-specific trials, 14 solid tumor trials with and 38 trials without an osteosarcoma-specific stratum). The trial number increased over time: 13.9 versus 7 trials/year (p = 0.06). Monotherapy remained the predominant treatment (62% vs. 62%, p = 1). Targeted therapies were increasingly evaluated (66% vs. 41%, P = 0.001). Heterogeneity persisted in the trial characteristics. The inclusion criteria were measurable disease (75%), evaluable disease (14%), and surgical remission (11%). 82% of the trials included pediatric or adolescent patients. Biomarker-driven trials accounted for 25% of the total trials. The survival endpoint use (rather than response) slightly increased (40% versus 31%), but the study H1/H0 hypotheses remained heterogeneous. Single-arm designs predominated over multiarm trials (n = 7). Available efficacy data on 1361 osteosarcoma patients in 58 trials remained disappointing, even though 21% of these trials were considered positive, predominantly those evaluating multi-targeted kinase inhibitors.Conclusion: Despite observed changes in trial design and an increased number of trials investigating new therapies, high heterogeneity remained with respect to patient selection, study design, primary endpoints, and statistical hypotheses in recently registered phase II trials for osteosarcoma. Continued optimization of trial design informed by a deeper biological understanding should strengthen the development of new therapies