VicTORia: a randomised phase II study to compare vinorelbine in combination with the mTOR inhibitor everolimus versus vinorelbine monotherapy for second-line chemotherapy in advanced HER2-negative breast cancer.

PURPOSE: Improving the outcome of patients with HER2-negative metastatic breast cancer experiencing tumour progression following first-line chemotherapy remains an urgent medical need. The purpose of the VicTORia trial was to show superiority of everolimus in combination with vinorelbine versus vinorelbine monotherapy as second-line chemotherapy for patients with advanced HER2 negative breast cancer. METHODS: In this randomised phase II trial, 133 patients were recruited in 32 centres in Germany. Patients were randomised 1:1 to second-line chemotherapy either with vinorelbine plus everolimus (arm1) or vinorelbine alone (arm2). Primary endpoint was progression-free survival (PFS). Secondary endpoints were PFS rate at 6 months, overall survival (OS), overall response rate (ORR) and safety. Baseline PI3 K mutational status was determined in plasma samples. RESULTS: Median progression-free survival was not different between arms (arm1 vs. arm2: 4.01 months, 95% CI 2.40-6.09 vs. 4.08, 95% CI 2.80-5.33). PFS rate at 6 months (arm1 vs. arm2: 39.4%, 95% CI 27.6-50.9% vs. 36.6%, 95% CI 24.6-48.6%), median OS (arm1 vs. arm2: 16.3 months, 95% CI 11.4-19.0 vs. 13.8 months, 95% CI 10.2-19.1) and ORR were not different between arms. Most frequent grade 3/4 adverse events were neutropenia (50% vs. 40%), gastrointestinal toxicities (19.1% vs. 6.1%), and infections (19.1% vs. 7.7%). PI3 K mutational status was neither associated with PFS nor with OS. CONCLUSION: Although well tolerated, the efficacy of everolimus and vinorelbine combination therapy was not superior to vinorelbine monotherapy. There was no correlation between PI3 K mutational status and efficacy. EudracCT No 2011-001024-38, ClinicalTrials.gov No NCT01520103.

Activity and substrate specificity of cytosolic and microsomal glutathione S-transferase in Australian black tiger prawns (Penaeus monodon) after exposure to cyanobacterial toxins.

Cyanobacterial toxins have been shown to have a far-reaching impact-from aquatic organisms to human health. Aquatic organisms are typically exposed in their natural environment to toxic cyanobacteria, and exposure can occur via ingestion of cyanobacterial cells or by bioaccumulation of water-borne toxin. The aquaculture and fisheries of crustaceans are among the most important seafood industries. Concomitant with the growth of this industry, the importance of the health of crustaceans increased. The black tiger prawn is the major cultivated prawn in Australia. The aquaculture of these prawns takes place in shallow ponds, where blooms, often of cyanobacteria, develop. Cyanobacterial toxins were hypothesized to contribute to the mortality of prawns. Many aquatic organisms have the possibility of detoxifying cyanobacterial toxins via conjugation to glutathione. The presence of several classes of the cytosolic glutathione S-transferase system in black tiger prawns-mu, pi, theta, alpha, and tau-was shown using different substrates for measurement. Injection experiments with microcystin-LR and feeding experiments with nodularin revealed elevation of GST activity in different types of prawn tissue in parallel with reduction in the GST classes. Correlation analyses of toxin content of the prawns with GST activity showed that low toxin content was correlated with high elevation of enzymes and high toxin content with low elevation of enzymes.

Cyanobacteria and prawn farming in northern New South Wales, Australia--a case study on cyanobacteria diversity and hepatotoxin bioaccumulation.

Harmful cyanobacteria pose a hazard to aquatic ecosystems due to toxins (hepatotoxic microcystins, nodularins, and cylindrospermopsin) they produce. The microcystins and nodularins are potent toxins, which are also tumor promoters. The microcystins and nodularins may accumulate into aquatic organisms and be transferred to higher trophic levels, and eventually affect vector animals and consumers. Prawn farming is a rapidly growing industry in Australia. Because information regarding effects of cyanobacteria at prawn farms was lacking, we examined diversity of cyanobacteria and toxin production plus bioaccumulation into black tiger prawns (Penaeus monodon) under both field (northern New South Wales, Australia, December 2001-April 2002) and laboratory conditions. Samples were analyzed for hepatotoxins using enzyme-linked immunosorbent assay (ELISA) and high-performance liquid chromatography (HPLC). The maximum density of cyanobacteria (1 x 10(6) to 4 x 10(6) cells/l) was reached in April. Cyanobacteria encountered were Oscillatoria sp. (up to 4 x 10(6) cells/l), Pseudanabaena sp. (up to 1.8 x 10(6) cells/l), Microcystis sp. (up to 3.5 x 10(4) cells/l), and Aphanocapsa sp. (up to 2 x 10(4) cells/l). An uncommon cyanobacterium, Romeria sp. (up to 2.2 x 10(6) cells/l), was also observed. Contrasting earlier indications, toxic Nodularia spumigena was absent. Despite that both Oscillatoria sp. and Microcystis sp. are potentially hepatotoxic, hepatotoxin levels in phytoplankton samples remained low (up to 0.5-1.2 mg/kg dw; ELISA) in 2001-2002. ELISA was found suitable not only for phytoplankton but prawn tissues as well. Enzymatic pretreatment improved extractability of hepatotoxin from cyanobacteria (nodularin from N. spumigena as an example), but did not generally increase toxin recovery from prawn hepatopancreas. There were slightly increasing hepatotoxin concentrations in prawn hepatopancreas (from 6-20 to 20-80 microg/kg dw; ELISA) during the study. Hepatotoxin concentrations in surface sediment remained low (<5 microg/kg dw; ELISA) throughout the study. Laboratory experiments indicated that prawn hepatopancreas, heart, and brain were primary organs for hepatotoxin bioaccumulation. Toxin concentration in other organs, including muscle, was less effective. Orally administered nodularin levels in hepatopancreas rapidly decreased from initial 830 to 250 microg/kg dw in 96 h. Similarly, concentration of microcystin-LR injected in prawns decreased from 130 to 30 microg/kg dw (hepatopancreas) in 2 h. These results demonstrate that potential risks caused by cyanobacteria in prawn farming (farmers, prawns, and consumers) were not substantial in 2001-2002. Although prawns may act as vectors for toxin transfer, they did not accumulate alerting amounts of hepatotoxins and were able to effectively detoxify them. Because bloom toxicity may vary, low-frequency toxin monitoring is recommended.