Combination of Trabectedin and Gemcitabine for Advanced Soft Tissue Sarcomas: Results of a Phase I Dose Escalating Trial of the German Interdisciplinary Sarcoma Group (GISG)

Background: Evaluation of the potential efficacy and safety of combination therapies for advanced soft tissue sarcomas (STS) has increased substantially after approval of trabectedin and pazopanib. Trabectedin’s introduction in Europe in 2007 depended mainly on its activity in so-called L-sarcomas (liposarcoma and leiomyosarcoma); combination of trabectedin with other chemotherapies used in STS seems of particular interest. Methods: We initiated within the German Interdisciplinary Sarcoma Group (GISG) a phase I dose escalating trial evaluating the combination of trabectedin and gemcitabine in patients with advanced and/or metastatic L-sarcomas (GISG-02; ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01426633","term_id":"NCT01426633"}}NCT01426633). Patients were treated with increasing doses of trabectedin and gemcitabine. The primary endpoint was to determine the maximum tolerated dose. Results: Five patients were included in the study. Two patients were treated on dose level 1 comprising trabectedin 0.9 mg/m² on day 1 and gemcitabine 700 mg/m² on days 1 + 8, every 3 weeks. Due to dose-limiting toxicity (DLT) in both patients (elevated transaminases and thrombocytopenia), an additional three patients were treated on dose level −1 with trabectedin 0.7 mg/m² plus gemcitabine 700 mg/m². Of these three patients, two demonstrated another DLT; therefore, the trial was stopped and none of the dose levels could be recommended for phase II testing. Conclusion: The GISG-02 phase I study was stopped with the conclusion that the combination of gemcitabine and trabectedin is generally not recommended for the treatment of patients with advanced and/or metastatic leiomyosarcoma or liposarcoma. Also, this phase I study strongly supports the necessity for careful evaluation of combination therapies.     

No evidence of superclones in leaf-feeding forms of austrian grape phylloxera (Daktulosphaira vitifoliae)

European Journal of Plant Pathology - The genetic structure of ten grape phylloxera populations, sampled in summer of 2006 and 2007 from four distinct viticultural areas in Austria, Daktulosphaira...     

Resistance mechanisms of wild tomato germplasm to infection of Oidium neolycopersici

Tomato powdery mildew (Oidium neolycopersici) is one of the most devastating diseases of cultivated tomatoes worldwide. Although the first epidemics were recorded more than 25 years ago many aspects of this host-pathogen interaction are still not well understood. Detailed morphological and molecular studies of the anamorphs confirmed that O. neolycopersici is phylogeneticaly close to Erysiphe aquilegiae var. ranunculi. Host range is rather broad, apart from Solanaceae hosts were found in the families Apocynaceae, Campanulaceae, Crassulaceae, Cistaceae, Cucurbitaceae, Linaceae, Malvaceae, Papaveraceae, Pedialiaceae, Scrophulariaceae, Valerianaceae a Violaceae. Non-host resistance within these families is not based on inhibition of formation of primary haustorium, however, on post-haustorial hypersensitive reponse and another type of non-hypersensitive resistance. Screening of wild Solanum species (previous Lycopersicon spp.) germplasm revealed valuable sources of resistance (S. habrochaites, S. pennellii, S. cheesmaniae, S. chilense, S. peruvianum). The main resistance mechanism was found to be a hypersensitive response (HR), in some cases followed by limited development of the pathogen. However, there is a broad variation in resistance response on the histological and cytological level. Interaction between many wild Solanum spp. and O. neolycopersici is race-specific, at least three races were differentiated. In some interspecific crosses (S. lycopersicum × S. habrochaites) adult plant resistance was observed. Biochemical studies focusing on production of reactive oxygen species (ROS) and peroxidase activity during infection of O. neolycopersici showed that production of ROS and activity of corresponding enzymes is related to activation of defence responses in genotypes of wild Solanum sect. Lycopersicon. The significance of nitric oxide (NO) in O. neolycopersici pathogenesis was supported by experiments with NO donors and scavengers. In moderately resistant genotype S. chmielewskii, treatment by heat stress caused slight deceleration of pathogen development, increased production of jasmonic acid (JA) and abscisic acid (ABA) and increased peroxidase activity in infected plants. The different degree of tomato resistance/susceptibility did not markedly change the rate and extent of photosynthetic response to O. neolycopersici; only minimal impairment of photosynthesis was found in both susceptible and moderately resistant genotypes during the first 9 days after inoculation. The accumulated evidence confirm a crucial role of localised increased production of ROS and reactive nitrogen species (RNS) in response to pathogen penetration into plant tissue and its involvement in the plant resistance responses including the initiation and progression of plant cell death in host wild Solanum species. Crucial points of further research are discussed.