Dual MET/EGFR therapy leads to complete response and resistance prevention in a MET-amplified gastroesophageal xenopatient cohort.

Amplification of the MET oncogene occurs in 2-4% of gastroesophageal cancers and defines a small and aggressive subset of tumors. Although in vitro studies have given very promising results, clinical trials with MET inhibitors have been disappointing, showing few and short lasting responses. The aim of the work was to exploit a MET-amplified patient-derived xenograft model to optimize anti-MET therapeutic strategies in gastroesophageal cancer. We found that despite the high MET amplification level (26 gene copies), in the absence of qualitative or quantitative alterations of EGFR, MET inhibitors induced only tumor growth inhibition, whereas dual MET/EGFR inhibition led to complete tumor regression. Importantly, the combo treatment completely prevented the onset of resistance, which quite rapidly appeared in tumors treated with MET monotherapy. We found that this secondary resistance was due to EGFR activation and could be overcome by dual MET/EGFR inhibition. Similar results were also obtained in a MET-addicted, established gastric cancer cell line. In vitro experiments performed on tumor-derived primary cells confirmed that MET inhibitors were not able to abrogate the activation of downstream transducers and that only the combined MET/EGFR treatment completely shut off the signaling. Previously reported cases, as well as those described here, showed only partial and transient sensitivity to anti-MET therapy. The finding that combined anti-MET/EGFR therapy-even in the absence of EGFR genetic alterations-induced complete and durable response, represents a proof of concept and guarantees further investigations, opening a new perspective of treatment for these patients.

137Cs and 40K soil-to-plant relationship in a seminatural grassland of the Giulia Alps, Italy.

To examine the soil-to-plant transfer of 137Cs and 40K, we performed a study based on sampling of natural soil and plants from an alpine pasture site situated in the Giulia Alps, Italy, during July 1997. High 137Cs activity was present in the upper most soil layer, and decreased one order of magnitude at a depth of 10 cm. An opposite gradient was observed for 40K. Simultaneous sampling of soil and plant material was performed in order to analyse transfer factor (TF) values. In spite of homogeneous 137Cs activities in soil, grass samples showed a high variability. A negative correlation was detected between 40K- and 137Cs-activities in plants. TF values for 137Cs were highly variable, thus suggesting that this parameter would be independent of 137Cs soil activity. Lower variability was observed for 40K TFs values. Our results suggest that TFs are highly variable parameters that appear to be independent on radionuclide soil activity. Because soil and plant characteristics strongly affect TF values, caution is necessary when TF values are used as the sole parameter to predict radionuclide uptake by plants in semi-natural ecosystems.

Ingested soil as a source of 137Cs to ruminants.

Ingestion of soil has been identified as a potentially important source of radionuclides, particularly to grazing ruminants. Soil artificially contaminated with radiocaesium was administered orally each day for 33 days to Bergamasca sheep and the transfer to milk measured. Two soil types were used, with a clay content of 11% and 16%, respectively. Transfer coefficient (fm) values to sheep milk, calculated at the equilibrium (period from 7th to 21st day after soil administration), were 3.72 x 10(-4) days l-1 (S.D. = 7.2 x 10(-5) days l-1) and 6.11 x 10(-4) days l-1 (S.D. = 9.1 x 10(-5) days l-1), respectively for the two soils. These low values indicate that radiocaesium is not removed from the binding sites on the clay minerals in the gut of the sheep.

Vertical transport of radiocesium in surface soils: model implementation and dose-rate computation.

A mathematical model on the Radionuclide Behaviour in Soil for the study of the migration of radionuclides in undisturbed soil profile has been developed. The model has been calibrated using 134Cs and 137Cs concentrations along soil samples gathered in a natural grassland and beech wood, respectively, located in the Friuli-Venezia Giulia region (northeastern part of Italy). In these sampling sites, the external exposure due to 134Cs and 137Cs distribution along the soil profile has been also assessed.

Transfer of Chernobyl fall-out caesium radioisotopes in the cow food chain.

From February to October 1987 samples of milk, grass and other components of the cow diet were regularly collected and analyzed for their radiocaesium contents in 26 sampling stations in a north-eastern region of Italy (Friuli-Venezia Giulia). In this paper we report the feed-to-milk transfer factors for radiocaesium obtained in 13 farms of this region of Italy.