Monitoring reversal of MET-mediated resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer using 3'-deoxy-3'-[18F]-fluorothymidine positron emission tomography.

PURPOSE: MET amplification is one of the mechanisms underlying acquired resistance to EGFR tyrosine kinase inhibitors (TKI) in non-small cell lung cancer (NSCLC). Here, we tested whether 3'-deoxy-3'-[(18)F]-fluorothymidine ([(18)F]FLT) positron emission tomography/computerized tomography (PET/CT) can detect MET-mediated resistance to EGFR TKIs and monitor the effects of MET inhibitors in NSCLC. EXPERIMENTAL DESIGN: H1993 and H820 NSCLC cells with high and low levels of MET amplification, respectively, and HCC827-expressing MET, but without gene amplification, were tested for the effects of MET inhibitors on the EGFR pathway and proliferation both in vitro and in vivo. Nude mice bearing NSCLCs with and without MET amplification were subjected to [(18)F]FLT PET/CT before and after treatment with crizotinib or erlotinib (50 mg/kg and 100 mg/kg p.o. for 3 days). RESULTS: H1993 cells showed high responsiveness to MET inhibitors and were resistant to erlotinib. Conversely, HCC827 cells showed high sensitivity to erlotinib and were resistant to MET inhibitors. Accordingly, H1993 tumors bearing MET amplification showed a mean reduction in [(18)F]FLT uptake of 28% and 41% after low- and high-dose treatment with crizotinib for 3 days, whereas no posttherapy changes of [(18)F]FLT uptake were observed in HCC827 tumors lacking MET amplification. Furthermore, a persistently high [(18)F]FLT uptake was observed in H1993 tumors after treatment with erlotinib, whereas HCC827 tumors showed up to 39% reduction of [(18)F]FLT uptake following erlotinib treatment. Imaging findings were confirmed by Ki67 immunostaining of tumor sections. CONCLUSIONS: [(18)F]FLT PET/CT can detect MET-mediated resistance to EGFR TKIs and its reversal by MET inhibitors in NSCLC.

Assessment of dual-energy x-ray absorptiometry for use in evaluating the effects of dietary and environmental management on Hermann's tortoises (Testudo hermanni).

OBJECTIVE: To assess dual-energy x-ray absorptiometry (DXA) for evaluating effects of diet and environment on bone mineral density in Hermann's tortoises (Testudo hermanni). ANIMALS: 26 Hermann's tortoises within 1 month after hatching. PROCEDURES: Group 1 was housed in an artificial setting and fed naturally growing vegetation. Group 2 was housed in an artificial setting and fed vegetables grown for human consumption. Group 3 was maintained in an outside enclosure and fed naturally growing vegetation. After 10 months, pyramidal growth, body weight, and adverse conditions were assessed. Bone mineral density (BMD) of the axial and appendicular skeleton, shell, vertebral column, and pelvis was measured via DXA. RESULTS: Group 2 had the highest mean ± SD body weight (65.42 ± 30.85 g), followed by group 1 (51.08 ± 22.92 g) and group 3 (35.74 ± 7.13 g). Mean BMD of the shell varied significantly among groups (group 1, 0.05 ± 0.03 g/cm(2)•m; group 2, 0.09 ± 0.15 g/cm(2)•m; and group 3, undetectable). The BMD of the axial and appendicular skeleton, vertebral column, and pelvis did not differ significantly among groups. Pyramidal growth was highest in group 1 and not evident in group 3. CONCLUSIONS AND CLINICAL RELEVANCE: Tortoises raised in artificial conditions did not have deficits in BMD, compared with results for outdoor-housed hibernating tortoises. Supplemental calcium was apparently not necessary when an adequate photothermal habitat and plant-based diet were provided. Higher BMD of captive-raised tortoises was morphologically associated with a higher incidence of pyramidal growth in captive-raised groups.