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Background: Gefitinib is a selective inhibitor of the epidermal growth factor (EGFR) tyrosine kinase, which is overexpressed in many cancers, including non-small-cell lung cancer (NSCLC). We carried out a clinical study to compare the relationship between EGFR gene copy number, EGFR protein expression, EGFR mutations, and Akt activation status as predictive markers for gefitinib therapy in advanced NSCLC. Methods: Tumors from 102 NSCLC patients treated daily with 250 mg of gefitinib were evaluated for EGFR status by fluorescence in situ hybridization (FISH), DNA sequencing, and immunohistochemistry and for Akt activation status (phospho-Akt [P-Akt]) by immunohistochemistry. Time to progression, overall survival, and 95% confidence intervals (CIs) were calculated and evaluated by the Kaplan-Meier method; groups were compared using the log-rank test. Risk factors associated with survival were evaluated using Cox proportional hazards regression modeling and multivariable analysis. All statistical tests were two-sided. Results: Amplification or high polysomy of the EGFR gene (seen in 33 of 102 patients) and high protein expression (seen in 58 of 98 patients) were statistically significantly associated with better response (36% versus 3%, mean difference = 34%, 95% CI = 16.6 to 50.3; P

OBJECTIVES: Sevoflurane is an inhalation halogenated anaesthetic widely used in day and paediatric surgery. We were interested in evaluating biological markers of exposure to sevoflurane, which should improve the health surveillance of occupationally exposed personnel. METHODS: A group of 36 subjects (13 male, 23 female) occupationally exposed to volatile anaesthetics in paediatric operating rooms was studied in a 2-week survey. Post-shift urine samples and specimens from passive samplers (for personal monitoring) were collected after 1.75-6 h morning exposure and analysed by headspace gas chromatography-mass spectrometry (GC-MS). Multiple determinations were assumed as independent values (in total, n = 78: 24 from men, 54 from women; 25 from smokers, 53 from non-smokers). RESULTS: Median sevoflurane external values were 0.13 parts per million (ppm) (range 0.03-18.82) (n = 78), urinary sevoflurane 0.6 microg/l urine (ND-18.5)(n = 76) and total urinary hexafluoro-isopropanol (HFIP) 0.49 mg/l urine (ND-6833.4) (n = 75). A lower limit of detection (LOD) was achieved for urinary sevoflurane (0.03 microg/l urine), allowing quantitation of all but one of the samples; >25% of urine samples were unquantifiable by HFIP and were assigned a value equal to half the LOD of 0.10 mg/l(urine). Urinary sevoflurane correlated well with breathing-zone data (r2 = 0.697 at log-log linear regression), whereas total urinary HFIP (r2 = 0.562 at log-log linear regression) seemed to be better described by a three-parameter logistic function and appeared to be influenced by smoking habits. Biological indices corresponding to National Institute for Occupational Safety and Health (NIOSH) exposure limits, calculated as means of linear regression slope and y intercept, were 3.9 mug/l(urine) and 1.4 microg/l urine for sevoflurane (corresponding to 2 ppm and 0.5 ppm, respectively), and 2.66 mg/l urine and 0.82 mg/l urine for HFIP. CONCLUSIONS: On the basis of our data, urinary unmodified, sevoflurane seems to be a more sensitive and reliable biomarker of short-term exposure to sevoflurane with respect to total urinary metabolite HFIP, which appears to be influenced by physiological and/or genetic individual traits, and seems to provide an estimate of integrated exposure

Background: The aim of the study was to assess whether loss of PTEN and expression of insulin-like growth factor receptor 1 (IGFR-1) could be responsible for intrinsic resistance to the tyrosine kinase inhibitor (TKI) gefitinib. Patients and methods: One hundred and twenty-four gefitinib-treated patients with advanced non-small-cell lung cancer (NSCLC) were analyzed for PTEN and IGFR-1 expression by immunohistochemistry. Results: IGFR-1 was evaluated in 77 patients and resulted positive in 30 (39.0%). IGFR-1 expression was not significantly associated with clinical or biological characteristics. No difference in response to gefitinib treatment (16.7% versus 12.8%, P = 0.74) and time to progression (2.6 versus 3.06 months, P = 0.83) was observed between IGFR-1+ and IGFR-1–. Median survival was significantly longer in IGFR-1+ patients (17.8 versus 7.3 months, P = 0.013). PTEN expression was successfully evaluated in 93 cases. Loss of PTEN was detected in 19 tumors (20.4%) and was not associated with any clinical or biological characteristic. No difference in terms of response, time to progression and survival was observed between PTEN+ and PTEN– patients. In multivariable analysis IGFR-1 negative status was significantly associated with higher risk of death (hazard ratio 2.21, P = 0.012). Conclusions: IGFR-1 expression and loss of PTEN are not associated with intrinsic resistance to gefitinib. Clinical relevance of these two biomarkers as determinant for acquired resistance, and the prognostic role of IGFR-1 expression in patients not exposed to TKIs should be evaluated further.

BACKGROUND AND OBJECTIVE: This study was performed to determine the individual exposure of paediatric operating theatre personnel to sevoflurane and to evaluate the impact of inhalation induction and various airway approaches on exposure to airborne sevoflurane. METHODS: Mean individual environmental (workplace air) exposure to sevoflurane and a biomarker of exposure (urinary sevoflurane) were monitored in 36 subjects (10 anaesthetists, 10 surgeons, 12 nurses and 4 auxiliary personnel) working in two paediatric operating rooms. RESULTS: Environmental and urinary values were significantly greater in anaesthetists compared with other groups, with median values of 0.65ppm (interquartile range 1.36; 95th percentile 4.36) for breathing zone sevoflurane and 2.1 microgL(-1) urine (interquartile range 2.6; 95th percentile 7.6) for urinary sevoflurane. Anaesthetists exceeded the 2ppm maximum allowed environmental concentration recommended by the National Institute for Occupational Safety and Health in 4 of 22 cases (18.1%). A positive correlation was found between the number of patients undergoing inhalational induction each day and mean values of breathing zone and urinary sevoflurane. An increase in the number of daily laryngeal mask insertions, or the use of rigid bronchoscopy, are statistically related to higher environmental and urinary values (P < 0.01 and