Insulin-like growth factor receptor 1 (IGFR-1) is significantly associated with longer survival in non-small-cell lung cancer patients treated with gefitinib.

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.

HER3 genomic gain and sensitivity to gefitinib in advanced non-small-cell lung cancer patients.

In non-small-cell lung cancer (NSCLC), sensitivity to tyrosine kinase inhibitors (TKIs) is associated with activating mutations and genomic gain of the epidermal growth factor receptor (EGFR). Preclinical data suggested that HER3 overexpression increases sensitivity to TKIs. A total of 82 NSCLC patients treated with gefitinib (250 mg), and previously evaluated for EGFR and HER2 status by fluorescence in situ hybridisation (FISH) and DNA sequencing, and for Phospho-Akt status by immunohistochemistry, were investigated for HER3 genomic gain by FISH. Patients with high polysomy and gene amplification were considered as HER3 FISH positive (+). HER3 FISH+ pattern was significantly associated with female gender (P=0.02) and never smoking history (P=0.02). Patients with HER3+ tumours (26.8%) had a significantly longer time to progression (3.7 vs 2.7, P=0.04) than patients with HER3- tumours, but not a significantly better response rate or survival. Patients with EGFR+/HER3+ tumours had higher objective response rate (36.4 vs 9.9%, P=0.03) and time to progression (7.7 vs 2.7 months, P=0.03) than patients with EGFR- and/or HER3- tumours, but no significantly longer survival. No difference in response was observed according to HER3 status in patients with EGFR+ tumours. Patients with HER2+/HER3+ tumours had similar outcome as patients with HER2- and/or HER3- tumours. Significantly different clinical end points were not observed between patients with HER3+/P-Akt+ and HER3- and/or P-Akt- tumours. Genomic gain for HER3 is not a marker for response or resistance to TKI therapy in advanced NSCLC patients.

Exposure of personnel to sevoflurane during paediatric anaesthesia: influence of professional role and anaesthetic procedure.

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 <0.00001 for breathing zone sevoflurane, P < 0.05 and <0.01 for urinary sevoflurane, respectively). CONCLUSIONS: Anaesthesia with sevoflurane can pose a hazard of chronic exposure with anaesthetists having the highest risk. Endotracheal intubation offers considerable protection against exposure. Routine anaesthesia using a standard facemask, a laryngeal mask or rigid bronchoscopy are risk factors for increased anaesthetic exposure.