No abstract

Signal transduction via protein kinases is of central importance in cancer biology and treatment. However, the clinical success of kinase inhibitors is often hampered by a lack of robust predictive biomarkers, which is also caused by the discrepancy between kinase expression and activity. Therefore, there is a need for functional tests to identify aberrantly activated kinases in individual patients. Here we present a systematic analysis of the tyrosine kinases in head and neck cancer using such a testfunctional kinome profiling. We detected increased tyrosine kinase activity in tumors compared with their corresponding normal tissue. Moreover, we identified members of the family of Src kinases (Src family kinases [SFK]) to be aberrantly activated in the majority of the tumors, which was confirmed by additional methods. We could also show that SFK hyperphosphorylation is associated with poor prognosis, while inhibition of SFK impaired cell proliferation, especially in cells with hyperactive SFK. In summary, functional kinome profiling identified SFK to be frequently hyperactivated in head and neck squamous cell carcinoma. SFK may therefore be potential therapeutic targets. These results furthermore demonstrate how functional tests help to increase our understanding of cancer biology and support the expansion of precision oncology.

BACKGROUND: Transnasal flexible videoendoscopy (TVE) of the larynx is a standard of care for the detection and staging of pharyngolaryngeal lesions in otorhinolaryngology. Patients frequently present with existing TVE examinations before anesthesia. Although these patients are considered high risk, the diagnostic value of TVE for airway risk stratification is currently unknown. How can captured images or videos be used for anesthesia planning, and which lesions are most concerning? This study aimed to develop and validate a multivariable risk prediction model for difficult airway management based on TVE findings and to determine whether the discrimination of the Mallampati score can be improved by adding this new TVE model. METHODS: This retrospective single-center development and validation study assessed 4021 patients who underwent 4524 otorhinolaryngologic surgeries at the University Medical Centre Hamburg-Eppendorf between January 1, 2011, and April 30, 2018, with electronically stored TVE videos and included 1099 patients who underwent 1231 surgeries. TVE videos and anesthesia charts were systematically reviewed in a blinded fashion. The Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis was used for variable selection, model development, and cross validation. RESULTS: The prevalence of difficult airway management was 24.7% (304/1231). Lesions at the vocal cords, epiglottis, or hypopharynx were not selected by the LASSO regression, while lesions at the vestibular folds (ß-coefficient 0.123), supraglottic region (ß-coefficient 0.161), arytenoids (ß-coefficient 0.063), and viewing restrictions on the rima glottidis that cover ≥50% of the glottis area (ß-coefficient 0.485) and pharyngeal secretion retention (ß-coefficient 0.372) were relevant risk factors for difficult airway management. The model was adjusted for sex, age, and body mass index. The area under the receiver operating characteristic curve (95% confidence interval) of the Mallampati score was 0.61 (0.57–0.65) and 0.74 (0.71–0.78) of the TVE model combined with Mallampati ( P < .001). CONCLUSIONS: Stored images and videos from TVE examinations can be reused for the purpose of predicting risk associated with airway management. Vestibular fold, supraglottic, and arytenoid lesions are most concerning, especially if they are accompanied by secretion retention or restrict the glottic view. Our data indicate that the TVE model improves discrimination of the Mallampati score and might, therefore, be a useful addition to traditional bedside airway risk examinations.