Targeting the MET Receptor Tyrosine Kinase as a Strategy for Radiosensitization in Locoregionally Advanced Head and Neck Squamous Cell Carcinoma.

Radiotherapy (RT) along with surgery is the mainstay of treatment in head and neck squamous cell carcinoma (HNSCC). Radioresistance represents a major source of treatment failure, underlining the urgent necessity to explore and implement effective radiosensitization strategies. The MET receptor widely participates in the acquisition and maintenance of an aggressive phenotype in HNSCC and modulates the DNA damage response following ionizing radiation (IR). Here, we assessed MET expression and mutation status in primary and metastatic lesions within a cohort of patients with advanced HNSCC. Moreover, we investigated the radiosensitization potential of the MET inhibitor tepotinib in a panel of cell lines, in vitro and in vivo, as well as in ex vivo patient-derived organotypic tissue cultures (OTC). MET was highly expressed in 62.4% of primary tumors and in 53.6% of lymph node metastases (LNM), and in 6 of 9 evaluated cell lines. MET expression in primaries and LNMs was significantly associated with decreased disease control in univariate survival analyses. Tepotinib abrogated MET phosphorylation and to distinct extent MET downstream signaling. Pretreatment with tepotinib resulted in variable radiosensitization, enhanced DNA damage, cell death, and G2-M-phase arrest. Combination of tepotinib with IR led to significant radiosensitization in one of two tested in vivo models. OTCs revealed differential patterns of response toward tepotinib, irradiation, and combination of both modalities. The molecular basis of tepotinib-mediated radiosensitization was studied by a CyTOF-based single-cell mass cytometry approach, which uncovered that MET inhibition modulated PI3K activity in cells radiosensitized by tepotinib but not in the resistant ones.

A Clinical and Radiological Approach to the Management of Benign Mesenchymal Sinonasal Tumors.

PURPOSE: Benign mesenchymal sinonasal neoplasms (BMSN) are rare and histologically heterogeneous. Differential diagnosis, appropriate management, and outcome are still a matter of debate. The aim of this study is to provide evidence for further refinement of assessment and treatment in the future. PROCEDURES: We retrospectively reviewed data on 93 patients with neuroradiologically verified BMSN treated at our university reference center during the past 22 years. RESULTS: The most frequent BMSN recorded in our cohort was osteoma of the frontal sinus. Only one-third of the patients affected were symptomatic at initial presentation. The 2 other common fibro-osseous tumor entities, fibrous dysplasia and ossifying fibroma, were confirmed in 12 and 6 patients, respectively. Patients with soft tissue tumor entities such as hemangioma, glomangiopericytoma, angiofibroma, and hamartoma were all symptomatic and underwent surgical resection. CONCLUSION: Understanding and recognizing the spectrum of appearances of benign mesenchymal sinonasal tumors will improve patient assessment and clinical management. The pathognomonic neuroradiological signs of a particular tumor entity should be actively sought as the neuroradiological features may be the diagnostic clues. Computed tomography and magnetic resonance imaging play complementary roles in identifying the morphological details and locoregional staging of benign mesenchymal sinonasal tumors.