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Overall Survival (OS) and late quality of life of patients with locally advanced, HPV-negative Head and Neck Squamous Cell Cancer (HNSCC) are not satisfactory. Nutritional status at the beginning of both surgical and non-surgical treatment with curative intent has been linked to OS and quality of life. Weight loss, body-mass index, functional parameters, and biochemical examinations have been associated with the risk of treatment-related adverse events, mortality, quality of life and outcome. Moreover, there is a strong need for effective preventive approaches that could be implemented after completion of curative treatment to reduce recurrences, second tumors and improve quality of life. Aerobic exercise training, which is known to stimulate the immune system, and nutritional interventions represent easy, acceptable and reproducible methods to increase immune and nutritional competence, impacting thus on the aforementioned objectives. Participating in exercise training programs has been well accepted by patients with HNSCC, underlining the feasibility of such an intervention. There are also immunological arguments to promote an adequate physical activity in HNSCC patients. Baseline and after treatment immune competence of HNSCC should be weighted, as it may impact on cancer recurrence and OS. Patients with HNSCC have significantly lower absolute numbers of CD3+, CD4+ and CD8 + T cells than normal controls, and lymphocyte counts, neutrophil/lymphocyte ratio and the prognostic nutritional index (PNI) are associated with prognosis. Aerobic exercise training prevents immune senescence, and therefore may prevent cancer development. The immune system activity is accompanied by an increased rate of metabolism, requiring energy sources, substrates for biosynthesis and regulatory molecules, which are ultimately derived from the diet. Hence, an adequate supply of a wide range of nutrients is essential to support the immune system to function optimally. Therefore, a regular nutritional counselling combined with personalized exercise training is a simple and very cheap way that could improve patient’s nutritional condition and immunological function, and ultimately impact on survival and quality of life. There is a strong need for well conducted clinical trials aimed at evaluating, in homogeneous groups of HNSCC patients, the impact of nutritional interventions (also comprising immunonutrition) and physical exercise. The evaluation of surrogate endpoints like circulating immune cells should also be explored to identify feasible and effective interventions. Integrating these interventions within immunotherapy approaches represents another area deserving further studies.

Despite the progress of surgery, radiotherapy, and neoadjuvant chemotherapy, the prognosis for advanced sinonasal cancers (SNCs) remains poor. In the era of precision medicine, more research has been conducted on the molecular pathways and recurrent mutations of SNCs, with the aim of understanding carcinogenesis, helping with diagnosis, identifying prognostic factors, and finding potentially targetable mutations. In the treatment of SNC, immunotherapy is rarely used, and no targeted therapies have been approved, partly because these tumors are usually excluded from major clinical trials. Data on the efficacy of targeted agents and immune checkpoint inhibitors are scarce. Despite those issues, a tumor-agnostic treatment approach based on targeted drugs against a detected genetic mutation is growing in several settings and cancer subtypes, and could also be proposed for SNCs. Our work aims to provide an overview of the main molecular pathways altered in the different epithelial subtypes of sinonasal and skull base tumors, focusing on the possible actionable mutations for which potential target therapies are already approved in other cancer types.