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Introduction Surgical treatment of maxillary tumours is often highly complex. The three-dimensional anatomy of the mid-face renders both correct intraoperative orientation and adequate oncological safety difficult to obtain. Recently, computer-assisted techniques and intraoperative navigation have been applied to oncological surgery treating head and neck cancer. However, only a few studies have explored whether preoperative virtual resection planning and intraoperative control of resection margins allow assessment of the surgical margins of the tumour. In our present feasibility study, we developed a protocol for preoperative mapping of tumour margins using computed tomography and/or magnetic resonance imaging, virtual planning of the surgical resection, and intraoperative navigation during actual resection of advanced maxillary tumours. Materials and methods Twenty patients were included in this feasibility study. We prospectively selected ten patients requiring surgery to treat malignant maxillary tumours. A control group of ten patients was retrospectively selected. The simulation protocol featured the following steps: 1. “Contouring” of the tumour: identification of the tumour and the borders thereof on the axial, sagittal, and coronal planes; 2. Definition of the resection margins by positioning “landmarks” at least 1 cm from the tumour edges on the axial, sagittal, and coronal planes; 3. Simulation of osteotomy lines passing through the landmarks, and evaluation of the bony defects to be reconstructed. Tumour margins were controlled by using a pointer to identify mobilised regions and then checking the overlap between the planned resection (shown on the LCD screen of the navigation system) and the real anatomical situation. Results A total of 127 margins were pathologically assessed in the test group, and 85 were assessed in the control group. Overall, 9% of surgical margins were positive in the test group, and 16% were positive in the control group (p = 0.0047). A significant difference was apparent in terms of deep margin evaluation: in test patients, 87% of margins were clear; this figure was 75% for the control group (p = 0.0038). No significant difference in either mucosal or bone margin clearance was evident. The preoperative planning errors were <5 mm for 91% of all planned resection margins. Conclusion The navigation-guided resection protocol seems to improve tumour-free margin status in patients with advanced maxillary tumours. Further confirmatory trial, enrolling a larger cohort of patients, is needed to strengthen these preliminary results and advantages of this procedure. [ABSTRACT FROM AUTHOR]