Tumour-free margins ( >5 mm) in head and neck malignancies improve prognosis, possibly impacting the need for adjuvant treatment. In this phase II prospective, non-randomised trial (NCT05499065), we investigate the use of fluorescence imaging using the tumour targeting fluorescent tracer cetuximab-IRDye800CW combined with fresh frozen sectioning to identify inadequate margins intraoperatively in patients with oral squamous cell carcinoma. Primary objectives of our study are intraoperative detection of inadequate margins and additional resections, and feasibility of implementing fluorescence-guided fresh frozen sectioning (FG-FFS) into the clinical workflow. In this study, 10 out of 20 patients show inadequate margins after initial surgery; FG-FFS correctly classifies margin in 19 patients. Additional resections increase tumour-free margin rates from 50% to 85%, where anatomical boundaries limit further improvement in one patient. Intraoperative margin adjustment reduces the need for adjuvant treatment in seven patients. These findings demonstrate that FG-FFS is a reliable and feasible method for intraoperative margin assessment without delaying surgery.

Background: Three-dimensional virtual surgical planning (Three-dimensional VSP) has become standard practice in the treatment of mandibular oral squamous cell carcinoma (OSCC) in the last decade. Dutch guidelines recommend a care pathway interval (CPI) of a maximum of 30 days, and a free bone margin of at least 5 mm. Fused MRI and CT data are used for accurate tumor delineation. Based on this data, a virtual surgical plan is created and transferred to the operating room using resection guides and patient-specific implants (PSIs). Long-term evaluation is needed to further optimize its clinical use. Objectives: This study evaluates adherence to bone margin and CPI guidelines in mandibular OSCC. Additionally, it assesses the accuracy of tumor resection and reconstruction using 3D-VSP and compares the complications of 3D-planned mandibular reconstruction using different kinds of osteosynthesis plates. Methods: All patients who underwent a segmental mandibulectomy between 2014 and 2024 at the University Medical Center Groningen were included. CPI, clinical outcomes, and complications were analyzed. The preoperative virtual plan was compared with the postoperative outcome to assess accuracy. Results: The median CPI was 34 days, and 93.7% of bone margins were tumor-free. Mean absolute resection deviation was 1.63 mm (±1.42). PSI reconstructions were significantly more accurate in intergonial distance and coronal angle compared to conventional plates. Plate-related complications were more common in non-bony reconstructions; PSI reconstructions showed significantly more plate exposure. Conclusions: 3D-VSP leads to high accuracy in resection and reconstruction and favorable bone margins. Shortening the CPI and reducing biological complications are essential to further improve oncological outcomes.

Inadequate surgical margins occur frequently in oral squamous cell carcinoma surgery. Fluorescence molecular imaging (FMI) has been explored for intraoperative margin assessment, but data are limited to phase-I studies. In this single-arm phase-II study (NCT03134846), our primary endpoints were to determine the sensitivity, specificity and positive predictive value of cetuximab-800CW for tumor-positive margins detection. Secondary endpoints were safety, close margin detection rate and intrinsic cetuximab-800CW fluorescence. In 65 patients with 66 tumors, cetuximab-800CW was well-tolerated. Fluorescent spots identified in the surgical margin with signal-to-background ratios (SBR) of ≥2 identify tumor-positive margins with 100% sensitivity, 85.9% specificity, 58.3% positive predictive value, and 100% negative predictive value. An SBR of ≥1.5 identifies close margins with 70.3% sensitivity, 76.1% specificity, 60.5% positive predictive value, and 83.1% negative predictive value. Performing frozen section analysis aimed at the fluorescent spots with an SBR of ≥1.5 enables safe, intraoperative adjustment of surgical margins.

Objective: New techniques have emerged to aid in preventing inadequate margins in oral squamous cell carcinoma (OSCC) surgery, but studies comparing different techniques are lacking. Here, we compared narrow band imaging (NBI) with fluorescence molecular imaging (FMI), to study which intraoperative technique best assesses the mucosal tumour margins. Materials and Methods: NBI was performed in vivo and borders were marked with three sutures. For FMI, patients received 75 mg of unlabelled cetuximab followed by 15 mg cetuximab-800CW intravenously-two days prior to surgery. The FMI borders were defined on the excised specimen. The NBI borders were correlated with the FMI outline and histopathology. Results: Sixteen patients were included, resulting in 31 NBI and 30 FMI measurements. The mucosal border was delineated within 1 mm of the tumour border in 4/31 (13 %) of NBI and in 16/30 (53 %) FMI cases (p = 0.0008), and within 5 mm in 23/31 (74 %) of NBI and in 29/30 (97 %) of FMI cases (p = 0.0048). The median distance between the tumour border and the imaging border was significantly greater for NBI (3.2 mm, range -6.1 to 12.8 mm) than for FMI (0.9 mm, range -3.0 to 7.4 mm; p = 0.028). Submucosal extension and previous irradiation reduced NBI accuracy. Conclusion: Ex vivo FMI performed more accurately than in vivo NBI in mucosal margin assessment, mainly because NBI cannot detect submucosal extension. NBI adequately identified the mucosal margin especially in early-stage and not previously irradiated tumours, and may therefore be preferable in these tumours for practical and cost-related reasons.

Intra-operative management of the surgical margin in patients diagnosed with head and neck squamous cell carcinoma (HNSCC) remains challenging as surgeons still have to rely on visual and tactile information. Fluorescence-guided surgery using tumor-specific imaging agents can assist in clinical decision-making. However, a standardized imaging methodology is lacking. In this study, we determined whether a standardized, specimen-driven, fluorescence imaging framework using ONM-100 could assist in clinical decision-making during surgery. Thirteen patients with histologically proven HNSCC were included in this clinical study and received ONM-100 24 ± 8 h before surgery. Fluorescence images of the excised surgical specimen and of the surgical cavity were analyzed. A fluorescent lesion with a tumor-to-background ratio (TBR) > 1.5 was considered fluorescence-positive and correlated to standard of care (SOC) histopathology. All six tumor-positive surgical margins were detected immediately after excision using fluorescence-guided intra-operative imaging. Postoperative analysis showed a median TBR (±IQR) of the fluorescent lesions on the resection margin of 3.36 ± 1.62. Three fluorescence-positive lesions in the surgical cavity were biopsied and showed occult carcinoma and severe dysplasia, and a false-positive fluorescence lesion. Our specimen-driven fluorescence framework using a novel, pH-activatable, fluorescent imaging agent could assist in reliable and real-time adequate clinical decision-making showing that a fluorescent lesion on the surgical specimen with a TBR of 1.5 is correlated to a tumor-positive resection margin. The binary mechanism of ONM-100 allows for a sharp tumor delineation in all patients, giving the surgeon a clinical tool for real-time margin assessment, with a high sensitivity.

In most oral cancer patients, surgical treatment includes resection of the primary tumor combined with excision of lymph nodes (LNs), either for staging or for treatment. All LNs harvested during surgery require tissue processing and subsequent microscopic histopathologic assessment to determine the nodal stage. In this study, we investigated the use of the fluorescent tracer cetuximab-800CW to discriminate between tumor-positive and tumor-negative LNs before histopathologic examination. Here, we report a retrospective ad hoc analysis of a clinical trial designed to evaluate the resection margin in patients with oral squamous cell carcinoma (NCT02415881). Methods: Two days before surgery, patients were intravenously administered 75 mg of cetuximab followed by 15 mg of cetuximab800CW, an epidermal growth factor receptor-targeting fluorescent tracer. Fluorescence images of excised, formalin-fixed LNs were obtained and correlated with histopathologic assessment. Results: Fluorescence molecular imaging of 514 LNs (61 pathologically positive nodes) could detect tumor-positive LNs ex vivo with 100% sensitivity and 86.8% specificity (area under the curve, 0.98). In this cohort, the number of LNs that required microscopic assessment was decreased by 77.4%, without missing any metastases. Additionally, in 7.5% of the LNs false-positive on fluorescence imaging, we identified metastases missed by standard histopathologic analysis. Conclusion: Our findings suggest that epidermal growth factor receptor-targeted fluorescence molecular imaging can aid in the detection of LN metastases in the ex vivo setting in oral cancer patients. This image-guided concept can improve the efficacy of postoperative LN examination and identify additional metastases, thus safeguarding appropriate postoperative therapy and potentially improving prognosis.

AbstractIntroductionWhen the application of a free vascularised flap is not possible, a segmental mandibular defect is often reconstructed using a conventional reconstruction plate. Mechanical failure of such reconstructions is mostly caused by plate fracture and screw pull‐out. This study aims to develop a reliable, mechanically superior, yet slender patient‐specific reconstruction plate that reduces failure due to these causes.Patients and MethodsEight patients were included in the study. Indications were as follows: fractured reconstruction plate (2), loosened screws (1) and primary reconstruction of a mandibular continuity defect (5). Failed conventional reconstructions were studied using finite element analysis (FEA). A 3D virtual surgical plan (3D‐VSP) with a novel patient‐specific (PS) titanium plate was developed for each patient. Postoperative CBCT scanning was performed to validate reconstruction accuracy.ResultsAll PS plates were placed accurately according to the 3D‐VSP. Mean 3D screw entry point deviation was 1.54 mm (SD: 0.85, R: 0.10–3.19), and mean screw angular deviation was 5.76° (SD: 3.27, R: 1.26–16.62). FEA indicated decreased stress and screw pull‐out inducing forces. No mechanical failures appeared (mean follow‐up: 16 months, R: 7–29).ConclusionReconstructing mandibular continuity defects with bookshelf‐reconstruction plates with FEA underpinning the design seems to reduce the risk of screw pull‐out and plate fractures.

Tumor-positive resection margins are present in up to 23% of head and neck cancer (HNC) surgeries, as intraoperative techniques for real-time evaluation of the resection margins are lacking. In this study, we investigated the safety and potential clinical value of fluorescence-guided imaging (FGI) for resection margin evaluation in HNC patients. We determined the optimal cetuximab-800CW dose by quantification of intrinsic fluorescence values using multi-diameter single-fiber reflectance, single-fiber fluorescence (MDSFR/SFF) spectroscopy. Methods: Five cohorts of three HNC patients received cetuximab-800CW systemically: three single dose cohorts (10, 25, 50 mg) and two cohorts pre-dosed with 75 mg unlabeled cetuximab (15 or 25 mg). Fluorescence visualization and MDSFR/SFF spectroscopy quantification was performed and were correlated to histopathology. Results: There were no study-related adverse events higher than Common Terminology Criteria for Adverse Events grade-II. Quantification of intrinsic fluorescence values showed a dose-dependent increase in background fluorescence in the single dose cohorts (p<0.001, p<0.001), which remained consistently low in the pre-dosed cohorts (p=0.6808). Resection margin status was evaluated with a sensitivity of 100% (4/4 tumor-positive margins) and specificity of 91% (10/11 tumor-negative margins). Conclusion: A pre-dose of 75 mg unlabeled cetuximab followed by 15 mg cetuximab-800CW was considered the optimal dose based on safety, fluorescence visualization and quantification of intrinsic fluorescence values. We were able to use a lower dose cetuximab-800CW than previously described, while remaining a high sensitivity for tumor detection due to application of equipment optimized for IRDye800CW detection, which was validated by quantification of intrinsic fluorescence values.

Background: 3D virtual planning and guided surgery has been proven to be an effective and safe tool for preparing resection and reconstruction of the mandible. Currently, most widely used 3D planning approaches to mandibular resection do not include detailed 3D tumor information in the virtual surgical planning.

Objectives In cT1‐2N0, oral squamous cell carcinoma (OSCC) occult metastases are detected in 23%‐37% of cases. Sentinel lymph node biopsy (SLNB) was introduced in head and neck cancer as a minimally invasive alternative for an elective neck dissection in neck staging. Meta‐analyses of SLNB accuracy show heterogeneity in the existing studies for reference standards, imaging techniques and pathological examination. The aim of this study was to assess the sensitivity and negative predictive value (NPV) of the SLNB in detecting occult metastases in cT1‐2N0 OSCC in a well‐defined cohort. Design Retrospective study. The SLNB procedure consisted of lymphoscintigraphy, SPECT/CT‐scanning and gamma probe detection. Routine follow‐up was the reference standard for the SLNB negative neck. Histopathological examination of sentinel lymph nodes (SLN) consisted of step serial sectioning, haematoxylin‐eosin and cytokeratin AE1/3 staining. Setting Two comprehensive oncology centres. Participants A total of 91 consecutive patients with primary cT1‐2N0 OSCC treated by primary resection and neck staging by SLNB procedure between 2008 and 2016. Main outcome measures Sensitivity and negative predictive value. Results In all cases, SLNs were harvested. A total of 25 (27%) patients had tumour‐positive SLNs. The median follow‐up was 32 months (range 2‐104). Four patients were diagnosed with an isolated regional recurrence in the SLNB negative neck side resulting in an 85% sensitivity and a 94% NPV. Conclusion In our cohort, the SLNB detected occult metastases in early OSCC with 85% sensitivity and 94% NPV. This supports that SLNB is a reliable procedure for surgical staging of the neck in case of oral cT1‐2N0 SCC.

A 74-year-old woman needed a subtotal bilateral maxillectomy due to squamous cell carcinoma of the palate. Immediate and secondary reconstruction of the defect was not feasible, so the defect was closed with an obturator prosthesis wired to the zygoma complex. To improve the patient's severely impaired speech and swallowing, a patient-specific sub-periosteal implant (psSPI) was designed that matched the remnants of the zygoma complex. First, the patient's post-surgical anatomy was visualized through segmentation of the pre- and post-maxillectomy computed tomography data. Next, based on the data, a customized zygoma-supported framework was designed to support the obturator prosthesis. Surgical guides for intraoperative navigation were designed and three-dimensionally printed, along with an obturator prosthesis to fit the planned outcome situation. The preoperatively manufactured psSPI and obturator prosthesis matched the intraoperative conditions. The postoperative results were favourable; within a week after surgery the patient could speak and swallow normally without nasal leakage. No problems occurred during follow-up. These results indicate that a psSPI-retained prosthesis can be considered for the restoration of speech and oral functioning in cases with a largely compromised maxillary bone anatomy, accompanied by impaired oral functioning and no feasible conventional reconstruction options.

OBJECTIVES:3D virtual surgical planning (VSP) and guided surgery has been proven to be an effective tool for resection and reconstruction of the mandible. Currently, most widely used 3D VSP approaches to mandibular resection do not include detailed tumour information in the VSP. This manuscript presents a strategy where the aim was to incorporate tumour visualisation into the 3D virtual plan. Three-dimensional VSP of the mandibular resections was based on the fusion of CT and MRI data which was subsequently applied in clinical practice. METHODS:All patients diagnosed with oral squamous cell carcinoma between 2014 and 2017 at the University Medical Centre Groningen were included. The tumour was delineated on the MRI data, after which this dataset was fused with the CT bone data in order to construct a 3D bone and tumour model for virtual resection planning. Guided resections were performed and post-operative evaluation quantified the accuracy of the resection. The histopathological findings and patient and tumour characteristics were compared to those of a historical cohort (2009-2014) of conventional mandibular continuity resections. RESULTS:Twenty-four patients were included in the cohort. The average deviation from planned resection was found to be 2.2 mm. Histopathologic analysis confirmed all resection planes (bone) were tumour free, compared to 96.4% in the historic cohort. CONCLUSION:MRI-CT base tumour visualisation and 3D resection planning is a safe and accurate method for oncologic resection of the mandible. It is an improvement on the current methods reported for 3D resection planning based solely on CT data.

Purpose: In mandibular reconstructive surgery, the osteosynthesis plates require contouring according to the patients' individual anatomical situation. These plates are frequently contoured around a three-dimensional (3D) printed model. However, the translation to the actual patient can introduce inaccuracies and unwanted rotations in the condyles and mandibular ramus, due to malpositioning of the pre-contoured plate. Materials and methods: This article describes an easy-access method for exact translation of the pre-contoured plate to the patient's mandible. This is done by using 3D printed guides that allow predrilling of screw holes in both the contour model and the patients' mandible. The accuracy of the Key Printed Solution was analysed by comparing the anatomical landmarks on both the 3D planned and post-operative models. Results: The method was applied to 4 cases. All landmarks were identified on both the 3D planning and post-operative computed tomographic data. This showed an average deviation of 1.0 mm between planning and the post-operative result. The inter-observer variation was 0.6 mm (intra-class correlation, 0.75). Conclusion: This article presents an easy-to-use method for pre-bending the osteosynthesis plate and subsequent accurate translation of the intended contour with corresponding screw hole locations. The method was proved to be accurate and time-efficient. (C) 2018 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

Objective. Assessment of the impact of a sentinel node biopsy (SNB) based strategy in cT1/T2 N0 oral cancer on the course of health related quality of life, psychological distress, and shoulder disability, and evaluation of the patients' perspective on neck management strategies.Study Design. Fifty-two patients (39 SNB negative; 13 SNB positive) completed the European Organization for Research and Treatment of Cancer (EORTC) questionnaires-QLQ-C30 and QLQ-H&N35, and the HADS, IES, and SDQ questionnaires at baseline, after SNB diagnosis and at 6 months of follow-up. Objective shoulder measurements were performed after 2 years and interviews were conducted after 4.5 months of follow-up.Results. All the scores of the questionnaires were not significantly different between SNB negative and SNB positive patients. Objective shoulder functioning was similar. Most patients preferred a SNB-based strategy to an elective neck dissection strategy.Conclusions. The impact of a SNB-based strategy in patients with cT1/T2 N0 oral cancer is comparable for SNB-negative and SNB-positive patients in terms of health-related quality of life, psychological distress and shoulder functioning. Most patients preferred the SNB-based strategy over the elective neck dissection strategy.

Background. There is debate if the lymphatic drainage pattern of oral maxillary cancer is to the retropharyngeal lymph nodes or to the cervical lymph nodes. Insight in drainage patterns is important for the indication for neck treatment. The purpose of this study was to identify the lymphatic drainage pattern of oral maxillary cancer via preoperative lymphoscintigraphy.Methods. Eleven consecutive patients with oral maxillary cancer treated in our center between December 1, 2012, and April 22, 2016 were studied. Sentinel lymph nodes identified by preoperative lymphoscintigraphy after injection of Tc-99m-nanocolloid and by intraoperative detection using a gamma-probe, were surgically removed and histopathologically examined.Results. In 10 patients, sentinel lymph nodes were detected and harvested at cervical levels I, II, or III in the neck. In 2 patients, a parapharyngeal sentinel lymph node was detected. One of the harvested sentinel lymph nodes (1/19) was tumor positive.Conclusion. This study suggests the likelihood of 73% of exclusively cervical level I to III sentinel lymph nodes in oral maxillary cancer. (C) 2016 Wiley Periodicals, Inc.

Leukoplakia of the oral mucosa is a potentially malignant disorder, which means that there is an elevated risk oftransformation into a squamous cell carcinoma. The term oral leukoplakia is a clinical diagnosis for a predominantly white lesion which is not immediately recognizable as another well definable lesion which is white in appearance. Oral leukoplakia is generally an asymptomatic disorder of the mucosa with a prevalence of less than 2 per cent in the adult population. Tobacco usage is considered to be the most important etiological factor. Malignant transformation into a squamous cell carcinoma occurs in about I per cent per year. A patient with oral leukoplakia is generally referred to an oral and maxillofacial surgeon, who takes a biopsy for a definitive histopathological diagnosis. The outcome of the histopathological study, which may vary from hyperkeratosis to invasive squamous cell carcinoma, will determine the treatment. It is preferable that every leukoplakia is removed to reduce the risk of malignant transformation. Long term follow-up is indicated. Follow-up may in some cases be performed by the general dental practitioner.

Objectives: Results of the Dutch multi-institutional trial on sentinel lymph node (SLN) biopsy in oral cancer.Patients and methods: Patients were consecutively enrolled from 4 institutions, with T1/T2 oral cancer and cN0 neck based on palpation and ultrasound guided fine needle aspiration cytology.Lymphatic mapping consisted of preoperative lymphoscintigraphy. For intraoperative SLN detection a gamma-probe was used and in some patients additional blue dye. SLN negative patients were carefully observed, SLN positive patients were treated by neck dissection, radiotherapy or a combination of both. Endpoints of the study were risk of occult lymp node metastases, neck control, accuracy, 5-year disease-free survival (DFS), overall survival (OS) and disease-specific survival (DSS).Results: Twenty of 62 patients (32%) had positive SLNs. Macrometastases were found in 9 patients, micrometastases in 8, and isolated tumour cells in 3 patients. Median follow-up was 52.5 months. Of the 42 SLN negative patients, 5 developed a regional recurrence of whom 4 patients could be successfully salvaged. DFS, OS and DSS of SLN negative patients were 72.0%, 92.7% and 97.4%, and for SLN positive patients these numbers were 73.7%, 79.7%, 85.0%, respectively (DFS: p = 0.916, OS: p = 0.134, DSS: p = 0.059, respectively). Neck control rate was 97% in SLN negative and 95% in SLN positive patients. Sensitivity was 80% and negative predictive value 88%.Conclusion: SLN biopsy is able to reduce the risk of occult lymph node metastases in T1/T2 oral cancer patients from 40% to 8%, and enables excellent control of the neck. (C) 2014 Elsevier Ltd. All rights reserved.