BACKGROUND:Submandibular gland pathology is common but rarely reported. This study was performed to evaluate demographic, pathological, and survival outcomes associated with submandibular gland extirpation. METHODS:Retrospective analysis of patients treated in a single quaternary-care institution between 1989 and 2022 was performed. RESULTS:Four hundred and sixty patients underwent submandibular gland extirpation with a female preponderance (n = 271, 59%) and a mean age of 51 years. Older age was associated with increased risk of malignancy (P < 0.001). Submandibular calculus was the most common pathology, with gland extirpation for this indication decreasing over time (P = 0.005). Pleomorphic adenoma was the most common benign tumour (n = 96, 52.7% of total tumours), and adenoid cystic carcinoma was the most common malignant tumour (n = 25, 13.7% of total tumours). CONCLUSIONS:Submandibular calculus remains the most common indication for submandibular gland extirpation, although the rate is decreasing over time. Pleomorphic adenoma continues to be the most common tumour of the submandibular gland, whilst adenoid cystic carcinoma is the most common malignant tumour. The incidence of benign versus malignant tumours has remained constant over the period of this study.

Purpose/Objective(s)The immune checkpoint receptor lymphocyte-activation gene 3 (LAG3) is upregulated in many tumor types including melanoma and cSCC and is frequently coexpressed with PD-L1. In the phase 3 RELATIVITY-047 study, 1L relatlimab (anti‒LAG3 antibody) + nivolumab (nivo; anti‒PD-1 antibody) prolonged PFS vs nivo in patients (pts) with unresectable advanced melanoma; and a phase 2 study showed high pathologic complete response (pCR) rate in resectable disease. Early phase studies have also shown promising antitumor activity and manageable safety with favezelimab (anti–LAG3 antibody) + pembrolizumab (pembro; anti‒PD-1 antibody). MK-4280A-010 is an ongoing basket study (NCT06036836) evaluating MK-4280A (coformulation of a fixed-dose combination of favezelimab + pembro) in selected solid tumors. We describe cohort A of this study, which evaluates MK-4280A vs pembro in pts with resectable cSCC.Materials/MethodsCohort A of this randomized, double-blind, phase 2 study will enroll pts aged ≥18 yrs with histologically confirmed stage II–IV cSCC as the primary site of malignancy (without M1; staging per AJCC 8th ed. for head/neck tumors or UICC 8th ed. for other tumor sites). Pts must have had no prior systemic therapy or radiotherapy (RT) to the index lesion and must have cSCC amenable to curative intent surgery, ECOG PS 0/1, and a tumor sample for biomarker analysis. Approximately 80 pts (40 per arm) will be randomized 1:1 (stratified by non-nodal vs nodal disease and head/neck vs other tumor site) to MK-4280A (favezelimab 800 mg + pembro 200 mg) or pembro 200 mg IV Q3W for ≤3 cycles in the neoadjuvant period, followed by surgical resection; and then MK-4280A or pembro, as allocated, Q3W for ≤14 cycles in the adjuvant period (with adjuvant RT per investigator discretion before the start of adjuvant treatment if no pCR by local assessment). Treatment duration (neoadjuvant + adjuvant) will be ∼ ≤1 yr or until PD/recurrence or intolerable AEs. Imaging occurs after the last neoadjuvant cycle before surgery, then Q12W starting day 1 of the adjuvant period through ≤1 yr. AEs are assessed throughout the study and graded per NCI CTCAE v5.0. Primary endpoint is pCR (no viable tumor in resected sample) by blinded central pathology review (BCPR). Secondary endpoints are pCR or clinical CR (no residual tumor per clinical exam/imaging) with negative biopsy, event-free survival and ORR (before surgery) per RECIST v1.1 by investigator review, major pathological response (≤10% viable tumor in resected sample) by BCPR, OS, and safety. pCR will be compared between treatment groups using the stratified Miettinen and Nurminen method. Enrollment began in Sep 2023 and is ongoing.ResultsTBDConclusionTBD

Background: Based on encouraging clinical outcomes in unresectable locally advanced or metastatic cutaneous squamous cell carcinoma (cSCC), the role of immune checkpoint inhibitor (ICI) immunotherapy in the (neo)adjuvant setting for earlier-stage [AJCC stage II-IV (M0)] disease is being investigated. Although pN1 disease is not included in current adjuvant trials, including C-POST (NCT03969004) and Keynote 630 (NCT03833167) where postoperative adjuvant radiotherapy remains a prerequisite, pathological staging is unavailable for neoadjuvant clinical trials and therefore, patients with isolated cN1 disease will still be included. Our anecdotal experience suggests significant differences in prognosis between the T3N0 and isolated N1 subgroups of stage III disease, with the latter having a significantly favourable outcome. Better risk-stratification of T3N0 versus isolated N1 disease is warranted to enable improved communication of the longer-term risks and benefits of neoadjuvant ICI, and critical appraisal of clinical trial data. The objective of this study is to undertake a systematic review and meta-analysis of survival outcomes in pT3N0 versus pN1 head and neck cSCC (HNcSCC). Methods: Five databases were searched for studies reporting survival outcomes (disease free survival; DFS or disease specific survival; DSS) in either pT3N0 or isolated pN1 HNcSCC between 2010 and January 2024. Two reviewers independently extracted data. Risk of bias was estimated with the Newcastle-Ottawa Scale. Kaplan-Meier curves were extracted, digitised and aggregated as per established procedure. The Kaplan-Meier method, log-rank test and univariate Cox analysis were used to describe and compare survival outcomes for aggregated pT3N0 and pN1 cohorts. Results: The aggregated groups contained 405 pT3N0 and 161 isolated pN1 patients. DFS could not be assessed due to lack of data. DSS was significantly worse for pT3N0 disease compared to pN1 disease (HR 1.800, 95% CI 1.168-2.774, log rank p-value = 0.007) with 5-year DSS of 69.3% [standard error (SE) 3.5%] for pT3N0 disease versus 81.6% (SE 3.0%) for pN1 disease (Figure 1). Figure 1 - Kaplan-Meier curve for disease specific survival in aggregated groups of patients with N1 versus T3N0 cutaneous squamous cell carcinoma of the head and neck Conclusions: The risk-benefit implications from ICI immunotherapy differ for T3N0 versus isolated N1 patients. Appreciation of the significant survival outcome difference between these two stage III subgroups is critical when designing neoadjuvant ICI clinical trials and interpreting trial data.

Survival in recurrent/metastatic head and neck mucosal squamous cell carcinoma (HNmSCC) remains poor. Anti-programmed death (PD)-1 therapies have demonstrated improved survival with lower toxicity when compared to standard chemotherapy. However, response to anti-PD-1 therapy remains modest, at 13-17%. We evaluated the tumor microenvironment (TME) using Imaging Mass Cytometry (IMC) on 27 tumor specimens from 24 advanced HNmSCC patients prior to receiving anti-PD-1 based treatment. We show significantly increased central memory T cells and B cells in responders (n=8) when compared to non-responders (n=16). Spatial mapping identified interactions between phenotypically distinct malignant squamous cells with CD8+ T cells, CD4+ Tregs and endothelial cells in responders, and avoidance of these cells in non-responders. Importantly, regional analysis shows responders have more abundant tertiary lymphoid structures (TLS), with TLS proportion >20% also associated with longer progression free survival. Together these findings define the immune landscape associated with response to anti-PD-1 treatment in HNmSCCs. ### Competing Interest Statement Conflicts of interest: JHL declares Honorarium from MSD, BMS, AstraZeneca, Conference support from Novartis, Advisory Board MSD, Sanofi.

Reconstructing critical-sized craniofacial bone defects is a global healthcare challenge. Current methods, like autologous bone transplantation, face limitations. Bone tissue engineering offers an alternative to autologous bone, with traditional approaches focusing on stimulating osteogenesis via the intramembranous ossification (IMO) pathway. However, IMO falls short in addressing larger defects, particularly in clinical scenarios where there is insufficient vascularisation. This review explores redirecting bone regeneration through endochondral ossification (ECO), a process observed in long bone healing stimulated by hypoxic conditions. Despite its promise, gaps exist in applying ECO to bone tissue engineering experiments, requiring the elucidation of key aspects such as cell sources, biomaterials and priming protocols. This review discusses various scaffold biomaterials and cellular sources for chondrogenesis and hypertrophic chondrocyte priming, mirroring the ECO pathway. The review highlights challenges in current endochondral priming and proposes alternative approaches. Emphasis is on segmental mandibular defect repair, offering insights for future research and clinical application. This concise review aims to advance bone tissue engineering by addressing critical gaps in ECO strategies.

Background: Despite introduction of extranodal extension (ENE) into the AJCC 8th edition of oral cancer staging, previous criticisms persist, such as limited discrimination between sub-stages and doubtful prognostic value of contralateral nodal disease. The purpose of this study was to compare our novel nodal staging system, based on the number of positive nodes and ENE, to the AJCC staging system in surgically treated patients. Methods: Retrospective analysis of 4710 patients with oral squamous cell carcinoma (OSCC) treated with surgery +/- adjuvant therapy in 8 institutions in Australia, North America and Asia. With overall survival (OS) and disease specific survival (DSS) as endpoint, the prognostic performance of AJCC 8th and 7th editions were compared using hazard consistency, hazard discrimination, likelihood difference and balance. Results: Our new nodal staging system (PN) a progressive and linear increase in hazard ratio (HR) from pN0 to pN3, with good separation of Kaplan Meier curves. Using the predetermined criteria for evaluation of a staging system, our proposed staging model outperformed AJCC 8th and 7th editions in prediction of OS and DSS. Conclusion: PN was the lymph node staging system that provided the most accurate prediction of OS and DSS for patients in our cohort of OSCC. Additionally, it can be easily adopted, addresses the shortcomings of the existing systems and should be considered for future editions of the TNM staging system.

The radial forearm free flap (RFFF) is widely used for oral reconstruction. The superficial circumflex iliac artery perforator (SCIP) flap is an increasingly utilized alternative. The cases of 165 patients who received either an RFFF or SCIP flap for oral reconstruction at Chris O'Brien Lifehouse, Sydney were reviewed. The aim was to report on patient, pathology, treatment, and outcome variables and to compare these between the two flap groups. A RFFF was used in 126 patients and a SCIP flap in 39 patients. SCIP flap patients were younger (P < 0.001) and had shorter operative times (P < 0.001), shorter anaesthetic times (P < 0.001), and more frequent recipient site dehiscence (P = 0.005) when compared to RFFF patients. The SCIP flap was significantly less frequently used for composite resections including bone when compared to the RFFF (P < 0.001). The primary site distribution was more even for RFFF patients (P < 0.001). There were no SCIP flap failures; three RFFF failures occurred. SCIP flaps performed comparably in terms of operative and clinical outcomes. Most SCIP flaps were utilized in younger patients with partial glossectomy defects.

PURPOSE Trismus secondary to head and neck neoplasm treatment impacts upon quality of life, nutrition, oral hygiene, and dentition. Current treatment options for trismus apply unquantified force to the jaw, and in many cases, the device costs are prohibitive. This study aimed to prospectively evaluate the impact of a novel trismus device. METHOD This single arm cohort study prospectively evaluated the impact of a novel trismus device on maximal incisal opening (MIO), trismus-related function and quality of life scores. Seventeen patients diagnosed with trismus were recruited to undergo a 10-week program using a novel device. The effect of the intervention was assessed by comparing pre- vs post-intervention validated measures. RESULT A significant improvement in MIO was observed post the 10-week intervention period (12.6 mm). This was associated with an improvement in patient reported trismus symptomology including quality of life, swallowing, speech, and jaw pain. CONCLUSIONS This pilot study demonstrates the feasibility of a novel device in the treatment of trismus. Further evaluation of this device is warranted to assess efficacy, safety, and cost-effectiveness in a larger cohort with appropriate controls.

BACKGROUND:Patients treated for head and neck cancer are at high risk of developing head and neck lymphedema (HNL). We describe outcomes of HNL management at an Australian institution from 2018 to 2020.METHODS:Electronic records from Chris O'Brien Lifehouse were retrospectively reviewed from January 1, 2018 to December 31, 2020. Objective changes in HNL were assessed using The M. D. Anderson Cancer Center (MDACC) HNL rating scale and Assessment of Lymphedema of the Head and Neck (ALOHA).RESULTS:Among the 100 patients referred for management of HNL, surgery was the most frequent treatment modality (80%; 70% with neck dissection) and 69% underwent radiotherapy. Manual lymphatic drainage (MLD) was most often prescribed (96%), followed by self-MLD (93%). Small but significant improvements in ALOHA measurements were observed for 50 patients (50%). Only 5/29 (17%) patients had post-treatment improvements on the MDACC scale.CONCLUSIONS:Standardized, prospective measurement of treatment approaches and outcomes is needed to further evaluate the service.

Background: For almost a decade, virtual reality (VR) has been employed in otology simulation. The realism and accuracy of traditional three-dimensional (3D) mesh models of the middle ear from clinical CT have suffered because of their low resolution. Although micro-computed tomography (micro-CT) imaging overcomes resolution issues, its usage in virtual reality platforms has been limited due to the high computational requirements. The aim of this study was to optimize a high-resolution 3D human middle ear mesh model suitable for viewing and manipulation in an immersive VR environment using an HTC VIVE VR headset (HTC and Valve Corporation, USA) to enable a seamless middle ear anatomical visualisation viewing experience in VR while preserving anatomical accuracy. Methods: A high-resolution 3D mesh model of the human middle ear was reconstructed using micro-CT data with 28 μm voxel resolution. The models were optimised by tailoring the surface model polygon counts, file size, loading time, and frame rate. Results: The optimized middle ear model and its surrounding structures (polygon counts reduced from 21 million polygons to 2.5 million) could be uploaded and visualised in immersive VR at 82 frames per second with no VR-related motion sickness reported. Conclusion: High-resolution micro-CT data can be visualized in an immersive VR environment after optimisation. To our knowledge, this is the first report on overcoming the translational hurdle in middle ear applications of VR.

The identification and therapeutic targeting of actionable gene mutations across many cancer types has resulted in improved response rates in a minority of patients. The identification of actionable mutations is usually not sufficient to ensure complete nor durable responses, and in rare cancers, where no therapeutic standard of care exists, precision medicine indications are often based on pan-cancer data. The inclusion of functional data, however, can provide evidence of oncogene dependence and guide treatment selection based on tumour genetic data. We applied an ex vivo cancer explant modelling approach, that can be embedded in routine clinical care and allows for pathological review within 10 days of tissue collection. We now report that ex vivo tissue modelling provided accurate longitudinal response data in a patient with BRAFV600E -mutant papillary thyroid tumour with squamous differentiation. The ex vivo model guided treatment selection for this patient and confirmed treatment resistance when the patient's disease progressed after 8 months of treatment.

Background: There is a wide range of commercial and custom-made devices available for the treatment of trismus (restricted jaw opening). They are used often in conjunction with a prescribed exercise program with the aim of improving maximal inter-incisal opening (MIO). This study compared the efficacy (MIO and patient reported outcome results), adverse events, consumer experience and cost of the different types of devices available. Methods: Four databases were searched between the years 2001-2021 using the terms 'trismus' and 'device'. Two independent authors assessed each paper for inclusion, then conducted a quality analysis. Results: Thirty-two studies met the criterion required for inclusion. The majority (n = 27) were in the context of established trismus, where the remaining five used the device preventatively. The trismus device improved MIO in 23 of the rehabilitation programs (pooled mean MIO increased by 9.5 mm in the intervention arm compared to 2.4 mm for controls; p = 0.0001). Improved MIO was not observed in the prevention studies. The Therabite (R) was the most common trismus device investigated and with a mean increase in MIO of 10.0 mm and cost of $499AUD. Forces applied by trismus devices were regulated by the perception of pain experienced by the patient, rather than a prescribed force by the treating health professional. Despite this guidance, several adverse events occurred (n = 8), including mandibular and molar fractures. Barriers experienced by consumers included pain, ill-fitting mouthpiece, adverse events, exercise adherence and cost. Conclusion: Trismus devices which use the application of force to the jaw can improve the MIO of patients with established trismus. However, their role is unproven in the setting of trismus prevention during radiotherapy and several significant barriers such as cost, exercise adherence and safety concerns have been demonstrated for the intervention setting.

Free flap surgery is currently the only successful method used by surgeons to reconstruct critical-sized defects of the jaw, and is commonly used in patients who have had bony lesions excised due to oral cancer, trauma, infection or necrosis. However, donor site morbidity remains a significant flaw of this strategy. Various biomaterials have been under investigation in search of a suitable alternative for segmental mandibular defect reconstruction. Hydrogels are group of biomaterials that have shown their potential in various tissue engineering applications, including bone regeneration, both through in vitro and in vivo pre-clinical animal trials. This review discusses different types of hydrogels, their fabrication techniques, 3D printing, their potential for bone regeneration, outcomes, and the limitations of various hydrogels in preclinical models for bone tissue engineering. This review also proposes a modified technique utilizing the potential of hydrogels combined with scaffolds and cells for efficient reconstruction of mandibular segmental defects.

BACKGROUND:Virtual surgical planning (VSP) is increasingly used in maxillomandibular osseous free flap reconstruction. Non-commercial ('in-house') VSP may offer the same level of accuracy and other benefits, without the inflated costs and time delays inherent in using commercial providers. Comparisons between commercial and in-house methods are lacking. This study aims to determine the accuracy of VSP, compare in-house and commercially planned cases, and explore predictors of the reconstruction error. METHODS:Seventy-six patients who had a virtually planned maxillomandibular reconstruction between January 2012 and July 2020 were retrospectively identified. The preoperative digital plan was compared to the postoperative CT scan in terms of length of bone segments, angle between adjacent segments and intercondylar, and intergonial angle distances (mandibular reconstructions only). RESULTS:Forty-four patients fulfilled the inclusion criteria. The mean intergonial and intercondylar distances error was 1.7 ± 1.01 mm, mean segment length error was 1.3 ± 1.40 mm, and mean angles error was 1.9 ± 2.32°. The difference in error of in-house VSP compared to commercial VSP was not statistically significant for intercondylar and intergonial distance (p = 0.76), segment length (p = 0.15), or angle between segments (p = 0.92). The increased error was associated with osteoradionecrosis as the indication for surgery, greater number of segments, and secondary reconstructions. CONCLUSION:VSP is an accurate method of maxillary and mandibular reconstruction. In-house VSP may be similar in accuracy to commercial VSP options. Higher levels of inaccuracy are likely to occur in more complex reconstructions, particularly secondary reconstructions, and in the setting of osteoradionecrosis.

Background: Virtual surgical planning (VSP) helps optimize vascularized bone flap reconstruction and dental rehabilitation in maxillomandibular defects, improving accuracy, reducing errors and reducing the time required for surgery. In this manuscript, we describe a robust but flexible virtual protocol for functional maxillomandibular reconstruction optimized for oral cancer patients using in-house digital planning and provide templates to streamline communication among the team members. Methods: Based on our previous experience of VSP in oral cancer (n=17), we derived a workflow to improve efficiency. It included a virtual surgical template and a protocol focused on the minimal time requirements for three different reconstructive approaches: prefabrication/prelamination, primary implant placement using the SM-ART approach, and digital planning without primary implant placement. We performed a prospective validation (n=4) to determine its validity and if the proposed timelines could be adhered to. Results: The protocol allowed a smooth and coordinated framework for team members to communicate and plan the patient’s treatment. The time period required for VSP was described for patients undergoing bony reconstruction with primary dental placement in those with and without custom plates, drill guides and for patients with prefabrication (Rohner’s procedure). The minimum time required for VSP ranged between 17 and 30 days. The protocol could be reliably applied to the prospective group without any modification. Conclusion: Bony reconstruction with primary dental implant placement in the context of oral cancer can be performed successfully with good functional outcomes. By adopting this protocol, virtual surgical planning can be performed efficiently, avoiding potentially costly delays in treatment.

OBJECTIVE:Immediate facial nerve reconstruction is the standard of care following radical parotidectomy; however, quality of life comparisons with those undergoing limited superficial parotidectomy without facial nerve sacrifice is lacking.METHOD:Patients who underwent parotidectomy were contacted to determine quality of life using the University of Washington Quality of Life and Parotidectomy Specific Quality of Life questionnaires. A total of 29 patients (15 in the radical parotidectomy and 14 in the limited superficial parotidectomy groups) completed and returned questionnaires.RESULTS:Using the University of Washington Quality of Life Questionnaire, similar quality of life was noted in both groups, with the radical parotidectomy group having significantly worse speech and taste scores. Using the Parotidectomy Specific Quality of Life Questionnaire, the radical parotidectomy group reported significantly worse speech, eye symptoms and eating issues.CONCLUSION:Those undergoing radical parotidectomy with reconstruction had comparable overall quality of life with the limited superficial parotidectomy group. The Parotidectomy Specific Quality of Life Questionnaire better identified subtle quality of life complaints. Eye and oral symptoms remain problematic, necessitating better rehabilitation and more focused reconstructive efforts.

The Sydney Modification of the Alberta Mandibular Reconstruction technique (SM-ART) is a hybrid of the Rohner method and the Alberta Reconstructive Technique (ART). SM-ART differs from ART in three ways, notably the use of custom plates, intraoral placement of implants via three-dimensionally printed guides and a skin graft buried deep into the skin paddle of the fibula flap in the first stage of the reconstruction.

micro cystic (80%), followed by tubular (30%), follicular (27.5%), papillary cystic (12.5%) and dedifferentiated (5%). Associated lymphoid stroma was present in (37.5%) of cases along with hemorrhage (50%), cystic degeneration (35%) necrosis (25%). Tumors were staged as T1 in (17.5%), T2 in (40%), and T3 in (42.5%) cases. Average follow-up was of 8 years with recurrence in 15%, metastases 10%, and death in15% of patients. Conclusions: ACC may show histological overlap with other carcinomas of salivary gland as it has diverse patterns. Correct diagnosis is possible if pathologists are aware of morphological variation. Dedifferentiation should be searched in all cases.