Human papillomavirus associated oropharyngeal cancer now the most common mucosal head and neck cancer in Queensland.

INTRODUCTION: The profile and outcomes of head and neck cancer throughout Australia has changed over the past decade. The aim of this study was to perform a population-based analysis of incidence, demographics, stage, treatments and outcomes of patients diagnosed with oropharyngeal squamous cell carcinoma (OPSCC), with a particular focus on HPV-associated disease. METHODS: This was a retrospective analysis of prospectively collected data within the Queensland Oncology Repository (QOR) and analysed by the Queensland Cancer Control Analysis Team. The cohort included patients diagnosed in Queensland between 1 January 2015 and 31 December 2019. Outcome measures included incidence of new OPSCC cases, age-standardised rates (ASR) (3-year average), demographics, p16 status, stage (8th Edition American Joint Commission on Cancer), treatments, and 2- and 5-year overall survival. RESULTS: There were 1527 newly diagnosed OPSCC, representing 96% (1527/1584) of all oropharyngeal cancers. It was the most common head and neck cancer diagnosed, with oral cavity cancer being the second most common (n = 1171). Seventy-seven percent were p16 positive (1170/1527), of which 87% (1019/1170) were male. The median age was 61 years and 49% (568/1170) presented with Stage I disease. The ASR was 6.3/100,000, representing a 144% incidence increase since 1982 (2.6/100,000). Radiotherapy was utilised in 91% of p16+ cases with 2- and 5- year overall survival of 89% and 79%, respectively. CONCLUSION: OPSCC is now the most common mucosal head and neck cancer diagnosed in Queensland, having surpassed oral cavity cancer. The majority are HPV-associated (p16+), presenting with early-stage disease with a favourable prognosis.

Surgical Resection and Reconstruction of Ameloblastoma: A 13-Year Retrospective Review.

BACKGROUND: Ameloblastoma is a locally aggressive, benign tumor presenting in the maxilla and mandible prone to recurrence. Resection greatly limits recurrence; however, reconstruction becomes critical to preserve patients' functionality and esthetics. PURPOSE: The aim of this study was to describe surgical resection and reconstructive approaches in the treatment of ameloblastoma and compare clinical outcomes to conservative methods of treatment. STUDY DESIGN, SETTING, SAMPLE: A retrospective case series was completed through analysis of patient records. The study population was composed of patients treated for ameloblastoma at the Royal Brisbane Hospital (Queensland, Australia) in the Oral and Maxillofacial Surgery Unit from January 1, 2008, to December 31, 2020. Patients without histological confirmation of intraosseous ameloblastoma were excluded from the study sample. PREDICTOR VARIABLE: Not applicable. MAIN OUTCOME VARIABLE(S): The primary outcome variable was time to recurrence. Secondary outcome variables included any surgical complications incurred. COVARIATES: The covariate variables collected included age at diagnosis/treatment, gender, ethnicity, location of lesion and site(s) of involvement, tumor extent, alveolar expansion, histopathological growth pattern, and soft tissue involvement. ANALYSES: Descriptive statistics were computed for each study variable. RESULTS: A total of 48 cases of histologically confirmed ameloblastoma were identified (41 mandibular, 7 maxillary) involving 50 excisional operations (44 resections, 6 enucleations). Of these cases, 44 were followed up > 12 months, with a mean length of follow-up time of 65.6 months. No recurrence was detected for resected lesions. One enucleated lesion recurred at 25 months. Thirty-seven reconstructive procedures were undertaken, including 32 immediate free flaps. All reconstructive flaps and grafts survived, and no major complications were recorded. CONCLUSION AND RELEVANCE: Resection of ameloblastoma limits recurrence and should be considered curative. Immediate microvascular free flap reconstruction of maxillary and mandibular defects from resection of ameloblastoma is safe and predictable.

A novel saliva-based miRNA profile to diagnose and predict oral cancer.

Oral cancer (OC) is the most common form of head and neck cancer. Despite the high incidence and unfavourable patient outcomes, currently, there are no biomarkers for the early detection of OC. This study aims to discover, develop, and validate a novel saliva-based microRNA signature for early diagnosis and prediction of OC risk in oral potentially malignant disorders (OPMD). The Cancer Genome Atlas (TCGA) miRNA sequencing data and small RNA sequencing data of saliva samples were used to discover differentially expressed miRNAs. Identified miRNAs were validated in saliva samples of OC (n = 50), OPMD (n = 52), and controls (n = 60) using quantitative real-time PCR. Eight differentially expressed miRNAs (miR-7-5p, miR-10b-5p, miR-182-5p, miR-215-5p, miR-431-5p, miR-486-3p, miR-3614-5p, and miR-4707-3p) were identified in the discovery phase and were validated. The efficiency of our eight-miRNA signature to discriminate OC and controls was: area under curve (AUC): 0.954, sensitivity: 86%, specificity: 90%, positive predictive value (PPV): 87.8% and negative predictive value (NPV): 88.5% whereas between OC and OPMD was: AUC: 0.911, sensitivity: 90%, specificity: 82.7%, PPV: 74.2% and NPV: 89.6%. We have developed a risk probability score to predict the presence or risk of OC in OPMD patients. We established a salivary miRNA signature that can aid in diagnosing and predicting OC, revolutionising the management of patients with OPMD. Together, our results shed new light on the management of OC by salivary miRNAs to the clinical utility of using miRNAs derived from saliva samples.

Improving accuracy in nodal staging of oral cancer: Proposal of a new system.

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.

Impact of dental state and surgical factors on postoperative neck infection in oral cancer patients.

Postoperative neck infection (PONI) is a known complication of neck dissection. In this study we explored the impact of dental status on the development of PONI, using orthopantomograms to assess edentulism, periodontal health, and caries status. Retrospective analysis was performed for all new oral cancer patients who had neck dissection between January 2008 and January 2020 in a tertiary head and neck centre. PONI risk factors assessed included patient characteristics, dental status, tumour, and surgical factors. Development of PONI was the primary outcome. Edentulous patients had lower risk of PONI (OR 0.06, p = 0.026) compared to those with 21 or more teeth. Periodontitis and dental caries were not statistically significant. Current smokers (OR 2.09, p = 0.044) and free flap reconstruction (OR 5.41, p < 0.001) were also significant predictors for development of PONI. This study highlights the presence of teeth as a potential source of infection post neck dissection and that orthopantomogram assessment may be inadequate to identify at risk patients. Future studies are required on direct clinical assessment of dentition to evaluate the impact of dental optimisation in prevention of PONI.

Detecting salivary host and microbiome RNA signature for aiding diagnosis of oral and throat cancer.

OBJECTIVE: Oral squamous cell carcinoma (OSCC) and oropharyngeal squamous cell carcinoma (OPSCC) can go undetected resulting in late detection and poor outcomes. We describe the development and validation of CancerDetect for Oral & Throat cancer™ (CDOT), to detect markers of OSCC and/or OPSCC within a high-risk population. MATERIAL AND METHODS: We collected saliva samples from 1,175 individuals who were 50 years or older, or adults with a tobacco use history. 945 of those were used to train a classifier using machine learning methods, resulting in a salivary microbial and human metatranscriptomic signature. The classifier was then independently validated on the 230 remaining samples prospectively collected and unseen by the classifier, consisting of 20 OSCC (all stages), 76 OPSCC (all stages), and 134 negatives (including 14 pre-malignant). RESULTS: On the validation cohort, the specificity of the CDOT test was 94 %, sensitivity was 90 % for participants with OSCC, and 84.2 % for participants with OPSCC. Similar classification results were observed among people in early stage (stages I & II) vs late stage (stages III & IV). CONCLUSIONS: CDOT is a non-invasive test that can be easily administered in dentist offices, primary care centres and specialised cancer clinics for early detection of OPSCC and OSCC. This test, having received FDA's breakthrough designation for accelerated review, has the potential to enable early diagnosis, saving lives and significantly reducing healthcare expenditure.

The dental management of patients irradiated for head and neck cancer.

Patients undergoing radiotherapy for head and neck cancers are prone to a range of dental complications, including mucositis, trismus, xerostomia, radiation caries and osteoradionecrosis. Specific considerations include the preventive, restorative and rehabilitative management of such patients, and the prevention and treatment of complications. This article aims to highlight the current understanding and management of dental needs for patients who have had or will undergo radiotherapy.

Prediction nomogram development and validation for postoperative radiotherapy in the management of oral squamous cell carcinoma.

BACKGROUND: Predictive nomograms are useful tools to guide clinicians in estimating disease course. Oral squamous cell carcinoma (OSCC) patients would benefit from an interactive prediction calculator that defines their levels of survival-risk specific to their tumors to guide the use of postoperative radiotherapy (PORT). METHODS: Patients with OSCC surgically treated with curative intent at four Head and Neck Cancer Centres were recruited retrospectively for development and validation of nomograms. Predictor variables include PORT, age, T and N classification, surgical margins, perineural invasion, and lymphovascular invasion. Outcomes were disease-free, disease-specific, and overall survivals over 5 years. RESULTS: 1296 patients with OSCC were in training cohort for nomogram analysis. Algorithms were developed to show relative benefit of PORT in survivals for higher-risk patients. External validation on 1212 patients found the nomogram to be robust with favorable discrimination and calibration. CONCLUSION: The proposed calculator can assist clinicians and patients in the decision-making process for PORT.

An objective analysis of composite free flap donor site morbidity in head and neck surgery: Prospective series.

BACKGROUND: A poor evidence basis exists regarding the objective donor site morbidity associated with osseous free flap harvest. This study prospectively assessed the objective donor site morbidity associated with osseous free flap harvest for the fibula, scapula, and iliac crest (DCIA) donor sites. METHODS: A single-site, prospective cohort clinical research study was conducted. Sixty-four patients were recruited between 2017 and 2021. Patients were assessed using a donor site specific assessment tool pre-operatively, and again >12 months post-operatively. RESULTS: There was a significant reduction post-operatively in assessment tool scores compared to the pre-operative period for the fibula, scapula and DCIA. Females were more likely to report a greater reduction in Harris Hip Score post-operatively compared to males. CONCLUSIONS: The fibula, scapula, and DCIA donor sites are associated with reduced objective function post-operatively compared to patient's pre-operative baseline. The implications are least pronounced for the fibula.

Workflow for Fabricating 3D-Printed Resorbable Personalized Porous Scaffolds for Orofacial Bone Regeneration.

Resorption of alveolar bone following tooth extraction is a physiological process that can often prevent the placement of dental implants due to the limited bone remaining. In severe cases, vertical bone augmentation, which aims to restore bone in an extraskeletal dimension (outside of the skeletal envelope), is required prior to implant placement. While current treatment strategies rely on autologous grafts, or "Guided Bone Regeneration" involving the placement of particulate bone grafting biomaterials under a protective membrane, the field is shifting to patient-matched solutions. Herein, we describe the various steps required for modeling the patient data, creating the patient-matched scaffold geometry and 3D-printing using the biodegradable polymer polycaprolactone for application in the oro-dental and craniofacial areas.

Do Post-injury Prophylactic Antibiotics Reduce Infection for Isolated Midface Fractures: A Cohort Study.

PURPOSE: Fractures of the midface are a core component to the practice of contemporary oral and maxillofacial trainees and surgeons. As such, in an era where antibiotic resistance is increasing it is important to investigate if antibiotics are required after midface fractures to prevent infections before follow-up in an outpatient setting. The purpose of this study is to determine whether postinjury prophylactic preoperative antibiotics reduce rates of infection after midface fracture. METHODS: A retrospective multicenter cohort study was conducted in Queensland, Australia. Patients who presented to Royal Brisbane Hospital and Townsville Hospital with isolated midface fractures between January 2017 and January 2019 were included. Clinical and demographic data of patients who received postinjury prophylactic antibiotics were compared to those who did not using the χ2 test. Logistic regression was used to determine factors associated with increased odds of postinjury prophylactic antibiotic prescription. RESULTS: In total, 1,353 patients with midfacial fractures over the 2-year period were included. In addition, 724 (53.5%) patients received postinjury antibiotics and 629 (46.5%) patients did not. The overall rate of infection was very low: 1 patient who received postinjury prophylactic antibiotics (0.1%) developed infection compared to 2 patients (0.3%) who did not receive postinjury prophylactic antibiotics, and this difference was not significant (χ2 = 0.49; P = .48). Male sex (odds ratio 1.4; 95% confidence interval, 1.1 to 1.7; P = .02) and tobacco use (odds ratio 1.4; 95% confidence interval, 1.1 to 1.7; P = .008) were associated with an increased odds of postinjury prophylactic antibiotic prescription in the univariate analyses, but were no longer significant once site, age, and fracture type were adjusted for in the multivariate model. CONCLUSIONS: The rate of infection after midface fracture was low and there was no significant difference in infection rates for patients who received postinjury prophylactic antibiotics compared to those who did not. Use of postinjury prophylactic preoperative antibiotics for midfacial fractures should be reconsidered.

Osseointegrated implant survival, success and prosthodontic outcomes in composite free flaps: A 10-year retrospective cohort study.

OBJECTIVES: To evaluate implant survival, success and prosthodontic outcomes in a variety of composite free flaps. MATERIAL AND METHODS: A retrospective analysis of patient records was used for data collection of implants placed into flaps. Free flap donor sites included fibula, iliac crest, scapula, medial femoral condyle and radial forearm. Kaplan-Meier survival curves were used to estimate survival. Cox regression was used to assess variables affecting survival, and binary logistic regression was utilised to determine effect of variables on prosthodontic outcomes. RESULTS: There were 150 implants placed into 45 fibula, 98 implants into 29 iliac crest, 62 implants into 22 scapula, 6 implants into 3 medial femoral condyle and 2 implants in radial forearm composite free flaps. There was no difference in survival or success between or within the various flaps. Active smoking, increasing age, male gender and radiotherapy were associated with implant failure. Of patients completing prosthodontic rehabilitation, 93% were successful. There was no difference in likelihood of failure between different flap types. Fixed implant-supported dentures were associated with poor oral hygiene compared with removable designs (OR2.9, 95%CI 1.1-7.8, p = .03). CONCLUSIONS: There is adequate survival and success of implants in common flaps. Caution is required when planning implants in patients exposed to radiotherapy and smokers. Ability to maintain adequate oral hygiene is an important prosthetic design consideration.

Geographical heterogeneity in the American Joint committee on Cancer oral cancer staging and prognostic implications.

OBJECTIVES: The AJCC 8th edition (AJCC 8) has introduced depth of invasion (DOI) and extranodal extension (ENE) into staging for oral squamous cell carcinoma (OSCC). Although validations have been performed on institutional datasets have shown a good performance, particularly in early OSCC, there have been no studies on diverse patient populations that determine the impact on prognostic heterogeneity. MATERIALS AND 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) as endpoint, the prognostic performance of AJCC 7th and 8th editions were compared using Akaike Information Criterion (AIC), Bayesian Information Criteria (BIC), Harrell's concordance index (C-index). RESULTS: When comparing AJCC 8 to AJCC 7, the heterogeneity in prediction of OS increased for T-category and N-category while remaining unchanged for TNM staging, suggesting AJCC 8 increased complexity with no improvement in predictive value. There were significant differences in median DOI and incidence of ENE between geographical regions, resulting in dissimilar rates of stage-migration when adopting AJCC 8. CONCLUSION: In an attempt to improve prognostic performance, AJCC 8 introduced more variables; however heterogeneity in these results in significant geographical differences in model discrimination and performance. Caution should be applied as this may result in inaccurate and unreliable prognostic predictions that may impact treatment recommendations.

Survival outcomes following modern multidisciplinary management of oral squamous cell carcinoma in Australia.

OBJECTIVE: Oral squamous cell carcinoma (SCC) has been traditionally described as a highly lethal disease. This study aims to provide updated multi-institutional data on the survival of patients with oral SCC in Australia. STUDY DESIGN: Retrospective survival analysis was performed between 2008 and 2016. All new patients with oral SCC treated with curative intent were recruited from 2 high-volume Australian head and neck oncology centers. Outcomes were measured in overall survival (OS), disease-specific survival (DSS), disease-free survival, and salvage rates for recurrences. RESULTS: Survival analysis included 771 patients with oral SCC. Five-year OS and DSS were 66.1% and 79.7%, respectively. Stage I and II oral SCC had significantly better survival than higher stages. Five-year OS and DSS for patients with stage I SCC were 79.7% and 93.4%, respectively, and for patients with stage IVB they were 37.9% and 54.3%, respectively. Two hundred forty-nine patients had disease recurrence (32.3%), with 66 patients (26.5% remaining disease free post salvage treatment. CONCLUSION: Survival outcomes for oral SCC among Australian patients have improved, possibly due to advances in multidisciplinary care. Early detection of oral SCC leads to highly favorable prognosis; there is therefore an opportunity for routine oral cancer screening to be performed by community health practitioners with the aim of improving survival from oral SCC.

CD155 on Tumor Cells Drives Resistance to Immunotherapy by Inducing the Degradation of the Activating Receptor CD226 in CD8+ T Cells.

The activating receptor CD226 is expressed on lymphocytes, monocytes, and platelets and promotes anti-tumor immunity in pre-clinical models. Here, we examined the role of CD226 in the function of tumor-infiltrating lymphocytes (TILs) and resistance to immunotherapy. In murine tumors, a large proportion of CD8+ TILs had decreased surface expression of CD226 and exhibited features of dysfunction, whereas CD226hi TILs were highly functional. This correlation was seen also in TILs isolated from HNSCC patients. Mutation of CD226 at tyrosine 319 (Y319) led to increased CD226 surface expression, enhanced anti-tumor immunity and improved efficacy of immune checkpoint blockade (ICB). Mechanistically, tumor-derived CD155, the ligand for CD226, initiated phosphorylation of Y319 by Src kinases, thereby enabling ubiquitination of CD226 by CBL-B, internalization, and proteasomal degradation. In pre-treatment samples from melanoma patients, CD226+CD8+ T cells correlated with improved progression-free survival following ICB. Our findings argue for the development of therapies aimed at maintaining the expression of CD226.

Systematic review and pooled analysis of survival rates, success, and outcomes of osseointegrated implants in a variety of composite free flaps.

The aim of this review was to provide an update on survival rates of osseointegrated implants into common composite free flaps used for maxillary and mandibular reconstructions and identify factors affecting outcomes. PubMed, Medline, Embase, and Cochrane databases were searched. Included studies reported implant survival by flap type. Results were pooled and survival was estimated with the Kaplan-Meier method. Variables affecting survival were assessed using Cox regression. Thirty-two of the 2631 articles retrieved were included, totaling 2626 implants placed into fibula, iliac crest, scapula, and radial forearm free flaps. Pooled survival showed 94% 5-year survival of implants in fibula and iliac crest with no difference between groups (P = .3). Factors effecting survival included radiotherapy (HR 2.3, 95% CI 1.2-4.6, P = .027) and malignant disease (HR 2.2, 95%CI 1.6-3.1, P < .001). Implant survival appears adequate across common flap types; however, there are limited numbers reported in less common flaps.

Oral HPV16 Prevalence in Oral Potentially Malignant Disorders and Oral Cavity Cancers.

The role of human papillomavirus type 16 (HPV16) in oral potentially malignant disorders (OPMD) and oral cavity carcinoma (OC) is still under debate. We investigated HPV16 prevalence in unstimulated saliva, oral rinse samples, oral swabs and tumour biopsies collected from OPMD (n = 83) and OC (n = 106) patients. HPV16 genotype, viral load, physical status (episomal vs. integrated) and tumour p16INK4a expression were determined. Oral HPV16 prevalence was higher in OC than in OPMD, but this difference was not statistically significant (7.5% (8/106) versus 3.6% (3/83), odds ratio (OR): 2.18, 95% confidence interval (CI): 0.56, 8.48, p = 0.26). There was a significant association (p < 0.05) between oral HPV16 infection and heavy tobacco consumption. Real-time PCR results indicated that no integration events occurred in either OPMD or OC cases based on the HPV16 E2/E6 ratio. HPV16 positive OPMD and OC patients had similar HPV16 E2 and E6 viral loads. The inter-rater agreement between tumour p16INK4a expression and oral HPV16 infection was considered as fair (k = 0.361) for OC. Our data suggest that the involvement of HPV16 in oral carcinogenesis is limited.

Variations in concerns reported on the patient concerns inventory in patients with head and neck cancer from different health settings across the world.

BACKGROUND: The aim was to collate and contrast patient concerns from a range of different head and neck cancer follow-up clinics around the world. Also, we sought to explore the relationship, if any, between responses to the patient concerns inventory (PCI) and overall quality of life (QOL). METHODS: Nineteen units participated with intention of including 100 patients per site as close to a consecutive series as possible in order to minimize selection bias. RESULTS: There were 2136 patients with a median total number of PCI items selected of 5 (2-10). "Fear of the cancer returning" (39%) and "dry mouth" (37%) were most common. Twenty-five percent (524) reported less than good QOL. CONCLUSION: There was considerable variation between units in the number of items selected and in overall QOL, even after allowing for case-mix variables. There was a strong progressive association between the number of PCI items and QOL.