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.

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.

A culture shock in dental hygiene: Exploring the management of oral health after head and neck cancer.

OBJECTIVES: Managing oral health after the treatment for head and neck cancer requires meticulous daily oral hygiene practices and regular professional dental care; however, the individual factors and health system structures required to achieve oral health are often not well considered. This study aimed to explore how oral health was understood and managed after head and neck cancer treatment and identify factors that influenced oral health behaviours and dental service utilization. METHODS: A qualitative, inductive approach was used for data collection and analysis. Sampling of participants was purposive, using a maximum variation approach, and data were analysed using thematic analysis. Participants were recruited from the maxillofacial clinic at a tertiary facility in Brisbane, Queensland, Australia. RESULTS: Twenty-one participants took part in the study. Findings described individual and structural factors that influenced the management of oral health post-treatment. Individual determinants of oral health behaviours included a cognitive shift towards lifelong oral health; management of unexpected barriers; and management of competing priorities. Structural factors included availability, accessibility of services, and continuity of care. The ability to fund oral health emerged as a salient theme that influenced both individual and structural factors. CONCLUSIONS: Strong self-efficacy and financial and spousal support enhanced the management of oral health, whereas difficulty managing competing issues post-treatment, such as psychological and financial stress, limited participants' capacity to prioritize and manage oral health. Policy initiatives are needed to address the structural barriers caused by a lack of timely access to general and preventive dental care post-treatment.

A Tip for the Reconstruction of Larger Maxillary Defects in Complicated Cleft Patients.

Residual alveolar cleft deficits can be difficult to treat. This is particularly the case in older and multiply operated patients as well as those with large oronasal defects and extensive scar tissue. In large and recalcitrant defects vascularized free tissue transfer should be considered as a definitive procedure. Vascularized free tissue transfer provides a 95% success rate and provides excellent bone for placement of osseointegrated implants for dental rehabilitation (Schwabegger et al., 2004). We feel that the scapula tip has a number of important advantages. These include reduced morbidity from the donor site, good bone quality and contour for implant placement, and a longer pedicle length.

Quality of life of head and neck cancer patients in urban and regional areas: An Australian perspective.

OBJECTIVE: Head and neck cancer treatment affects quality of life. There are differences in quality of life outcomes and perceived supportive care needs between cancer patients living in metropolitan and regional-remote areas. This study investigated quality of life over the first 6 months following head and neck cancer diagnosis and observed differences in quality of life by geographical location. DESIGN: Prospective observational study. SETTING: Tertiary hospital in Brisbane, Australia. PARTICIPANTS: Newly diagnosed patients who were referred for the diagnosis, and/or treatment of head and neck cancer. MAIN OUTCOME MEASURE(S): Quality of life was measured by the University of Washington Quality of Life Survey, version 4 (UW-QoL). Participants completed the UW-QoL questionnaire prior to starting treatment, 1 month and 6 months post treatment. Metropolitan and regional or remote status was classified according to the Australian Standard Geographic Classification-Remoteness Area system. RESULTS: Ninety-five participants were included at baseline; 49 and 41 participants completed the 1-month and 6-month follow-ups, respectively. Scores in most UW-QoL domains decreased between baseline and 1 month post treatment and increased towards pre-treatment scores at the 6-month follow-up (except for anxiety and saliva). Pain at baseline was significantly worse in the regional-remote participants compared with metropolitan participants. No other statistically significant differences in UW-QoL score by geographical location were observed. CONCLUSION: The findings generally did not support significant differences in quality of life outcome between metropolitan and regional-remote head and neck cancer patients. The difference in pain experience between metropolitan and regional-remote groups requires further investigation.

High-Volume Surgeons Deliver Larger Surgical Margins in Oral Cavity Cancer.

PURPOSE: In oral cavity cancer surgery there are many factors that contribute to the surgical margin; thus, the factors determining patient outcomes are still not completely understood. The aim of this study was to determine which variable or variables had the greatest influence on increasing the size of the surgical margin. MATERIALS AND METHODS: A retrospective cohort study was conducted at the Royal Brisbane and Women's Hospital of patients who underwent resective surgery for a primary oral cavity cancer from January 1, 2008 through December 31, 2012. The primary outcome variable was the surgical margin, defined as the closest distance between the surgical edge and invasive cancer. A heterogeneous set of predictor variables was identified as potentially affecting the primary outcome variable: demographic, 5 surgical, and 7 histologic variables. The data then underwent statistical analysis using univariable linear regression, and variables that were found to have a statistical association were retained in a non-interaction multivariable model. RESULTS: This study included 250 patients. The results showed that high-volume surgeons delivered larger surgical margins than low-volume surgeons. The single most important variable associated with larger surgical margins was who performed the resective operation. The following variables also were associated with smaller surgical margins: retromolar trigone location, non-squamous cell carcinomas, perineural invasion, and a lip-split mandibulectomy surgical approach. CONCLUSION: There was a strong association between high-volume surgeons and larger surgical margins, supporting the rationalization of oral cavity cancer management in high-volume centers and by high-volume surgeons.

Primary angiosarcoma of the mandible: a case report.

Angiosarcomas are rare but aggressive vascular cancers of endothelial cell origin. Characteristically, they have a high local recurrence rate and an early metastatic potential. They rarely migrate to the skeleton, and even more unlikely, they may originate in the bones of the face. We present a rare occurrence of a primary angiosarcoma of the mandible. This case highlights the scarce literature available and difficulties in diagnosing and managing this aggressive tumor.

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.

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.

Manual reduction of mandibular fractures before internal fixation leads to shorter operative duration and equivalent outcomes when compared with reduction with intermaxillary fixation.

PURPOSE: Open reduction of mandibular fractures before internal fixation is most commonly performed by 1 of 2 methods: intermaxillary fixation (IMF) or manual reduction. There are risks to both patient and clinician associated with using IMF. Furthermore, previous retrospective studies have failed to show any advantage in its use. The purpose of this study was to directly compare the use of manual reduction (experimental group) and IMF (control group) in open reduction-internal fixation of mandibular fractures. MATERIALS AND METHODS: Patients who presented with isolated mandibular fractures at 2 hospitals in Queensland, Australia, from May 2009 to June 2010 were enrolled in a prospective controlled trial comparing IMF and manual reduction. The outcome measures were operative duration (primary outcome), as well as radiographic outcome, occlusal outcome, and complications (secondary outcomes). The patient and assessor were blinded to the type of reduction used before fixation. The study hypothesis is that manual reduction allows internal fixation in a shorter time than IMF with an equivalent outcome. RESULTS: We recruited 50 patients, 26 allocated to IMF and 24 allocated to manual reduction before internal fixation of mandibular fractures. IMF was associated with an increased duration of procedure (P < .001) and increased complication rate (P = .063), without any observable benefit with regard to either radiographic outcome or occlusal outcome. CONCLUSIONS: IMF is not required in open reduction-internal fixation of mandibular fractures that met our inclusion criteria. IMF is associated with increased costs to the health service and risks to both the patient and clinician.

Fibular free flap with arteria peronea magna: the role of preoperative balloon occlusion.

The free fibular osteocutaneous flap is a commonly used donor for reconstruction of mandibular defects. Vascular abnormalities and leg trauma are relative contraindications to the use of a fibular free flap. Peroneal arteria magna (PAM) is one such vascular abnormality that may preclude the use of the graft due to the high risk of lower-limb ischemia. Lower-limb angiography is the standard for assessing the lower-limb vascular anatomy; however, the indications remain controversial. Although balloon occlusion has been used to assess the vascular supply in distal bypass surgery, there have no reported cases of balloon occlusion to assess the viability of the distal extremity with PAM. Intraoperative assessment of vascular anatomy with an aborted harvest can lead to significant morbidity and cost. Balloon occlusion provides a relatively safe and minimally invasive technique for assessment of potential lower-limb ischemia in patients with PAM.

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.

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.

The fate of the free flap pedicle after free tissue transfer to the head and neck area.

OBJECTIVES: Little is understood about what happens to the vascular pedicle following free tissue transfer in the head and neck region. The viability of a free flap completely depends on the vascular supply by its vascular pedicle until neovascularization occurs from surrounding tissues. The aim of this study is to find out how long a vascular pedicle lasts following free tissue transfer in the head and neck region. MATERIALS AND METHODS: Patients were recruited from the Maxillofacial Unit at the Royal Brisbane & Women's Hospital. A Doppler ultrasound was used to map the vascular pedicle immediately postoperatively, at 2weeks, 6weeks, 3months and 6months. RESULTS: Fifty-seven consecutive free flaps underwent colour Doppler ultrasonography at the timepoints described demonstrating the status of the vascular pedicle. All the patients underwent reconstructive head and neck surgery with a wide variety of soft tissue and composite free flaps. CONCLUSION: This study is the first to document the fate of the vascular pedicle over a long time period for a wide variety of head and neck free flaps. This information is important when undertaking revision surgery to the free flap, or planning the vascular supply for a second or third free flap to the head and neck region.

Radiotherapy-associated dental extractions and osteoradionecrosis.

BACKGROUND: Preradiotherapy dental extractions often form a part of the management plan for patients treated with radiotherapy for head and neck cancers in order to prevent complications, such as osteoradionecrosis. There is contention about whether these extractions should be performed and the timing of such extractions. The purpose of this study was to determine if pre-RT extractions were associated with the development of osteoradionecrosis of the jaws. METHODS: Retrospective data on patients treated with RT for oropharyngeal cancer were pooled with a cross-sectional survey. RESULTS: Pre-radiotherapy dental extractions were associated with a statistically significant increase in the risk of developing ORN. CONCLUSION: Pre-radiotherapy dental extractions do not protect against the development of osteoradionecrosis. © 2016 Wiley Periodicals, Inc. Head Neck 39: 128-132, 2017.

Osseointegrated implants into a variety of composite free flaps: A comparative analysis.

BACKGROUND: Significant oral function is often lost after surgical therapy for head and neck cancer. The use of osseointegrated implants for reconstruction in patients with head and neck surgery has shown to significantly improve the quality of life for these patients. Variable success rates range from 99% to 70%. METHODS: A retrospective audit of patient records was performed looking at cumulative survival of implants. Inclusion criteria were patients who were treated at 1 of 2 designated Australian Head and Neck Units and received oral osseointegrated implants. RESULTS: Fifty-nine patients were included for analysis. One hundred ninety-nine implants were placed into vascularized bone grafts (VBGs). There were 11 implant failures with an overall success rate of 94.5%. There was 1 significant adverse outcome with a pathological fracture of a flap after implant placement. Implant success in scapula and iliac crest flaps was comparable to fibula flaps. CONCLUSION: Implants placed into VBGs have a reasonable success rate in well-selected patients. © 2016 Wiley Periodicals, Inc. Head Neck 39: 443-447, 2017.

Cost-effectiveness of monitoring free flaps.

Methods of free flap monitoring have become more sophisticated and expensive. This study aims to determine the cost of free flap monitoring and examine its cost effectiveness. We examined a group of patients who had had free flaps to the head and neck over a two-year period, and combined these results with costs obtained from business managers and staff. There were 132 free flaps with a success rate of 99%. The cost of monitoring was Aus $193/flap. Clinical monitoring during this time period cost Aus$25 476 and did not lead to the salvage of any free flaps. Cost equivalence is reached between monitoring and not monitoring only at a failure rate of 15.8%. This is to our knowledge the first study to calculate the cost of clinical monitoring of free flaps, and to examine its cost-effectiveness.

Preradiotherapy dental extractions and health-related quality of life.

OBJECTIVE: The aim of this study was to investigate the connection between preradiotherapy dental extractions and self-reported health-related QoL. STUDY DESIGN: Retrospective data on patients treated with radiotherapy for oropharyngeal cancer were pooled with the results of a cross-sectional survey. RESULTS: Greater than eight preradiotherapy dental extractions, p16 negative status, female gender, and positive smoking status were associated with statistically significant reduced QoL. CONCLUSIONS: Preradiotherapy dental extractions do not result in improved QoL and, in fact, may worsen it.