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Immune checkpoint inhibitor (ICI) modality has had a limited success (SPiD) improved profiling of local immune cell types relevant to disease progression, (iii) identified clinically relevant alternative treatments and a rational explanation for checkpoint inhibitor therapy failure through comparative analysis of pre- and post-failure tumor data and, (iv) discovered ligand-receptor interactions as potential lead targets for personalized drug treatments. Our work establishes a clear path for incorporating spatial-omics in clinical settings to facilitate treatment personalization.

Oropharyngeal cancer is increasingly caused by human papillomavirus (HPV), and this increase is believed to be caused by changing sexual behaviour. It has been hypothesised that an immune response to HPV through sexual intercourse is much stronger than an immune response elicited from oral sex. Therefore, people who have their debut of oral sex before or at the same time as sexual intercourse would have a weaker immune response to HPV and hence be more likely to develop a persistent oral HPV infection and oropharyngeal cancer. Drake et al (Cancer. 2021;127[7]:1029-1038) found some evidence that supported this hypothesis. We have reanalysed two of our Australian cohorts with similar data in order to provide a perspective of Drake and colleagues' publication, as sexual behaviour varies depending on culture and geographical location. We found that engaging in oral sex (OR 4.46, 95% CI [1.88-10.62]) and being younger than 20 years at oral sex debut (OR 9.46, 95% CI [3.53-25.31]) were both very strong risk factors for oropharyngeal cancer. Participants in the general population cohort who had their sexual intercourse debut before the age of 18 were more likely to be oral HPV positive (OR 2.69, 95% CI [1.50-4.83]). Oral sex debut before sexual intercourse debut was quite uncommon in our two Australian cohorts. However, timing of or sexual debuts may further add to risks of oropharyngeal cancer, and future studies should be designed to investigate timing and order of sexual debuts to help clarify the roles of these potential causal factors.

Immune checkpoint inhibitors have shown promising antitumour activity. Application in head and neck cutaneous squamous cell carcinoma (cSCC) large nerve perineural spread (PNS) is limited.Retrospective review of 13 patients with PNS receiving anti-PD-1 therapy from September 2017 to May 2021 is presented. Primary endpoints were objective response (complete or partial response) and median time to progression, determined by Head and Neck Multi-Disciplinary Team (MDT) and independent radiology review of magnetic resonance imaging (MRI) and/or computed tomography/positron emission tomography (CT/PET).Objective response was observed in 9/13 patients (69%), with complete response in 6 (46%) and partial response in 3 patients (23%). Median time to response was 2.1 months (IQR 1.8-2.7 months). There were 3 (23%) patients with progressive disease, with median time to progression of 3.5 months. There were no grade 3-4 treatment related adverse events.This case series supports developing evidence for anti-PD-1 checkpoint inhibitor therapy for perineural spread, supporting future prospective clinical trials in this patient population.

Nasopharyngeal carcinoma (NPC) is an Epstein–Barr virus (EBV)-associated heterogeneous disease and is characterized by peritumoral immune infiltrate. Adoptive T-cell therapy (ACT) has emerged as a potential therapeutic strategy for NPC. However, the tumor microenvironment remains a major roadblock for the successful implementation of ACT in clinical settings. Expression of checkpoint molecules by malignant cells can inhibit the effector function of adoptively transferred EBV-specific T cells. Here we present a novel case report of a patient with metastatic NPC who was successfully treated with a combination of EBV-specific ACT and programmed cell death-1 blockade therapy. Following combination immunotherapy, the patient showed complete resolution of metastatic disease with no evidence of disease relapse for 22 months. Follow-up immunological analysis revealed dramatic restructuring of the global T-cell repertoire that was coincident with the clinical response. This case report provides an important platform for translating these findings to a larger cohort of NPC patients.

Background: Smoking status at point of diagnosis is not used in defining risk groups for human papillomavirus (HPV)-associated oropharyngeal cancer (OPC) despite its prognostic value in head and neck cancer. Methods: Retrospective analysis of consecutive patients treated with chemoradiotherapy between January 2005 and July 2017 was performed with multivariable analysis to explore the impact of smoking status at diagnosis (current/former/never) on overall survival (OS), cancer-specific survival (CSS) and progression-free survival (PFS). Results: Median follow-up was 61 months. Four hundred and four patients were included. Current smokers had inferior OS versus never and former smokers [adjusted HR 2.37 (95% CI 1.26–4.45, p < 0.01) and 2.58 (95% CI 1.40–4.73, p < 0.01), respectively] and inferior PFS versus never smokers [adjusted HR 1.83 (95% CI 1.00–3.35, p = 0.04)]. Smoking status did not predict for CSS. Conclusion: Detailed smoking behavior should be considered in refining risk groups in HPV-associated OPC treated with radiotherapy and in future trial design eligibility and stratification.

We conducted a phase 1 dose escalation study (ACTRN12618000140257 registered on 30/01/2018) to evaluate the safety, tolerability and immunogenicity of a therapeutic human papillomavirus (HPV) DNA vaccine (AMV002) in subjects previously treated for HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Eligible subjects had to have no evidence of recurrent and/or metastatic disease at least 12 weeks following the completion of treatment. Three dosing cohorts each consisted of four subjects: group 1: 0.25 mg/dose, group 2: 1 mg/dose, group 3: 4 mg/dose. AMV002 was delivered intradermally on days 0, 28 and 56. Incidence and severity of treatment-emergent adverse events (TEAE) including local reaction at the injection site, and vaccination compliance were recorded. T cell and antibody responses to HPV16 E6 and E7 were measured by interferon gamma (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assay and enzyme-linked immunosorbent assay (ELISA). All subjects completed the vaccination programme and experienced mild discomfort at the injection site(s). Pre-immunisation, cell-mediated responses to HPV16 E6 and E7 were evident in all subjects, and E7-specific antibodies were detected in 11 (91.7%), reflecting previous exposure to HPV. Post-vaccination, 10 of 12 (83.3%) subjects responded to one or more of the E6 and/or E7 peptide pools, while 2 (16.7%) did not show additional vaccine-induced cell-mediated responses. Vaccination resulted in a ≥ 4-fold increase in anti-HPV16 E7 antibody titre in one subject in group 3. AMV002 was well tolerated at all dose levels and resulted in enhanced specific immunity to virus-derived tumour-associated antigens in subjects previously treated for HPV-associated OPSCC.

Contains fulltext : 220257.pdf (Publisher’s version ) (Closed access) The speed and scale of the global COVID-19 pandemic has resulted in unprecedented pressures on health services worldwide, requiring new methods of service delivery during the health crisis. In the setting of severe resource constraint and high risk of infection to patients and clinicians, there is an urgent need to identify consensus statements on head and neck surgical oncology practice. We completed a modified Delphi consensus process of three rounds with 40 international experts in head and neck cancer surgical, radiation, and medical oncology, representing 35 international professional societies and national clinical trial groups. Endorsed by 39 societies and professional bodies, these consensus practice recommendations aim to decrease inconsistency of practice, reduce uncertainty in care, and provide reassurance for clinicians worldwide for head and neck surgical oncology in the context of the COVID-19 pandemic and in the setting of acute severe resource constraint and high risk of infection to patients and staff.

Background: Head and neck squamous cell carcinoma, and in particular hypopharyngeal squamous cell carcinoma, has long been associated with disfiguring treatment options, significant morbidity and limited long-term survival outcomes. Total pharyngolaryngectomy (TPL) with free flap reconstruction followed by post-operative radiation therapy or chemoradiotherapy is a widely accepted treatment of choice for advanced disease of the hypopharynx. Methods: Our unit undertook a 11-year review of all primary TPL patients aiming to provide an update on survival outcomes, morbidity, post-operative complications and evolving management strategies. We report one of the largest single-centre series to date with 89 patients undergoing primary TPL between 2003 and 2013, and compare these outcomes to 180 patients undergoing TPL at the same facility in the previous 23 years. Results: Between study periods, we saw a shift in patient population towards higher stage disease (T-stage 3 or 4 97% 2003–2013; 68% 1979–2002) and increased nodal involvement (node positive 88% 2003–2013; 70% 1979–2002) without a subsequent reduction in 5-year disease-specific survival (52% 2003–2013; 52% 1979–2002) or 5-year overall survival (32% 2003–2013; 33% 1979–2002).

Now is an exciting era of development in immunotherapy checkpoint inhibitors and their effect on the treatment of NPC. While the general prognosis of R/M disease is poor, immunotherapy offers some promise in a malignancy associated with EBV and characterized by a peritumoural immune infiltrate. Our study aims to review past and on-going clinical trials of monoclonal antibody therapies against the checkpoint inhibitors (e.g. PD1 and CTLA-4), in R/M NPC. All randomized and nonrandomized controlled trials involving immune checkpoint inhibitor interventions for treatment of NPC were included in the study. We utilized a validated "risk of bias" tool to assess study quality. Four separate Phase I-II trials report the potential of PD1 inhibitor treatment for patients with NPC. Within the observed groups, camrelizumab combined with chemotherapy achieved an objective response in 91% of patients as first-line treatment for metastatic NPC (PFS 68% at 1-year) but this was associated with a high rate of grade >3 adverse events (87%; CTCAE version 4.03). The remaining three studies focused on recurrent NPC disease in patients who had received at least one line of prior chemotherapy. Within this group, camrelizumab monotherapy achieved an objective response in 34% of patients (PFS 27% at 1-year; range across all three studies 20.5-34%). No NPC trial has yet reported on specific outcomes for non-PD1 checkpoint inhibitors but 11 on-going studies include alternative targets (e.g. PD-L1/CTLA-4) as combination or monotherapy treatments. In considering checkpoint immunotherapies for NPC, initial results show promise for anti-PD1 interventions. Further phase I-III trials are in progress to clarify clinical outcomes, fully determine safety profiles, and optimize drug combinations and administration schedules.

This article provides an overview of the natural history and management of adenoid cystic carcinoma infiltrating the skull base (SB ACC). A comprehensive review of the available literature and discussion regarding the current management of SB ACC. This review describes the unique pathology, appropriate diagnostic work-up and contemporary management options in SB ACC. There is a specific focus on the role of surgical resection with post-operative radiotherapy, given the literature suggesting a superior locoregional control rate. The importance of surgical decision making and varying surgical approaches are detailed. In addition, the emerging role of biological agents is discussed. The gold standard for SB ACC is surgical resection and post-operative radiation, given the superior locoregional control. In patients not amendable to surgery, palliative radiation should be considered. The role of biological agents is still evolving. The complexity of SB ACC management mandates experienced multi-speciality management.

Background: Tigilanol tiglate, a short-chain diterpene ester, is being developed as intratumoral treatment of a broad range of cancers. We conducted the first-in-human study of intratumoral tigilanol tiglate in patients with solid tumors. Methods: Tigilanol tiglate was administered in a multicentre, non randomized, single-arm study, with escalating doses beginning with 0·06 mg/m2 in tumors estimated to be at least twice the volume of injection (dose-escalation cohorts). Patients with smaller tumors were assigned to the local effects cohort and received the appropriate dose for tumor size. Findings: Twenty-two patients were enrolled. The maximum dose was 3·6 mg/m2 and the maximum tolerated dose was not reached. There was one report of dose-limiting toxicity (upper airway obstruction), two serious adverse events (upper airway obstruction and septicemia), 160 treatment-emergent adverse events, and no deaths. Injection site reactions in all tumors and tumor types occurred even at the lowest dose. Six of the 22 patients experienced a treatment response, with four of the six patients achieving complete response. Interpretation: Intratumoral tigilanol tiglate was generally well tolerated, the maximum tolerated dose was not reached, and clinical activity was observed in 9 tumor types including complete response in four patients. These results support the continued development of tigilanol tiglate for intratumoral administration. Funding: QBiotics Group Limited Brisbane, Queensland, Australia was the sponsor of the study. Keywords: Diterpene ester, EBC-46, Intratumoral, Protein kinase C, Tigilanol tiglate

To demonstrate safety of a developed intranasal dexamethasone-infused in situ gelling formulation, quantification of a validated clinical biomarker indicative of cytotoxic potential using a human sinonasal explant model was first confirmed. Systematic cytotoxicity studies using the lactate dehydrogenase (LDH) detection assay revealed no elevation from baseline, in LDH levels, with tissue integrity of explanted human nasal mucosa also maintained; this was further corroborated using tissue histopathological examination. Next, with safety confirmed ex vivo, freshly excised human nasal tissue was utilised to quantify dexamethasone release from the lead sol–gel systems; this being achieved through development and validation of a HPLC-UV analytical method, which reliably quantified controlled therapeutic release and deposition into mucosal tissue. Collectively, these findings indicate promise in the safety of each excipient within the concentrations employed in the functional sol–gel system, complemented by successful and reliable drug release and deposition into human nasal mucosal tissue. These findings pave the way for application of the dexamethasone-based sol–gel system to the extended delivery of corticosteroids to nasal mucosa in the management of localised inflammatory conditions of an acute and chronic nature, such as chronic rhinosinusitis, which can be expected to benefit from controlled and extended drug delivery characteristics imparted by appropriately engineered in situ gelling systems. Keywords: Intranasal soluble gels, Sinusitis, Explant human nasal mucosa, Tissue toxicity, LDH assay, Drug deposition in human nasal mucosa

Malignancies in and around the temporal bone are aggressive and difficult to manage. In Queensland (Australia), where skin cancer rates are exceedingly high, tumours extending to the temporal bone from surrounding structures occur more commonly than primary cancers. Yet, a paucity of evidence exists as to their management and outcomes. This study aimed to review an Australian centre's experience of managing temporal and peritemporal bone malignancies, reporting on patient and tumour characteristics, treatment, and survival outcomes.Retrospective analysis of patients with primary temporal bone cancer and cancers extending to the temporal bone managed by the Queensland Skull Base Unit (Princess Alexandra Hospital) between 2000 and 2019.A total of 222 patients were identified, of which 203 (91.4%) had cutaneous primaries, with 167 (75.2%) being squamous cell carcinoma (SCC). 73.9% presented with locoregionally recurrent or residual disease. Secondary tumours (92.8%) were 12 times more frequent than primary malignancies (7.2%), with the preauricular subsite the most common (45.5%). In the 201 patients (90.5%) who underwent curative intent surgery, 5-year overall survival, disease-free survival (DFS), and disease-specific survival was 46.6%, 52.2%, and 65.9%, respectively. The preauricular subsite (p = 0.004), melanoma (vs. SCC, p = 0.027), involved margins (p 0.001), and pathologically involved nodes (p 0.001) were associated with significantly worse DFS.This is one of the largest studies of temporal bone malignancy in the literature, comprised primarily of secondary cutaneous malignancies. Although clear differences in epidemiological characteristics exist around the world, survival remains poor. Treatment should focus on achieving a clear margin of resection to optimize outcomes.

The natural history of adenoid cystic carcinoma (ACC) is relentless, defined by treatment failure heralded by reasonable locoregional recurrence and poor long-term distant metastatic disease. In this review, we present an update of clinical features, molecular classification, current targeted therapies, immune landscapes and novel treatment targets with their respective clinical trials. The presented results are defined by a lack of overall response rate and limited progression free survival, with restriction to stable. In addition, ACC is resistant to immune checkpoint inhibition due to low tumour immunogenicity and lack of PD-L1 expression. Here we present a new prospective research paradigm for ACC, including the potential to target prostate specific membrane antigen (PSMA) and the potential for manipulation of target receptors in the clinic. The presentation of this review aims to promote future research to improve response rates and outcomes for therapeutics undergoing clinical trial in ACC.

Summary We describe an ex vivo EGF ligand internalization assay using fresh patient tumor biopsies to determine how antigen targets will be trafficked before patients receive mAb treatment. This protocol facilitates a sensitive and reproducible indication as to mAbs surface retention times during treatment. EGF uptake protocols can also be used to analyze EGFR heterogeneity and localization of EGFR in both tumor and xenograft tissue. The technology can be adapted to analyze other receptors such as PD-L1 for which methods are provided. For complete details on the use and execution of this protocol, please refer to Joseph et al. (2019) and Chew et al. (2020)., Graphical Abstract, Highlights • A robust protocol for spatiotemporal analysis of tumor surface receptors/antigens • Can be used to analyze tumor surface target retention and internalization. • Can be used to analyze surface retention and turnover of tumor therapy/target • Can potentially be used as diagnostic tool for mAb response in patients, We describe an ex vivo EGF ligand internalization assay using fresh patient tumor biopsies to determine how antigen targets will be trafficked before patients receive mAb treatment. This protocol facilitates a sensitive and reproducible indication as to mAbs surface retention times during treatment. EGF uptake protocols can also be used to analyze EGFR heterogeneity and localization of EGFR in both tumor and xenograft tissue. The technology can be adapted to analyze other receptors such as PD-L1 for which methods are provided.

Objectives The major cause of mucosal squamous cell carcinomas of the head and neck (HNSCCs) has been attributed to human papillomavirus (HPV) infection. Here we investigate if microRNA expression in HNSCC can be used as a prognostic tool with or without HPV status. Materials and Methods We performed a discovery miRNA microarray (miRBase v.21) profiling of 52 tonsillar SCCs with TaqMan real-time PCR validation of 228 HNSCCs. Patients had a histologically confirmed primary SCC of the oropharynx, oral cavity, hypopharynx or larynx. Logistic regression models were used to estimate the magnitude of the effect of association with clinical factors and miRNAs associated with HPV status. For recurrence and survival analysis, we used unadjusted and multivariable adjusted Cox proportional hazard regression models. Results Seventeen miRNAs were significantly associated with better prognosis in the discovery phase and were validated in the extended dataset. The best fitting model (AUC = 0.92) for HPV status included age, smoking, and miRNAs: miR-15b, miR-20b, miR-29a, miR-29c, miR-142, miR-146a and miR-205. Using Cox regression model for recurrence, miR-29a was associated with 49% increased risk of recurrence while miR-30e and miR-342 were associated with decreased risk of recurrence with HRs 0.92 (95% CI 0.85–0.99) and 0.84 (95% CI 0.73–0.98), respectively. Our best fitting model for survival included age, gender, alcohol consumption, N stage, recurrence, HPV status, together with miRNAs-20b, 29a, and 342. Conclusion miRNAs show potential to serve as usual biomarkers to predict the clinical course of patients with mucosal HNSCC.

Background and purpose Human papillomavirus-associated oropharyngeal cancer (HPV+ OPC) with regional lymph node metastases has a good prognosis following (chemo)radiation therapy (C/RT) but lymph nodes may remain detectable for several months. Delayed [18F]-Fluorodeoxyglucose positron emission tomography/computed tomography (PET) can identify patients who may avoid post-treatment neck dissection (PTND). We investigated the rate of PTND in HPV+ OPC treated with C/RT and delayed PET-directed management of the neck. Materials and methods This is a retrospective cohort study from a prospectively updated institutional database. Eligible patients were treated between January 2005 and July 2017 with a minimum of 18 months follow up, had node-positive, non-distant metastatic HPV+ OPC and were treated with RT (70 Gy/35#/5 per week) with concurrent Cisplatin or Cetuximab, or accelerated RT alone (68 Gy/34#/6 per week). The primary endpoint was rate of PTND. Secondary endpoints were locoregional failure free survival (LRFFS), regional failure free survival (RFFS), distant metastatic failure free survival (DMFFS), overall survival (OS) and oropharyngeal cancer-specific survival (CSS). Results 418 patients were eligible. Nineteen patients (4.5%) received a PTND. None of the tested variables were associated with an increased risk of PTND. Five-year probabilities for LRFFS, RFFS, DMFS, OS and CSS were, 91.2% (95% CI 88.3–94.2), 93.4% (95% CI 90.8–96.0), 91.2% (95% CI 88.3–94.2), 86.4% (95% CI 83.0–90.1) and 90.2% (95% CI 87.1–93.4), respectively. Conclusion In a large cohort with good median follow up and protocolized C/RT, delayed PET-directed management of the neck affords a lower rate of PTND than reported in historical series without compromising disease control and survival.

Data relating to the efficacy of immune checkpoint inhibitors (ICI) for salivary gland carcinomas (SGC) is gradually evolving with responses varying among different histotypes. To address these disparities, this retrospective analysis examined the prevalence of recognized biomarkers of response to ICI; namely programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), combined positive score (CPS), epidermal growth factor receptor (EGFR), and microsatellite instability (MSI) in patients with SGC with an aim to determine any prognostic or survival benefits and stratify the use of ICI in this disease. Of 52 patients with primary SGC eligible for this study, the most common histological types were adenoid cystic carcinoma (n = 17, 33%), salivary duct carcinoma (n = 14, 27%), mucoepidermoid carcinoma (n = 11, 21%), and acinic cell carcinoma (n = 6, 11%). Immunohistochemistry (IHC) was performed using the Ventana Discovery Ultra auto-staining platform for EGFR, PD-1, PD-L1, and mismatch repair (MMR) proteins. CPS ≥1 defined PD-L1 positive cases and log-rank testing was performed to examine the relationship between PD-L1 expression status and disease-free survival (DFS) and overall survival (OS). CPS positivity was seen in 9 (17.3%) patients, none of which were adenoid cystic carcinoma. All 52 (100%) cases expressed retained MMR proteins inferring microsatellite stability (MSS) and EGFR expression was identified in 45 of 52 (86.5%) patients. CPS positivity (score ≥1) was significantly associated with advanced pathological T status (P = .021), advanced pathological N status (P = .006), high histological tumor grade (P = .045), and positive histological margin (P = .023). Patients with PD-L1 positivity in tumor cells did not have an inferior 3-year OS (P = .93). The data from this retrospective study highlighting the uniform microsatellite stability alongside the low prevalence of CPS positivity suggests that only a minority of SGC patients may benefit from ICI therapy alone. The high rates of EGFR expression in SGC may be a target to augment immune checkpoint therapy response.

Recent studies have evidenced the potential of combining anti-EGFR therapies with anti-PD-1/PD-L1 checkpoint therapies. Both anti-EGFR and anti-PD-1/PD-L1 have been separately tested in the treatment of cutaneous SCC (cSCC). Here, we review recent data on EGFR in the context of cancer progression, as a prognostic and as a therapeutic target in cSCC. Anti-EGFR/checkpoint immunotherapy and other combination therapy approaches are discussed. With the advent of immunotherapy, EGFR is still a valid cSCC target.

To examine contemporary management of squamous cell carcinoma (SCC) involving the temporal bone. The modified Pittsburgh criteria have gained acceptance by many institutions for staging, planning treatment and comparing outcomes. Often primary SCC as well as secondary cutaneous SCC involving the temporal bone can be managed in a similar fashion. T1 tumours should undergo lateral temporal bone resection (LTBR) due to the higher risk of positive margins and recurrence rates with lesser surgical procedures. T2 tumours require LTBR and superficial parotidectomy. T3 and T4 tumours often require a subtotal resection of the temporal bone (STBR), parotidectomy and cutaneous soft tissues as an en bloc excision. Advanced lesions are associated with a diminished survival especially if margins are involved. Patient outcomes are improved by a combination of surgery and postoperative radiotherapy. Preoperative imaging with high resolution CT and MRI is useful, particularly if there is evidence of large nerve perineural spread and nodal disease.

Objective:To prospectively evaluate the incidence, risk factors and natural history of postoperative cerebral venous sinus thrombosis (pCVST) in translabyrinthine vestibular schwannoma microsurgical resection and propose a potential management paradigm.Study Design:Prospective, single cohort, multicenter study.Setting:State-wide academic tertiary referral centers.Patients:Fifty-four consecutive patients who underwent translabyrinthine vestibular schwannoma resection.Main Outcome Measures:Incidence of pCVST on postoperative imaging on Day 7, Day 28, and 12 months postoperatively. Patients and tumor characteristics, risk factors, length of stay, intraoperative parameters, complications, and follow-up were analyzed.Results:pCVST was demonstrated in 21 patients (38.9%) on postoperative imaging. All patients with pCVST were treated conservatively and remained asymptomatic in the immediate postoperative period and long-term follow-up. There were no instances of venous infarction, intracranial hemorrhage, or neurological deficits. A majority (61.1%) of pCVST recannalised on long-term follow up with conservative management. There was a statistical association with pCVST and surgery on the side of the non-dominant cerebral venous drainage (n=17, 80.1%, p=0.034). Patients with pCVST were significantly more likely to have a postoperative cerebrospinal fluid (CSF) leak (n=5, 23.8%, p=0.017).Conclusion:The incidence of pCVST following translabyrinthine vestibular schwannoma resection is much higher than previously recognized. pCVST is more likely to occur when surgery is performed on tumors situated on the side of non-dominant cerebral venous drainage. Despite the high prevalence of this iatrogenic phenomenon, all patients were asymptomatic and a majority resolved, thereby suggesting that conservative management is safe. Correlation between pCVST and increased incidence of CSF leak requires further investigation.

A significant proportion of mucosal squamous cell carcinomas of the head and neck (HNSCC; particularly of the oropharynx) are directly attributable to the human papillomavirus (HPV). The increase in the incidence of HPV-related tumours has been postulated to be due to changing sexual practices in the community. We analysed 136 formalin-fixed paraffin-embedded squamous cell carcinomas from the oral cavity (n=40) and oropharynx (n=96) recruited from the Princess Alexandra Hospital (Brisbane, Australia). Samples were analysed for the presence of HPV DNA using a combination of mucosal HPV general primer GP+ PCR and sequencing; p16INK4a expression was assessed by immunohistochemistry. Each patient completed a questionnaire detailing their lifestyle factors, such as tobacco smoking and alcohol consumption, marital status, and sexual behaviour and history. The HPV DNA prevalence was 5 % in the oral cavity cancers and 72 % in the oropharyngeal cancers (P

The purpose of this study was to examine the relationship between physical impairments, quality of life and disability in patients following neck dissection, with consideration of patient and clinical characteristics. Cross-sectional study of patients

Conclusions: We did not identify any strong associations between HPV-16 viral load and any of the clinical or lifestyle factors. Objective: The epidemiology of oropharyngeal SCC is changing, with an increasing proportion of HPV-positive cases seen in the last decade. It is known that a high viral load is linked to the development of cervical cancer, the relation between viral load and oropharyngeal SCC is less clear. We sought to determine HPV-16 viral load in HPV-positive oropharyngeal SCCs using highly sensitive digital PCR and to identify clinical and lifestyle factors associated with viral load. Subjects and methods: We analysed 45 HPV-16 positive oropharyngeal SCCs diagnosed between 2013 and 2015. All patients completed a lifestyle questionnaire and clinical data were extracted from medical charts. Viral load was determined using digital PCR assays for HPV-L1 and RNAseP. Results: We found large variations in HPV-16 viral load from 1 to 930 copies per cell (median 34 copies per cell).

Summary The five-year survival rate for patients with head and neck squamous cell carcinoma (HNSCC) has remained at ~50% for the past 30 years despite advances in treatment. Tigilanol tiglate (TT, also known as EBC-46) is a novel diterpene ester that induces cell death in HNSCC in vitro and in mouse models, and has recently completed Phase I human clinical trials. The aim of this study was to optimise efficacy of TT treatment by altering different administration parameters. The tongue SCC cell line (SCC-15) was identified as the line with the lowest efficacy to treatment. Subcutaneous xenografts of SCC-15 cells were grown in BALB/c Foxn1nu and NOD/SCID mice and treated with intratumoral injection of 30 μg TT or a vehicle only control (40% propylene glycol (PG)). Greater efficacy of TT treatment was found in the BALB/c Foxn1nu mice compared to NOD/SCID mice. Immunohistochemical analysis indicated a potential role of the host’s innate immune system in this difference, specifically neutrophil infiltration. Neither fractionated doses of TT nor the use of a different excipiant led to significantly increased efficacy. This study confirmed that TT in 40% PG given intratumorally as a single bolus dose was the most efficacious treatment for a tongue SCC mouse model.

The development of cancer vaccines has been intensively pursued over the past 50 years with modest success. However, recent advancements in the fields of genetics, molecular biology, biochemistry, and immunology have renewed interest in these immunotherapies and allowed the development of promising cancer vaccine candidates. Numerous clinical trials testing the response evoked by tumour antigens, differing in origin and nature, have shed light on the desirable target characteristics capable of inducing strong tumour-specific non-toxic responses with increased potential to bring clinical benefit to patients. Novel delivery methods, ranging from a patient’s autologous dendritic cells to liposome nanoparticles, have exponentially increased the abundance and exposure of the antigenic payloads. Furthermore, growing knowledge of the mechanisms by which tumours evade the immune response has led to new approaches to reverse these roadblocks and to re-invigorate previously suppressed anti-tumour surveillance. The use of new drugs in combination with antigen-based therapies is highly targeted and may represent the future of cancer vaccines. In this review, we address the main antigens and delivery methods used to develop cancer vaccines, their clinical outcomes, and the new directions that the vaccine immunotherapy field is taking.

Patients with head and neck cancer can report reduced health-related quality of life several years after treatment. The aim of this study was to identify risk factors for reduced quality of life in patients up to 5 years following neck dissection. This cross-sectional study was conducted at two hospitals in Brisbane, Australia. Patients completed two measures of quality of life: the Neck Dissection Impairment Index (NDII), a region- and disease-specific tool, and the Assessment of Quality of Life-4 Domains, a general tool. Generalised linear modelling was used to determine which demographic and clinical variables were associated with quality of life. The cohort included n = 129 patients (71% male, median age 61, median 3 years since surgery). Positive nodal disease was associated with better quality of life on the NDII [e.g. N2 vs N0 coeff (95% CI) = 22.84 (7.33, 38.37)]. Worse quality of life was associated with adjuvant treatment [e.g. Independent Living domain model: surgery with chemoradiation vs surgery only coeff (95% CI) = -0.11 (-0.22, -0.01)]. Positive nodal disease was associated with better quality of life, which may be a reflection of response shift. Multimodality treatment leads to worse quality of life compared with surgery only.

Objective:Co-Phenylcaine Forte is a nasal spray routinely prescribed by otolaryngologists in Australia. The taste of Co-Phenylcaine Forte is typically described as unpleasant. This study sought to improve the overall patient experience associated with Co-Phenylcaine Forte by generating a Co-Phenylcaine Forte formulation, referred to as Co-Phenylcaine Zest, which contains an added vanilla flavour and masking agent.Methods:Participants were randomised to receive two actuations of Co-Phenylcaine Forte in each nostril followed by two actuations of Co-Phenylcaine Zest, or vice versa. There was a 6–36-hour washout period between each treatment. After the administration of each spray, participants completed a questionnaire to rate various sensory attributes of each formulation on seven-point ordinal scales. Patients reported their overall formulation preference after receiving both treatments.Results:A total of 86 participants completed the trial. Seventy-four per cent of patients preferred Co-Phenylcaine Zest, 21 per cent preferred Co-Phenylcaine Forte and 5 per cent had no preference (p < 0.001). The satisfaction score associated with Co-Phenylcaine Zest was 1.22 points greater than with Co-Phenylcaine Forte (p < 0.001).Conclusion:A novel formulation of Co-Phenylcaine Forte was created by adding a flavour and a masking agent; this formulation was preferred by most patients.

Objectives To determine whether the International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S) for HPV associated oropharyngeal carcinoma (HPV + OPC) is a better discriminator of overall survival (OS), compared with the 7th edition (7th Ed) AJCC/UICC TNM staging following curative radiotherapy (RT). Material and methods The 5-year OS for all patients with non-metastatic (M0) p16-confirmed OPC treated between 2005 and 2015 was determined and grouped based on the 7th Ed AJCC/UICC TNM and ICON-S staging. Results A total of 279 patients met the inclusion criteria. The 5-year OS with the 7th Ed TNM classification were Stage I/II 88.9% (95% CI; 70.6–100%), Stage III 93.8% (95% CI; 85.9–100%), Stage IVa 86.4% (95% CI; 81.6–91.5%) and Stage IVb 62.3% (95% CI; 46.8–82.8%). On multivariate Cox regression analysis there was no statistically significant OS difference when comparing Stage I/II with, Stage III (p = 0.98, HR = 0.97, 95% CI; 0.11–8.64), IVa (p = 0.67, HR = 1.56, 95% CI; 0.2–11.94) and IVb (p = 0.11, HR = 5.54, 95% CI; 0.69–44.52), respectively. The 5-year OS with ICON-S staging were Stage I 93.6% (95% CI; 89.4–98.0%), Stage II 81.9% (95% CI; 73.7–91.1%) and Stage III 69.1% (95%; 57.9–82.6%). There was a consistent decrease of OS with increasing stage. On multivariate Cox regression analysis, when compared to Stage I, OS was significantly lower for stage II (p = 0.007, HR = 2.84, 95% CI; 1.33–6.05) and stage III (p Conclusion The ICON-S staging provides better OS stratification for HPV + OPC following RT compared with the 7th Ed TNM staging.

Mucoadhesive in situ gelling systems (soluble gels) have received considerable attention recently as effective stimuli-transforming vectors for a range of drug delivery applications. Considering this fact, the present work involves systematic formulation development, optimization, functional evaluation and ex vivo performance of thermosensitive soluble gels containing dexamethasone 21-phosphate disodium salt (DXN) as the model therapeutic. A series of in situ gel-forming systems comprising the thermoreversible polymer poloxamer-407 (P407), along with hydroxypropyl methyl cellulose (HPMC) and chitosan were first formulated. The optimized soluble gels were evaluated for their potential to promote greater retention at the mucosal surface, for improved therapeutic efficacy, compared to existing solution/suspension-based steroid formulations used clinically. Optimized soluble gels demonstrated a desirable gelation temperature with Newtonian fluid behaviour observed under storage conditions (4-8°C), and pseudoplastic fluid behaviour recorded at nasal cavity/sinus temperature (≈34°C). The in vitro characterization of formulations including rheological evaluation, textural analysis and mucoadhesion studies of the gel form were investigated. Considerable improvement in mechanical properties and mucoadhesion was observed with incorporation of HPMC and chitosan into the gelling systems. The lead poloxamer-based soluble gels, PGHC4 and PGHC7, which were carried through to ex vivo permeation studies displayed extended drug release profiles in conditions mimicking the human nasal cavity, which indicates their suitability for treating a range of conditions affecting the nasal cavity/sinuses.

The incidence of oropharyngeal squamous cell carcinomas (SCCs) is increasing and is believed to reflect changing sexual practices in recent decades. For this case-case comparative study, we collected medical and life-style information and data on sexual behavior from 478 patients treated at the head and neck clinic of a tertiary hospital in Brisbane, Australia. Patients were grouped as (i) oropharyngeal SCC (n 5 96), (ii) oral cavity, larynx and hypopharynx SCC ("other HNSCCs," n 5 96), (iii) other SCCs (n 5 141), and (iv) other diagnoses (n 5 145). We fitted multivariable logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) associated with lifestyle factors and sexual behaviors. Compared to the other three patient groups, the oropharyngeal SCC patients had overall more sexual lifetime partners (kissing, oral sex and sexual intercourse). Oropharyngeal SCC patients were significantly more likely to have ever given oral sex compared to the other three patient groups-93% of oropharyngeal SCC patients, 64% of other HNSCC patients, and 58% of patients with other SCC or other diagnoses. Oropharyngeal SCC patients were significantly more likely to have given oral sex to four or more partners when compared to patients with other HNSCC (odds ratio [OR] 11.9; 95% CI 3.5-40.1), other SCC (OR 16.6; 95% CI 5.3-52.0) or patients with other diagnoses (OR 25.2; 95% CI 7.8-81.7). The very strong associations reported here between oral sex practices and risks of oropharyngeal SCC support the hypothesis that sexually transmitted HPV infections cause some of these cancers.

Summary A safe and controlled manipulation of endocytosis in vivo may have disruptive therapeutic potential. Here, we demonstrate that the anti-emetic/anti-psychotic prochlorperazine can be repurposed to reversibly inhibit the in vivo endocytosis of membrane proteins targeted by therapeutic monoclonal antibodies, as directly demonstrated by our human tumor ex vivo assay. Temporary endocytosis inhibition results in enhanced target availability and improved efficiency of natural killer cell-mediated antibody-dependent cellular cytotoxicity (ADCC), a mediator of clinical responses induced by IgG1 antibodies, demonstrated here for cetuximab, trastuzumab, and avelumab. Extensive analysis of downstream signaling pathways ruled out on-target toxicities. By overcoming the heterogeneity of drug target availability that frequently characterizes poorly responsive or resistant tumors, clinical application of reversible endocytosis inhibition may considerably improve the clinical benefit of ADCC-mediating therapeutic antibodies.

Malignant skull base tumours are a rare and diverse group of histological entities that cross the skull base. Their management requires a multidisciplinary approach that aims to achieve microscopically clear margins, dural reconstitution to avoid cerebrospinal fluid (CSF) leak, soft tissue reconstruction and where possible, an en bloc resection. Both traditional craniofacial and more modern endoscopic techniques can be utilized, if the surgical and management goals can be achieved successfully. This is then combined with adjuvant therapy, typically radiotherapy, to maximize prognosis. We discuss both anterior and lateral skull base tumours as well as consider the special case of perineural spread as an example of complex disease at the skull base.

Background Adenoid cystic carcinoma (ACC) is a salivary gland malignancy with a propensity for perineural spread and diffuse soft tissue infiltration. In the head and neck this unique biological behaviour can result in skull base involvement. A lack of consensus regarding management of ACC involving the skull base in conjunction with the technical and reconstructive challenges of oncological resection in this region has led to variation in practice between institutions. Method Retrospective multicentre review of patients with advanced ACC infiltrating the skull base, treated surgically by the Queensland Skull Base Unit between 2005 and 2017, with a minimum follow up time of 24 months. Results 32 patients were treated for ACC with skull base involvement with oncological resection and post-operative radiation in the study period with a median follow up of 82.18 months (33.11–159.53 months). 5 and 10 year locoregional control were both 88.2% (95% CI 67.5–96.1) despite a high rate of microscopically positive margins (81.3%). Metastatic disease rates were high, resulting in low rates of disease free survival (DFS) (53.0% at 5 years (95% CI 33.7–69.0) and 23.0% at 10 years (9.5–39.8)). Overall survival (OS) was high (5 year 91.8% (95% CI 71.1–97.9), 10 year 63.7% (95% 37.5–81.2)), despite the advanced nature of disease. Conclusion High rates of locoregional control can be achieved in skull base ACC with oncological resection of disease and post-operative radiation. Whilst disease recurrence rates are high, a majority of recurrence is metastatic and does not confer poor intermediate term overall survival.

Objective: To compare the neck and shoulder motor function of patients following neck dissection, including comparison with a group of healthy volunteers. Study Design: Cross-sectional study. Setting: Two tertiary hospitals in Brisbane, Australia. Subjects and Methods: Participants included patients 0.5 to 5 years after unilateral nerve-sparing neck dissection and healthy control subjects. Demographic and clinical information was collected with cervical and shoulder motor function measures (scapular resting position, active range of motion, and isometric muscle strength). Differences between groups were examined via regression analyses that included statistical adjustment for the potential effect of age, sex, body mass index, and other disease-related variables. Results: The 57 patients (68%, men; median age, 62 years) were typically older than the 34 healthy controls (47%, men; median age, 46 years). There were no differences between types of nerve-preserving neck dissection for any of the motor function measures. When adjusted for age, sex, and body mass index, healthy volunteers (vs patients) had significantly greater cervical range (eg, extension coefficient [95% CI]: 11.04° [4.41°-17.67°]), greater affected shoulder range (eg, abduction: 16.64° [1.19°-31.36°]), and greater isometric strength of the cervical flexors (eg, men: 4.24 kgf [1.56-6.93]) and shoulder flexors (eg, men: 8.00 kgf [1.62-14.38]). Conclusions: Strength and flexibility of the neck and shoulder are impaired following neck dissection in comparison with healthy controls. Clinicians and researchers are encouraged to consider the neck—and the neck dissection as a whole—as a source of motor impairment for these patients and not just the status of the accessory nerve.

Objectives/Hypothesis To investigate balance, community mobility, gaze instability, and dizziness handicap and assess falls risk in people who are conservatively managed with small vestibular schwannoma (VS). Study Design Cross-sectional study with controls. Methods The study involved 18 people (mean age 58.7 ± 12.2 years) diagnosed with VS (

BackgroundWhile human papillomavirus (HPV) is an accepted risk factor for oropharyngeal squamous cell carcinoma (SCC), its aetiological role in oral cavity SCC remains unclear. This study aimed to determine the HPV prevalence in an Australian population.

Understanding the natural history of diseases enables the clinician to better diagnose and treat their patients. Perineural spread of head and neck cancers are poorly understood and often diagnosis is delayed resulting in poorer outcomes and more debilitating treatments. This article reviews a large personal series of head and neck malignancy presenting with perineural spread along almost exclusively the trigeminal and/or facial nerves. A detailed analysis of squamous cell carcinoma of cutaneous origin is presented including an analysis of likely primaries, which most often have occurred months to years prior. The importance of early detection is reinforced by the highly significant (p

Spread of head and neck cancer along the cranial nerves is often a lethal complication of this tumour. Current treatment options include surgical resection and/or radiotherapy, but recurrence is a frequent event suggesting that our understanding of this tumour and its microenvironment is incomplete. In this study, we have analysed the nature of the perineural tumour microenvironment by immunohistochemistry with particular focus on immune cells and molecules, which might impair anti-tumour immunity. Moderate to marked lymphocyte infiltrates were present in 58.8% of the patient cohort including T cells, B cells and FoxP3-expressing T cells. While human leukocyte antigen (HLA) class I and more variably HLA class II were expressed on the tumour cells, this did not associate with patient survival or recurrence. In contrast, galectin-1 staining within lymphocyte areas of the tumour was significantly associated with a poorer patient outcome. Given the known role of galectin-1 in immune suppression, the data suggest that galectin inhibitors might improve the prognosis of patients with perineural spread of cancer.

Adenoid cystic carcinoma (ACC) is a rare and highly aggressive malignant tumor that affects the salivary glands, lacrimal and ceruminous glands of the head and neck region. ACC tends to spread to neighboring regions via perineural methods and metastasize from the primary region to the lung, liver and bones. Current treatment includes surgical resection of the primary lesion followed by radiotherapy. However, about 80% of the patients develop metastatic disease with poor prognosis; hence, new treatment is necessary for ACC patients. EGFR is known to be overexpressed in most of salivary gland carcinomas, particularly ACC. Numerous targeted therapies, including anti-EGFR monoclonal antibody, have been trialed in ACC patients, with disease stabilization reported in approximately half of the trial patients. Our laboratory is examining a combination therapy in which we combined the use of a dynamin inhibitor with monoclonal antibody to enhance antibody-dependent cellular cytotoxicity (ADCC) response in murine models and now in clinical trial. As preclinical data, we examined the signaling profile of the tumor cells in the combination therapy with different dynamin inhibitors. Citation Format: Hui Yi Chew, Benedict Panizza, Caroline Cooper, Riccardo Dolcetti, Jim Coward, Adam McCluskey, Phillip J. Robinson, James W. Wells, Fiona Simpson. Examining EGFR-mediated PI3K/Akt pathway in combination therapy of cetuximab and dynamin inhibition [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B12.

Objectives To assess the utility of a repeat positron emission tomography/computed tomography (PET/CT) instead of immediate neck dissection (ND) for incomplete nodal response (IR) in Human Papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPC) following chemoradiotherapy/radiotherapy [(chemo)RT]. Materials and methods Patients with non-distant metastatic, node positive (N+) disease treated between Jan/2005 to Jan/2016, achieved complete response at the primary with no distant relapse on a 12-week re-staging PET/CT were evaluated. Patients underwent surveillance after complete nodal response (CR). Patients with IR underwent repeat PET/CT at 16 weeks to direct neck management. Primary endpoints were CR conversion rate and subsequent regional failure following a 16-week PET/CT directed ND. Secondary endpoints were predictive values (PV) of the 12- and 16-week PET/CT for residual nodal disease, predictors for requiring the 16-week PET/CT, 5 year regional, locoregional failure free survival (FFS) and overall survival (OS). Results 235 patients were evaluated. Median follow up was 56 (range 19–60) months. 41 patients underwent 16-week re-staging PET/CT, 29 (71%) converted to CR. No subsequent regional failures occurred following a 16-week PET/CT directed ND. Positive and negative PV of the 12- and 16-week PET/CT for residual nodal disease was 12% & 98%, and 33% & 97%, respectively. N-category (AJCC/UICC 7th edition) predicted for requiring a 16-week PET/CT on univariate analysis (P-value 0.02). 5 year regional, locoregional FFS and OS was 95.8%, 93.4% and 90.8%, respectively. Conclusion For N+ HPV-associated OPC achieving IR on the 12-week re-staging PET/CT following (chemo)RT, a repeat 16-week PET/CT can spare patients from unnecessary surgery.