Sexual debut and association with oral human papillomavirus infection, persistence and oropharyngeal cancer-An analysis of two Australian cohorts.

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.

Recommendations for head and neck surgical oncology practice in a setting of acute severe resource constraint during the COVID-19 pandemic: an international consensus.

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.

Optimising intratumoral treatment of head and neck squamous cell carcinoma models with the diterpene ester Tigilanol tiglate.

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.

Toxicity evaluation and nasal mucosal tissue deposition of dexamethasone-infused mucoadhesive in situ nasal gelling systems.

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.

Sexual behaviour, HPV status and p16INK4a expression in oropharyngeal and oral cavity squamous cell carcinomas: a case-case comparison study.

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<0.0001). HPV-16 was the most commonly detected HPV type (found in 91 % of all HPV-positive tumours). There was a strong correlation between HPV DNA positivity and positive p16INK4a staining in oropharyngeal tumours (P<0.0001). Having an HPV-related tumour was associated with being married or having been married previously (P=0.046), an increasing number of passionate kissing partners (P=0.046), ever having given oral sex (P=0.0007) and an increasing number of oral sex partners (P=0.0015). This study found a higher prevalence of HPV in oropharyngeal compared to oral cavity tumours, with a strong association being identified between oral sex behaviours and HPV-positive tumours. Further research is needed to establish that vaccines will reduce the transmission and carriage of oropharyngeal HPV infections.

An Update on Cellular MicroRNA Expression in Human Papillomavirus-Associated Head and Neck Squamous Cell Carcinoma.

Squamous cell carcinoma of mucosal sites in the head and neck (HNSCC) is the sixth most common cause of cancer worldwide, and despite advances in conventional management, it still has significant morbidity and mortality associated with both diagnosis and treatment. Advances in our understanding of the biological mechanisms underlying this disease have demonstrated a significant difference between human papillomavirus (HPV)-associated, HPV and tobacco associated, and HPV-negative disease. It remains important to further elucidate the biologic and genetic differences between HPV-associated and tobacco-associated disease, with the aim of earlier diagnosis through screening, and advances in management including the development of novel therapeutic agents. MicroRNAs (miRNAs) are small, non-coding RNAs that function as post-transcriptional regulators of gene expression, and have effects on almost every cellular function, and have potentially important applications to diagnosis, management and prognosis in HNSCC. Establishing a cellular miRNA expression profile for HPV-associated disease may therefore have important implications for the screening and treatment of this disease. This review summarises the current findings regarding miRNA expression in mucosal HNSCC, and focuses particularly on miRNA expression in HPV-associated tumours.

Past sexual behaviors and risks of oropharyngeal squamous cell carcinoma: a case-case comparison.

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 = 96), (ii) oral cavity, larynx and hypopharynx SCC ("other HNSCCs," n = 96), (iii) other SCCs (n = 141), and (iv) other diagnoses (n = 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.

Predictors of health-related quality of life in patients treated with neck dissection for head and neck cancer.

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.

Galectin-1 is associated with poor prognosis in patients with cutaneous head and neck cancer with perineural spread.

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.

Evaluation of facial nerve perineural spread from cutaneous squamous cell carcinoma using 3T MR neurography.

INTRODUCTION: Perineural spread (PNS) is a rare but potentially fatal consequence of cutaneous squamous cell carcinoma (cSCC) of the head and neck. We aimed to evaluate the accuracy of 3T MR neurography in detecting and defining the extent of facial nerve (VII) PNS from cSCC, and highlight characteristic radiological features in peripheral branches to improve early diagnosis. METHODS: Single-institution retrospective review of 38 patients with clinical, radiological, and/or histopathological findings consistent with VII PNS from cSCC who underwent pre-operative 3T MR neurography. RESULTS: Compared to histopathology (gold standard), 3T MR neurography had a sensitivity of 89% and positive predictive value of 97%. In true-positive cases (n = 33), zonal extent was correctly identified in 100%. Seventy-nine% had simultaneous trigeminal nerve (V) PNS, mostly involving the auriculotemporal branch of the mandibular nerve (64%). When the causative lesion was absent (n = 23), the extra-temporal VII demonstrated asymmetrical enhancement alone (n = 6), bulky expansion (n = 8), or extra-neural spread (n = 9). Peripheral VII branch involvement, particularly the buccal and zygomatic, was readily identified using known anatomical landmarks. CONCLUSION: 3T MR neurography is highly accurate in evaluating VII PNS from cSCC, and thus should be specifically requested by physicians if suspicious for disease. Coexistent V PNS was common, highlighting the need to examine V branches to allow complete treatment planning. The unique radiological patterns identified showcases disease progression. As early detection improves patient outcomes, the radiologist must look for peripheral VII involvement in specific anatomical areas, which is within the capabilities of 3T MR neurography.

Fascial layers encountered in the lateral skull base region: A cadaveric and radiological analysis.

BACKGROUND: In our experience, the anterior carotid sheath forms an important plane of dissection when excising temporal bone region cancers. However, its anatomical composition, relationships, and radiological appearance remains unclear. METHODS: Eight sides of cadaveric heads were dissected. Anatomical findings were correlated with a high-resolution baseline T1 MRI. RESULTS: The anterior carotid sheath was formed by the tensor-vascular-styloid fascia, stylopharyngeal fascia, buccopharyngeal fascia (BPF), and longus capitis fascia (LCF), and appeared as a hypointense line on MRI. Not previously described, the glossopharyngeal nerve pierced the sheath 9.0 mm (SD 2.1 mm) below the skull base and traveled through its LCF and BPF layers to exit near the pharynx. CONCLUSION: Multiple fascial layers formed the anterior carotid sheath at the skull base, and this was radiologically identifiable. Further studies are required to validate findings and investigate the role this fascial plane has in forming an effective barrier to spread of malignancy.

Patterns of spread and anatomical prognostic factors of pre-auricular cutaneous squamous cell carcinoma extending to the temporal bone.

BACKGROUND: Improvements can be made in the management and staging of advanced pre-auricular cutaneous squamous cell carcinoma (cSCC). We aimed to analyze radiological patterns of spread and clinico-anatomical prognostic factors. METHODS: Retrospective review of 54 patients with pre-auricular cSCC (cutaneous/nodal) who underwent temporal bone resection with curative intent. RESULTS: Involvement of the cartilaginous external auditory canal (EAC) (79.6%) and retromandibular space (63.0%) was common. Styloid process/anterior carotid sheath (ACS) (11.1%) and bony EAC (7.4%) involvement were rare. ACS involvement resulted in high rates of involved surgical margins (100%) and poor outcomes on univariable analysis. Negative prognostic factors on multivariable analysis included salvage surgery and invasion of the bony EAC, mandible, pterygoid muscle(s), and dura. CONCLUSION: The bony EAC and ACS can form temporary barriers to tumor spread, with the latter representing a potential limit of resectability. Prognostic factors revealed can lead to the development of a more appropriate staging tool.

Development of an in vivo murine model of perineural invasion and spread of cutaneous squamous cell carcinoma of the head and neck.

Introduction: Cutaneous squamous cell carcinoma of the head and neck (cSCCHN) can metastasize by invading nerves and spread toward the central nervous system. This metastatic process is called perineural invasion (PNI) and spread (PNS). An in vivo sciatic nerve mouse model is used for cSCCHN PNI/PNS. Here we describe a complementary whisker pad model which allows for molecular studies investigating drivers of PNI/PNS in the head and neck environment. Methods: A431 cells were injected into the whisker pads of BALB/c Foxn1nu and NSG-A2 mice. Tumor progression was monitored by bioluminescence imaging and primary tumor resection was performed. PNI was detected by H&E and IHC. Tumor growth and PNI were assessed with inducible ablation of LOXL2. Results: The rate of PNI development in mice was 10%-28.6%. Tumors exhibited PNI/PNS reminiscent of the morphology seen in the human disease. Our model's utility was demonstrated with inducible ablation of LOXL2 reducing primary tumor growth and PNI. Discussion: This model consists in a feasible way to test molecular characteristics and potential therapies, offers to close a gap in the described in vivo methods for PNI/PNS of cSCCHN and has uses in concert with the established sciatic nerve model.

Facial nerve perineural spread from cutaneous squamous cell carcinoma of the head and neck: A single institution analysis of epidemiology, treatment, survival outcomes, and prognostic factors.

BACKGROUND: This study aimed to examine patients with facial nerve (VII) perineural spread (PNS) from cutaneous squamous cell carcinoma of the head and neck. METHODS: Retrospective analysis of patients managed by an Australian tertiary center between 2000 and 2019. RESULTS: Seventy three patients were included. Most presented with recurrent disease (89.0%) and simultaneous trigeminal nerve (V) involvement (67.1%). Of the 55 patients (75.3%) who received curative intent treatment, 48 received surgery plus/minus post-operative radiotherapy. In these patients, 5-year disease-free survival, disease-specific survival, and overall survival was 50.7%, 68.7%, and 58.1%, respectively. Pathological nodal disease, involved margins, increasing VII zonal extent, and concurrent zone 2 V PNS significantly worsened outcomes. CONCLUSION: High rates of recurrent disease reflects the importance of adequate treatment of the primary. Surgery and post-operative radiotherapy remains the mainstay treatment. Outcomes are improved in early-stage disease and with clear surgical margins, reinforcing the need for prompt diagnosis and intervention.

Epidemiology and treatment outcomes of cutaneous squamous cell carcinoma extending to the temporal bone.

BACKGROUND: Accurate epidemiological and outcomes data regarding cutaneous squamous cell carcinoma (cSCC) extending to the temporal bone is lacking. METHODS: Retrospective analysis of 167 Australian patients with primary and peri-temporal bone cSCC. RESULTS: cSCC extending from secondary subsites (93.4%) was 14 times more frequent than primary temporal bone SCC (6.6%). For patients who underwent curative surgery ± post-operative radiotherapy (n = 146, 87.4%), 5-year disease-free survival, locoregional recurrence-free survival, disease-specific survival, and overall survival was 53.0%, 59.4%, 67.9%, and 44.7%, respectively. External ear and pre-auricular tumors, salvage surgery, tumor size (≥40 mm medial-lateral), nodal disease, and involved margins were negative predictors of survival in multivariable analysis. CONCLUSION: In regions of high sun exposure, cSCCs extending to the temporal bone are more common than primary cancers. Outcomes are improved with clear margins, justifying the need for radical resection. Further research regarding pre-auricular cancers is required given poorer associated survival outcomes.

Malignancies requiring temporal bone resection: An Australian single-institution experience.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Evolution of Cancer Vaccines-Challenges, Achievements, and Future Directions.

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.

Phase I dose-escalation study to determine the safety, tolerability, preliminary efficacy and pharmacokinetics of an intratumoral injection of tigilanol tiglate (EBC-46).

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.

Neck and Shoulder Motor Function following Neck Dissection: A Comparison with Healthy Control Subjects.

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.