ABSTRACT:Although human papillomavirus (HPV)–positive oropharyngeal squamous cell carcinoma (OPSCC) is associated with better prognosis than HPV-negative disease, ∼30% of cases relapse despite curative-intent radiotherapy (±chemotherapy). We aimed to develop a proteomic signature associated with risk of recurrence within HPV+OPSCC. We analyzed tumor specimens from 124 patients with T1–4N0–3M0 HPV+OPSCC: 50 patients with residual or recurrent disease within 5 years of treatment and 74 age and performance status–matched patients with no recurrence. Proteomic analysis was performed on archival formalin-fixed, paraffin-embedded primary tumor core biopsy specimens and matched normal adjacent tissues using quantitative data-independent acquisition mass spectrometry. Recurrence-free survival (RFS), both locoregional and distant, was the primary endpoint. Univariate Cox regression analysis identified peptides associated with RFS, from which a risk score was established to generate a peptide-based signature. A total of 7,597 protein groups were identified across the cohort, 1,565 of which were differentially abundant between tumor and normal adjacent tissues, with 1,218 being significantly increased in tumors. Improved 5-year RFS (q-value < 0.5) was associated with 405 differentially abundant peptides (from 233 unique proteins) within the 124 tumors. Among them a 26-peptide signature encompassing 26 protein groups was associated with RFS and was able to stratify patients into low, intermediate, or high risk of recurrence (concordance index = 0.941, P < 0.0001). Data available via ProteomeXchange PXD036891. Overall, a 26-peptide signature can be used to risk-stratify HPV+OPSCC. Validation of this proteomic prognostic signature in an independent cohort is required to assess its potential use in future clinical trials to better tailor initial therapy. SIGNIFICANCE:HPV+OPSCC incidence is increasing, with heterogeneous treatment outcomes despite favorable prognosis. Current de-escalation strategies show inferior results, highlighting the need for precise risk stratification. Using data-independent acquisition mass spectrometry proteomics, we identified a 26-peptide signature that stratifies patients into risk categories, potentially enabling personalized treatment decisions and optimal patient selection for de-escalation trials.

ABSTRACTBackgroundPerineural spread of cutaneous head and neck squamous cell carcinoma is most effectively managed by surgical resection with a clear central margin at the affected nerve. For ophthalmic nerve disease, there is no clear consensus regarding the extent of spread which is resectable via an orbit‐preserving neurectomy, either in regard to oncological outcome or technical feasibility.MethodsCadaveric anatomical study of 10 human orbits, with endoscopic and exoscopic dissection of the frontal division of the ophthalmic nerve, to quantify the maximal extent of resection via orbit‐preserving techniques and to discern the advantages and disadvantages of exoscopic versus endoscopic visualization aids.ResultsMean achievable resection length measured from the supraorbital ridge was 40.9 mm (n = 10). No branching patterns were identified which would preclude neurectomy as an oncologically sound option.ConclusionsOrbit‐preserving resection of the ophthalmic nerve is technically feasible to a distance of approximately 4 cm, encompassing the majority of Williams Zone 1.

ABSTRACTBackgroundStandardized surgical approaches to advanced pre‐auricular cutaneous squamous cell carcinomas (cSCC) are lacking.MethodsFifty–four patients who underwent lateral temporal bone resection (LTBR) for pre‐auricular cSCC were grouped into “Levels” of increasing disease spread. Surgical approaches to achieve negative‐margin resection were designed for each Level and replicated on cadaveric specimens.ResultsLevel 1 extended to the external auditory canal, requiring LTBR ± superficial parotidectomy. Level 2 involved the retromandibular space ± temporomandibular joint, necessitating partial mandibulectomy, in addition to the above. Level 3 and 4 involved the deep parotid, being situated either away from (> 5 mm) or close (≤ 5 mm) to the anterior carotid sheath (ACS), respectively. These tumors require radical parotidectomy, with incorporation of the ACS for Level 4. Level 5 involved the ACS at the skull base and should be treated non‐surgically.ConclusionThis Level‐based system will hopefully lead to further prospective studies and improvements in outcomes for advanced pre‐auricular cSCC.

The high rates of pathologic complete response (pCR) after neoadjuvant immunotherapy have generated interest for a risk adaptive surgical and radiotherapy-free management approach to reduce morbidity in resectable cutaneous squamous cell carcinoma (cSCC). We conducted a phase II, multicenter study to evaluate pembrolizumab in patients with resectable stage II-IV (M0) cSCC. Patients received pembrolizumab, administered at a dose of 200 mg once every 3 weeks for four cycles, before undergoing a 18F-labeled fluorodeoxyglucose-positron emission tomography assessment. Patients who achieved a clinical complete response (cCR), defined as a complete metabolic response and negative mapping biopsies of the target site(s), avoided planned surgery and radiotherapy (total de-escalation). In the absence of a cCR, patients underwent surgery with the recommendation of omitting adjuvant radiotherapy (partial de-escalation) on the basis of a pCR. Patients proceeded to 13 additional cycles of maintenance pembrolizumab. The primary end point of a clinical or pathologic complete response (cpCR) was the combined rate of cCR and pCR. Key secondary end points included omission of surgery ± radiotherapy, event-free survival, and adverse events (AEs). A total of 27 patients received pembrolizumab. A cpCR was observed in 17 patients (63% [95% CI, 42 to 80), composed of a pCR in four (15%) and a cCR in 13 (48%). Total and partial de-escalation was achieved in 48% and 15%, respectively. With a median follow-up of 18 months, no recurrence was seen in those patients with a cpCR. Treatment-related AEs of grade ≥3 were observed in two patients (7%). There were no treatment-related deaths. Pembrolizumab led to a high rate of cpCR in resectable cSCC and demonstrated the potential to avoid surgery and radiotherapy.

Formalin-fixed paraffin-embedded (FFPE) tissues present an important resource for cancer proteomics. They are more readily available than fresh frozen (FF) tissues and can be stored at ambient temperature for decades. FFPE blocks are largely stable for long-term preservation of tumour histology, but the antigenicity of some proteins in FFPE sections degrades over time resulting in deteriorating performance of immunohistochemistry (IHC). It is not known whether FFPE sections that have previously been cut from blocks and used for liquid chromatography-mass spectrometry (LC–MS) analysis at a later time are affected by storage time or temperature. We determined the stability of FFPE sections stored at room temperature (RT) versus − 80 °C over 48 weeks. The stored sections were processed at different timepoints (n = 11) and compared to sections that were freshly cut from FFPE blocks at each timepoint (controls). A total of 297 sections (rat brain, kidney and liver stored at RT, − 80 °C or freshly cut) were tryptically digested and analysed on TripleTOF 6600 mass spectrometers in data-dependent acquisition (DDA) mode. Kidney and liver digests were also analysed in data-independent acquisition (DIA) mode. The number of proteins and peptides identified by DDA with ProteinPilot and some common post-translational modifications (PTMs) were unaffected by the storage time or temperature. Nine of the most common FFPE-associated modifications were quantified using DIA data and all were unaffected by storage time or temperature. Therefore, FFPE tissue sections are suitable for proteomic studies for at least 48 weeks from the time of sectioning.

9514 Background: Neoadjuvant anti-Programmed Death therapy has shown a 64% complete or major pathological response rate in patients (pts) with resected stage II-IV(M0) cSCC. The De-Squamate study (NCT05025813) evaluated the feasibility of a risk adapted surgical de-escalation approach guided by clinical, radiological and pathological response in resectable cSCC pts of all sites receiving neoadjuvant pembrolizumab. Methods: This multi-centre, open-labelled, non-randomised, single-arm phase 2 study evaluated the response of neoadjuvant Pembrolizumab for 4 cycles administered IV 200mg Q3W in immunocompetent pts with Stage II-IV (M0) resectable cSCC. Pts underwent CT/MRI and 18F-FDG-PET imaging at baseline and following completion of neoadjuvant pembrolizumab. In those with a complete metabolic response, mapping biopsies of target site(s) were performed and if negative for residual SCC (clinical complete response [CCR]), surgery and post operative radiation therapy (PORT) were omitted. Patients with clinical or radiological residual disease/ positive mapping biopsy underwent surgical resection. PORT was de-escalated if there was a pathological complete response (PCR - no residual tumour cells) or major pathological response (MPR - less than or equal to 10% viable tumour cells). Pts proceeded to 13 cycles of maintenance Pembrolizumab. The primary endpoint was the combined rate of PCR, MPR and CCR following neoadjuvant Pembrolizumab and secondary endpoint includes treatment de-escalation and safety. Results: All 27 patients were enrolled and received a minimum of 2 cycles of neoadjuvant Pembrolizumab. The primary endpoint was observed in 17 patients (63%, 95% CI: 42-80), comprised of PCR (15%), MPR (0%) and CCR (48%). De-escalation of both surgery and PORT was achieved in 48% and a further 15% avoided PORT alone. With a minimum follow up of 6 months, no pts with PCR/MPR/CCR recurred. Investigator assessed treatment-related adverse events ≥ grade 3 was seen in 2 patients (7%). Conclusions: Pembrolizumab led to a high rate of PCR and CCR in resectable cSCC. The de-squamate study design effectively selected pts for surgical and PORT de-escalation and demonstrated a sustained response in this cohort. Clinical trial information: NCT05025813 .

BACKGROUND:There are no large studies reporting oncological or survival outcomes for patients diagnosed with perineural spread (PNS) of cutaneous squamous cell carcinoma (cSCC) via the ophthalmic nerve (V1). Where orbital exenteration may be necessary for curative treatment, it is critical to have survival data with which the morbidity associated with surgical treatment can be justified. Furthermore, with the emerging treatment option of immunotherapy, current standard of care outcomes are needed to help guide future trial design and eventually changed management guidelines. OBJECTIVE:To determine the oncological and survival outcomes observed in patients with PNS of cSCC via V1. MATERIALS AND METHODS:Retrospective analysis of prospectively maintained cohort of patients with PNS of cSCC via V1 treated in a tertiary Australian head and neck oncology/skull base referral center. Consecutive sample of 53 patients managed between March 1, 1999 and April 30, 2020. Follow-up closure date was September 1, 2021. Curative-intent surgery, curative-intent radiotherapy, or palliative care was undertaken. Endpoints included five-year overall, disease-specific, and disease-free survival from the date of treatment. RESULTS:Five-year Kaplan-Meier overall survival was 61.9% (95% CI 46.2%-74.3%), with disease-specific survival of 74.6% (95% CI 58.8%-85.3%), and disease-free survival 62.1% (95% CI 46.5%-74.3%). Survival was superior in patients treated via surgery and adjuvant radiotherapy than in those receiving surgery alone or definitive radiotherapy. Survival was superior among patients with less advanced disease as assessed by the Williams zonal staging system; patients with Zone 1 disease had disease-specific survival of 94.1% at 5 years with 82.5% disease-free survival. DISCUSSION:Five-year oncological and survival outcomes in this cohort were favorable. Superior survival was observed in patients treated with curative-intent surgery and adjuvant radiotherapy. Less extensive disease as delineated by the Williams zonal staging system was associated with improved survival. CONCLUSION:Surgical resection with adjuvant radiotherapy confers favourable oncological and survival outcome in patients with V1 PNS, particularly with early disease limited to Zone 1.

BACKGROUND:Advanced skull base malignancies are a heterogenous subset of head and neck cancers, and management is often complex. In recent times, there has been a paradigm shift in surgical technique and the advent of novel systemic options. Our goal was to analyse the long-term outcomes of a single quaternary head and neck and skull base service. METHODS:A retrospective review of 127 patients with advanced anterior skull base malignancies that were treated at our institution between 1999 and 2015 was performed. Multiple variables were investigated to assess their significance on 5 and 10-year outcomes. RESULTS:The mean age was 60.9 (± 12.6 SD). Sixty-four percent were males and 36% were females. Ninety percent of patients had T4 disease. Median survival time was 133 months. The 5-year overall survival (OS) was 66.2%, disease-specific survival (DSS) was 74.7%, and recurrence-free survival (RFS) was 65.0%. The 10-year OS was 55.1%, DSS was 72.1%, and RFS was 53.4%. Histological type and margin status significantly affected OS & DSS. CONCLUSION:Surgical management of advanced skull base tumours has evolved over the last few decades at our institution with acceptable survival outcomes and complication rates. Histological diagnosis and margin status are the main predictors of survival. The addition of neoadjuvant systemic agents in current trials may improve outcomes.

Objective To report the natural history of vestibular schwannoma (VS) who elected an initial period of observation and identify prognostic factors. To describe the natural history of growing VS, identify prognostic factors, and review the most recent literature. Study Design Prospective cohort study and literature review. Setting Tertiary referral center. Patients Adult patients diagnosed with a VS between January 1998 and February 2023. Intervention Magnetic resonance imaging surveillance. Main Outcome Measure(s) Growth-free survival and subsequent growth-free survival considering significant growth as a change in size of ≥2 mm. Results Of 430 patients undergoing observation with serial magnetic resonance imaging, 193 (44.9%) demonstrated significant growth at a median of 1.6 years (interquartile range, 0.94–3.51). Of the 193 patients who presented an initial episode of growth, 137 elected to continue to be observed. Of those, 83 (60.6%) presented a second episode of growth at a median of 1.43 years (interquartile range, 1.00–2.49). The subsequent growth-free survival rates (95% confidence interval) at 1, 3, 5, 7, and 10 years were 91.79% (87.26–96.56%), 64.44% (56.56–73.42%), 52.52% (44.23–62.35%), 42.23% (33.92–52.56%), and 36.11% (27.89–46.76%), respectively. Univariate and multivariate Cox regression analyses showed that EC tumor location and initial growth rate were significant predictors of subsequent growth. Conclusions Close observation after documentation of growth is an appropriate management in well-selected cases given that only around 56% of the tumor will continue to grow. Extracanalicular tumor location and initial growth rate are promising prognostic factors to help determine which patient would be a better candidate for close surveillance after initial documentation of growth.

BackgroundProgrammed cell death ligand 1 (PD-L1) inhibitors have limited efficacy as monotherapy in patients with recurrent/metastatic (R/M) Human Papilloma Virus (HPV) oropharyngeal squamous cell carcinoma (OPSCC). A phase I study of the therapeutic HPV-16 DNA vaccine AMV002 in curatively treated patients with OPSCC demonstrated a measurable immune response against HPV while being associated with high safety and tolerability. This prospective phase Ib single centre pilot study aims to test the safety and tolerability of combined PD-L1 inhibitor, Durvalumab, with AMV002 in 12 patients with recurrent OPSCC.MethodsParticipants had evidence of R/M HPV-associated OPSCC. They received three intradermal administrations of AMV002 with Durvalumab followed by Durvalumab maintenance. Safety and tolerability data was the primary endpoint. The study was conducted with ethical approval (HREC/2018/QMS/47293) in Brisbane, Australia.FindingsThe most common adverse event (AE) related to vaccine administration was erythema at the injection site. There were no grade 3 or 4 vaccine related AEs. There was one presumed immune-related grade 3 elevation in lipase secondary to Durvalumab with no intervention required. No patient ceased study due to treatment-related AEs. At week 16, objective response rate was 8% (N=1) and disease control rate was 17% (N=2). At a median follow up of 25.6 (20.0-26.6) months there was one long term complete response while all other participants developed progressive disease. Of the 11 evaluated patients, 9, (82%) had E6 and/or E7-specific T cell responses to the vaccine.ConclusionThe combination of AMV002 therapeutic HPV-16 vaccine and Durvalumab was found to be safe and well tolerated with no increased safety signals generated. T cell responses to vaccine were observed but further work will be required to improve efficacy.

Immune checkpoint inhibitor (ICI) modality has had a limited success (<20%) in treating metastatic recurrent Head & Neck Oropharyngeal Squamous cell carcinomas (OPSCCs). To improve response rates to ICIs, tailored approaches capable to capture the tumor complexity and dynamics of each patient’s disease are needed. Here, we performed advanced analyses of spatial proteogenomic technologies to demonstrate that: (i) compared to standard histopathology, spatial transcriptomics better-identified tumor cells and could specifically classify them into two different metabolic states with therapeutic implications; (ii) our new method (Spatial Proteomics-informed cell deconvolution method or 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.

ANZ Journal of SurgeryVolume 93, Issue 10 p. 2281-2282 EDITORIAL Time is function and survival Stijn Bekkers MD, Stijn Bekkers MD Queensland Skull Base Unit and Department of Otolaryngology, Head and Neck Surgery, Princess Alexandra Hospital, Brisbane, Queensland, Australia Department of Otorhinolaryngology and Head and Neck Surgery, Radboud University Medical Centre, Nijmegen, The Netherlands Department of Otolaryngology, Hospital Gelderse Vallei, Ede, The Netherlands Contribution: Data curation, Formal analysis, Writing - original draft, Writing - review & editingSearch for more papers by this authorLinda Stewart BHlthSc, MBBS, Linda Stewart BHlthSc, MBBS Queensland Skull Base Unit and Department of Otolaryngology, Head and Neck Surgery, Princess Alexandra Hospital, Brisbane, Queensland, Australia Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia Contribution: Data curation, Formal analysis, Writing - review & editingSearch for more papers by this authorBenedict J. Panizza MBBS, MBA, FRACS, FACS, Benedict J. Panizza MBBS, MBA, FRACS, FACS orcid.org/0000-0002-3724-3773 Queensland Skull Base Unit and Department of Otolaryngology, Head and Neck Surgery, Princess Alexandra Hospital, Brisbane, Queensland, Australia Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia Contribution: Conceptualization, Data curation, Formal analysis, Writing - review & editingSearch for more papers by this author Stijn Bekkers MD, Stijn Bekkers MD Queensland Skull Base Unit and Department of Otolaryngology, Head and Neck Surgery, Princess Alexandra Hospital, Brisbane, Queensland, Australia Department of Otorhinolaryngology and Head and Neck Surgery, Radboud University Medical Centre, Nijmegen, The Netherlands Department of Otolaryngology, Hospital Gelderse Vallei, Ede, The Netherlands Contribution: Data curation, Formal analysis, Writing - original draft, Writing - review & editingSearch for more papers by this authorLinda Stewart BHlthSc, MBBS, Linda Stewart BHlthSc, MBBS Queensland Skull Base Unit and Department of Otolaryngology, Head and Neck Surgery, Princess Alexandra Hospital, Brisbane, Queensland, Australia Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia Contribution: Data curation, Formal analysis, Writing - review & editingSearch for more papers by this authorBenedict J. Panizza MBBS, MBA, FRACS, FACS, Benedict J. Panizza MBBS, MBA, FRACS, FACS orcid.org/0000-0002-3724-3773 Queensland Skull Base Unit and Department of Otolaryngology, Head and Neck Surgery, Princess Alexandra Hospital, Brisbane, Queensland, Australia Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia Contribution: Conceptualization, Data curation, Formal analysis, Writing - review & editingSearch for more papers by this author First published: 17 October 2023 https://doi.org/10.1111/ans.18680 Editorial: Factors Affecting Timeliness in Management of Head and Neck Cancer. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1Kwok M, Wong A, Prasad J. Factors affecting the timeliness in management of head and neck cancer. ANZ J. Surg. 2023; 93: 2388–2393. 10.1111/ans.18521 Google Scholar 2 Cancer Council Victoria and Department of Health Victoria 2021, Optimal Care Pathway for People with Head and Neck Cancer, 2nd edn. Melbourne: Cancer Council Victoria, 2021. www.cancer.org.au/OCP. Google Scholar 3Schutte HW, van den Broek GB, Steens SCA et al. Impact of optimizing diagnostic workup and reducing the time to treatment in head and neck cancer. Cancer 2020; 126: 3982–3990. 10.1002/cncr.33037 PubMedWeb of Science®Google Scholar 4Murphy CT, Galloway TJ, Handorf EA et al. Survival impact of increasing time to treatment initiation for patients with head and neck cancer in the United States. J. Clin. Oncol. 2016; 34: 169–178. 10.1200/JCO.2015.61.5906 CASPubMedWeb of Science®Google Scholar 5van Harten MC, Hoebers FJ, Kross KW, van Werkhoven ED, van den Brekel MW, van Dijk BA. Determinants of treatment waiting times for head and neck cancer in The Netherlands and their relation to survival. Oral Oncol. 2015; 51: 272–278. 10.1016/j.oraloncology.2014.12.003 PubMedWeb of Science®Google Scholar 6Graboyes EM, Kompelli AR, Neskey DM et al. Association of treatment delays with survival for patients with head and neck cancer. JAMA Otolaryngol. Head Neck Surg. 2019; 145: 166–177. 10.1001/jamaoto.2018.2716 PubMedWeb of Science®Google Scholar 7 Dutch Head and Neck Society. Multidisciplinaire Normering Oncologische Zorg in Nederland. SONCOS Normeringrapport 5–2017; 2017. Available from URL: https://richtlijnendatabase.nl/gerelateerde_documenten/f/11825/43SONCOS-normeringsrapport-versie-5.pdf Google Scholar 8Lyhne NM, Christensen A, Alanin MC et al. Waiting times for diagnosis and treatment of head and neck cancer in Denmark in Denmark in 2010 compared to 1992 and 2002. Eur. J. Cancer 2013; 49: 1627–1633. 10.1016/j.ejca.2012.11.034 CASPubMedWeb of Science®Google Scholar 9Roennegaard AB, Rosenberg T, Bjorndal K et al. The Danish Head and Neck Cancer fast-track program: a tertiary cancer centre experience. Eur. J. Cancer 2018; 90: 133–139. 10.1016/j.ejca.2017.10.038 PubMedWeb of Science®Google Scholar 10 Cancer Waiting Times Team. Independent Cancer Taskforce – NHS England. Available from URL: https://www.england.nhs.uk/wp-content/uploads/2016/10/cancer-one-year-on.pdf Google Scholar 11Schoonbeek RC, de Vries J, Bras L, Plaat BEC, van Dijk BAC, Halmos GB. Determinants of delay in the head and neck oncology care pathway: the next step in value-based health care. Eur. J. Cancer Care (Engl). 2021; 30: e13419. https://doi.org/10.1111/ecc.13419. 10.1111/ecc.13419 PubMedWeb of Science®Google Scholar Volume93, Issue10October 2023Pages 2281-2282 ReferencesRelatedInformation

6055 Background: Although HPV-related LA-OPSCC is associated with better prognosis than HPV-negative disease, ~30% of cases relapse despite curative-intent chemoradiotherapy. New prognostic biomarkers are needed to rationalise curative-intent treatment without compromising efficacy. We aimed to develop a proteomic signature associated with risk of recurrence from diagnostic biopsies of patients with HPV-positive OPSCC. Methods: We analysed 139 formalin fixed paraffin embedded archival core biopsy specimens from 124 patients with HPV-related (p16 IHC positive) T1-4N0-3M0 LA-OPSCC tumours. All patients were treated with definitive chemoradiotherapy at the Princess Alexandra Hospital (Brisbane, Australia) between 2007-2019. The cohort included 50 patients with recurrence less than five years from diagnosis and 74 age/performance-status matched patients with no recurrence. Proteomic analysis was performed utilizing data-independent acquisition mass spectrometry (DIA-MS). A proteomic prognostic signature associated with recurrence free survival (RFS) at five years was the primary endpoint of interest. It was developed using a computational pipeline comprising an initial univariate Cox model step, followed by multiple runs of multivariate Cox models with Least Absolute Shrinkage and Selection Operator (LASSO) regularization, and then a final step of recursive feature selection. Results: A total of 7,597 proteins were quantified and 665 were differentially expressed proteins between tumour and normal adjacent tissues. There were 5,199 proteins remaining in the tumour samples after filtering. RFS was significantly (q-value < 0.05) associated with 252 proteins, whose functions are enriched in adaptive and innate immunity and MAPK6/MAPK4 signalling pathways. A 16-protein signature associated with RFS stratified patients into low, intermediate, or high-risk groups (C-index = 0.885, p < 0.0001). The 16-protein signature outperformed clinico-pathological covariates including age, stage, ECOG and smoking history with the highest area under the receiver operating characteristic curve (AUROC 0.95). Conclusions: DIA-MS-based proteomics on core biopsies can be used to risk stratify HPV-related OPSCC patients. A 16-protein signature associated with RFS was successfully identified as a basis for future studies. Validation of this proteomic prognostic signature in independent cohorts is required and may be used to inform future clinical trials to better tailor upfront therapy.

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.

6043 Background: Hearing loss with cisplatin (CP) chemotherapy is common. DB-020 is a formulation of thiosulfate for intratympanic (IT) injection being developed to reduce CP ototoxicity. The primary objective of this Phase 1 study was to evaluate the safety and tolerability of repeated IT injections of DB-020. A secondary objective was to compare hearing changes with DB-020 vs. placebo. Methods: Subjects scheduled for at least 3 cycles of CP and cumulative exposure of ≥280 mg/m 2 were randomized to blinded, bilateral, IT injection with DB-020 (12% or 25%) in one ear and placebo in the other, once every 3 or 4 weeks, up to 3 hours before receiving CP. Subjects with moderate or severe hearing loss at baseline were excluded. Ototoxicity was defined by American Speech-Language-Hearing criteria: ≥20 dB threshold increase at any one test frequency, or ≥10 dB threshold increase in any two adjacent frequencies, or loss of response at three consecutive frequencies where responses were previously obtained. Severe ototoxicity was ≥20 dB threshold increase in any two adjacent frequencies. A pre-specified interim analysis evaluated safety, ototoxicity (with Mcnemar’s test using the last observation carried forward), and average threshold shifts (from air conduction audiometry, analyzed with a mixed model with repeated measures). Results: Nineteen subjects were randomized, with mean age of 57 years (84% male and 100% white) and mean cumulative CP dose 248 mg/m 2 . Most (95%) had head and neck cancers (5% had lung cancer). Seventeen subjects had both baseline and follow-up audiometry, and 16/17 had baseline audiograms within 5 dB of the median threshold for age-matched controls. Free CP systemic levels were similar to reference values. Ear pain (15/19 subjects, 78.9%) and tinnitus (8/19 subjects, 42.1%) were common. Ear pain was more common in DB-020 treated ears, and tinnitus was more common in placebo treated ears. There were no tympanic perforations, no serious adverse events in the category of ear and labyrinth disorders, and no deaths. Ototoxicity was significantly more common and more severe in placebo treated ears (Table). As the overall study objectives were met at this interim analysis, no further enrollment was pursued. Conclusions: In this initial clinical trial experience there was no significant safety signal, and DB-020 IT injections showed a meaningful reduction in cisplatin ototoxicity. These results warrant further clinical development. Clinical trial information: NCT04262336 . [Table: see text]

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.