Individuals living with and beyond head and neck cancer (HNC) often experience many consequences related to the cancer and its treatment which can persist long-term and have detrimental effects on overall quality of life. Despite the potentially profound impact of these consequences of cancer, the evidence around long-term outcomes among individuals living with and beyond HNC is varied. The objective of this study is to describe the evidence on long-term outcomes among individuals living with and beyond HNC. This scoping review followed Joanna Briggs Institute methodology and was reported according to the PRISMA-ScR checklist. Structured language, keywords, and synonyms were used for each concept (patients diagnosed with HNC, outcomes, long-term) were used to search six databases. Eligible studies were those that reported outcomes beyond survival and recurrence at least 5-years after diagnosis of HNC. Two independent reviewers conducted screening (title and abstract then full-text screening), and data abstraction using a standardized form. The abstracted data from the evidence sources was synthesized using descriptive statistics, and qualitative data was categorized into themes. The search identified 6072 potential evidence sources, of which 2339 full-texts were screened and 166 met eligibility criteria and were included. Most commonly, evidence sources were studies conducted in the USA (35

The non-canonical translation of specific mRNAs has been implicated in oncogenesis and cancer progression. We previously identified eukaryotic Initiation Factor 5B (eIF5B) as a key factor in Internal Ribosome Entry Site (IRES) mediated translation of a subset of mRNAs encoding anti-apoptotic proteins. Here, we demonstrate that EIF5B is predominantly expressed in cancer cells compared to other cell types in the Oral Squamous Cell Carcinoma (OSCC) microenvironment. Higher EIF5B mRNA and protein expression are associated with poor patient outcomes. We show that eIF5B depletion in OSCC cells blunted pro-growth, pro-inflammatory, and pro-angiogenic signaling pathways and significantly increased TNF related apoptosis-inducing ligand (TRAIL) induced cell death. This is achieved through decreased translation of mRNAs encoding critical factors associated with OSCC pathophysiology. Importantly, the level of interaction of eIF5B with tRNAiMet was significantly higher in OSCC cells compared to noncancerous fibroblasts. This suggests that OSCC cells (but not noncancerous fibroblasts) rely heavily on eIF5B for translation initiation. In an in vivo flank xenograft model using nude mice, eIF5B knockdown in UMSCC29 cells led to a significant reduction in tumor volume compared to control tumors. Also, the immunohistochemical analysis of the xenografted tumor sections demonstrated decreased staining intensity of critical factors associated with OSCC pathophysiology in eIF5B depleted tumors relative to controls. Collectively, our data demonstrate that OSCC cells are uniquely dependent on eIF5B tRNAiMet interactions to sustain translation of pro-survival mRNAs. Targeting eIF5B disrupts these oncogenic programs, sensitizing OSCC cells to apoptosis and suppressing pro-angiogenic and pro-growth signaling. ### Competing Interest Statement The authors have declared no competing interest. Cancer Research Society, https://ror.org/00t38a349, 1280259 Natural Sciences and Engineering Research Council, https://ror.org/01h531d29, RGPIN-2017-05463, RGPIN-2024-04035, 510937-2018, 584836-2024 Canada Foundation for Innovation, https://ror.org/000az4664, 35017

Background/Objectives: Head and neck cancer (HNC) is associated with unique risks of catastrophic health events throughout the care continuum. This scoping review evaluated distinct domains of catastrophic health events in HNC and the associated risk factors to inform the development of risk prediction models. Methods: Five electronic databases were searched to identify peer-reviewed journal articles published from 2015 to 2025. Eligible studies were primary observational studies involving adults (≥18) with HNC that reported a catastrophic (or similar term) health event and assessed the associated risk factors using multivariable regression modelling. Results: Fifty-six studies involving 941,329 patients with HNC were included. Half (n = 28, 50.0%) of these studies were conducted in North America, followed by Asia and Europe (n = 13 each, 23.2%). Four domains of catastrophic health events were identified: sudden or premature deaths (n = 22, 39.3%), severe treatment-related complications (n = 19, 33.9%), unplanned acute care encounters (n = 22, 39.3%), and severe patient-reported symptoms (n = 6, 10.7%). Across all domains, comorbidity was the most repeatedly identified risk factor, followed by treatment characteristics (e.g., surgery duration), older age, and advanced cancer stage. Conclusions: Risk prediction models in HNC should always include variables of comorbidity. The varied measurability of risk factors requires strategic efforts when developing prediction algorithms for different domains of catastrophic health events.

Facial nerve palsy affecting the lower face may compromise essential functions such as speech and eating. The associated facial asymmetry can contribute to social isolation. Facial nerve reconstruction using a combination of interposition nerve grafts and/or nerve transfers offers significant improvement. However, these options are limited by insufficient donor nerves and unwanted synkinesis if a single donor nerve is used for the entire hemi-face. To ameliorate both limitations, we perform an ansa cervicalis to marginal mandibular nerve transfer to restore tone and symmetry to the lower third of the face. We have found this a safe and feasible technique with minimal donor site morbidity. The anatomy is favorable both in terms of donor nerve length and size match between nerves. We report 9 cases with at least 6 months follow up which demonstrate improved lower lip tone and symmetry and improved oral competence. Early donor site morbidity and postoperative complications are minimal. This method is a reliable adjunct in facial nerve reconstruction to address the marginal mandibular nerve paralysis.

Importance:The standard of care for patients with oral cavity squamous cell carcinoma (OCSCC) is generally primary surgical resection with or without adjuvant therapy (AT), based on pathological factors. Identifying preoperative factors that are associated with the receipt of AT may enhance treatment planning. Objective:To identify preoperative patient and tumor factors associated with receiving AT, either radiation therapy (RT) or chemoradiation therapy (CRT), in patients with OCSCC. Design, Setting, and Participants:This cohort study, spanning January 2005 to December 2019 at 9 academic centers in Canada, was conducted as part of the Canadian Head & Neck Collaborative Research Initiative, a national network of head and neck surgical oncologists. Participants included patients with oral cavity cancer who underwent surgery. The data analysis was performed in March 2024. Exposures:Preoperative variables, including demographics (age, sex, smoking history, and Charlson Comorbidity Index [CCI]) and tumor characteristics (clinical T and N stage, biopsy grade, tumor size). Main Outcomes and Measures:The main outcomes were the receipt of AT vs surgery alone; the type of AT, either RT or CRT; and the presence of a strong pathologic indicator for AT. Results:Of the 3980 patients, 2438 underwent surgery alone (61%) and 1542 received AT (39%). Of these, 1907 (48%) had a strong pathologic indicator for AT. The mean (SD) age was 63 (13) years, and 1498 participants (38%) were female. On multivariable analysis, factors independently associated with AT included being older than 65 years (odds ratio [OR], 0.50 [95% CI, 0.38-0.64]), CCI of 4 or higher (OR, 1.83 [95% CI, 1.26-2.65]), previous head and neck cancer (OR, 0.40 [95% CI, 0.26-0.62]), maxillary alveolus (OR, 2.16 [95% CI, 1.11-4.22]) and retromolar trigone (OR, 1.85 [95% CI, 1.04-3.29) subsites, tumor dimension (OR, 1.35 [95% CI, 1.22-1.50] per cm), increasing clinical T and N stages, and worse grade on biopsy (poorly differentiated: OR, 1.89 [95% CI, 1.25-2.84]). Among those receiving AT, poorly differentiated grade (OR, 2.40 [95% CI, 1.34-4.30]) and advanced N stage were associated with CRT rather than RT. Among patients with strong pathologic indicators for AT, factors associated with not receiving AT included age, CCI, grade, stage, and tumor dimension. The prediction model showed good discriminatory power (area under the receiver operating characteristic curve, 0.84 [95% CI, 0.82-0.86]). Conclusions and Relevance:The results of this cohort study suggest that preoperative variables can help to identify patients with OCSCC who are more likely to receive AT, despite many factors not being predictable until the postoperative period. Early identification of patients at high risk may improve treatment planning and reduce delays in initiating AT, potentially enhancing patient outcomes.

Background: The SUMO E3 ligase PIAS1 (Protein Inhibitor of Activated STAT1) regulates pathways such as TGFβ signaling and has been implicated in multiple cancers. However, its role in the tumor microenvironment (TME), particularly in non-malignant stromal and immune cells, remains poorly understood. This study aimed to characterize the expression and functional relevance of PIAS1 within the TME of oral squamous cell carcinoma (OSCC). Methods: PIAS1 protein expression was assessed via immunohistochemistry (IHC) on OSCC tissue microarrays. Single-cell RNA-sequencing (scRNA-seq) datasets from OSCC tumors and normal tissues were analyzed to map cell-type-specific PIAS1 expression. Downstream effects were evaluated using differential gene expression, Ingenuity Pathway Analysis (IPA), gene set enrichment analysis (GSEA), and cell–cell communication inference. Results: IHC analysis revealed that higher stromal PIAS1 levels correlated with improved survival. scRNA-seq analysis showed an increase in the proportion of PIAS1-expressing cells across most stromal and immune cell populations within OSCC-derived tumors compared to their counterparts in adjacent normal tissue. However, when comparing PIAS1-positive cells, expression levels were significantly reduced in cancer cells, CAFs, TAMs, T cells, and endothelial cells within the TME. PIAS1-positive CAFs, TAMs, and T cells exhibited activation of apoptotic and tumor-suppressive pathways, while PIAS1-negative counterparts showed enrichment of immunosuppressive signaling and immune checkpoint expression. Cell–cell communication analyses indicated that PIAS1 fosters an immune-activated TME by promoting pro-inflammatory signaling, M1-like TAM polarization, and T cell activation. Conclusions: PIAS1 expression in stromal and immune cells is associated with tumor-suppressive reprogramming of the OSCC microenvironment. These findings position PIAS1 as a potential modulator of anti-tumor immunity and candidate target for therapeutic intervention.

Background: Within a resource-limited healthcare system, an emphasis on financial accountability is imperative. Over the past decade at our institution, there have been many operational changes employed to improve patient care during oncologic head and neck resections with free flap (HNFF) reconstruction. The objective of this study is to assess whether these changes are associated with cost savings. Methods: A retrospective cohort study that included consecutive patients treated from January 2007 to February 2020 was performed. The perspective of the third payer party was used and direct costs were considered. The peri-operative period was defined as the day of surgery and subsequent admission. Total peri-operative cost was defined as staffing, material, reconstructive surgeon, anesthetist, and admission costs. Costs are represented in Canadian Dollars ($CAD) adjusted for inflation. Results: There were 590 consecutive cases. Average age was 61 with a male proportion of 69% (n = 409). Tumor type, need for tracheostomy, neck dissection, anatomic region resected, 30-day re-operation, and re-admission did not change significantly over the study period (P > 0.05). The mean total operative time per case decreased by 4.1 h over the study period. The median length of stay per patient decreased by 4.5 days. The total peri-operative cost per patient during the study period decreased by $19,928. Net cost savings to the third-party payer over the study period was $8,142,962. Conclusion: A culture of improvement-focused teamwork allowed for several advances over the study period. These were associated with improved patient care, operative efficiency, and significant cost savings of HNFF reconstruction.

(1) Background: To compare oncologic outcomes of South Asian (SA) patients treated for oral squamous cell carcinoma (OSCC) to the general population. (2) Methods: Adult patients who underwent surgical resection of OSCC +/− adjuvant treatment between 2009 and 2022 (N = 697) at a regional cancer centre in Canada were included. SA patients, identified using a validated method, were compared to non-SA patients. Kaplan–Meier methods were used to compare the primary outcomes, disease-specific survival (DSS) and recurrence-free survival (RFS) across baseline univariate characteristics, including betel nut consumption. Median follow-up time was 36.4 months. Cox proportional hazard models were used to identify independent predictors of survival with significance set at p < 0.05. (3) Results: SA patients (9% of cohort, N = 64) were significantly younger and had lower rates of smoking and alcohol consumption compared to non-SA patients (p < 0.05). SA patients had a two-fold higher risk of recurrence and significantly worse disease-specific survival, even after adjusting for stage and high-risk features [RFS: HR 2.01 (1.28–3.14), DSS: HR 1.79 (1.12–2.88)]. The consumption of betel nut was not associated with outcomes. (4) Conclusions: SA patients had significantly worse oncologic outcomes, even after controlling for known predictors of poor prognosis. These findings are novel and can inform personalized treatment decisions and influence public health policies when managing patients with different ethnic backgrounds.

Importance:Oral cavity cancer often requires multidisciplinary management, subjecting patients to complex therapeutic trajectories. Prolonged treatment intervals in oral cavity cancer have been associated with poor oncological outcomes, but there has yet to be a study investigating treatment times in Canada. Objective:To report treatment delays for patients with oral cavity cancer in Canada and evaluate the outcomes of treatment delays on overall survival. Design, Setting, and Participants:This multicenter cohort study was performed at 8 Canadian academic centers from 2005 to 2019. Participants were patients with oral cavity cancer who underwent surgery and adjuvant radiation therapy. Analysis was performed in January 2023. Main Outcomes and Measures:Treatment intervals evaluated were surgery to initiation of postoperative radiation therapy interval (S-PORT) and radiation therapy interval (RTI). The exposure variables were prolonged intervals, respectively defined as index S-PORT greater than 42 days and RTI greater than 46 days. Patient demographics, Charlson Comorbidity Index, smoking status, alcohol status, and cancer staging were also considered. Univariate (log rank and Kaplan-Meier) and multivariate (Cox regression) analyses were performed to determine associations with overall survival (OS). Results:Overall, 1368 patients were included; median (IQR) age at diagnosis was 61 (54-70) years, and 896 (65%) were men. Median (IQR) S-PORT was 56 (46-68) days, with 1093 (80%) patients waiting greater than 42 days, and median (IQR) RTI was 43 (41-47) days, with 353 (26%) patients having treatment time interval greater than 46 days. There were variations in treatment time intervals between institutions for S-PORT (institution with longest vs shortest median S-PORT, 64 days vs 48 days; η2 = 0.023) and RTI (institution with longest vs shortest median RTI, 44 days vs 40 days; η2 = 0.022). Median follow-up was 34 months. The 3-year OS was 68%. In univariate analysis, patients with prolonged S-PORT had worse survival at 3 years (66% vs 77%; odds ratio 1.75; 95% CI, 1.27-2.42), whereas prolonged RTI (67% vs 69%; odds ratio 1.06; 95% CI, 0.81-1.38) was not associated with OS. Other factors associated with OS were age, Charlson Comorbidity Index, alcohol status, T category, N category, and institution. In the multivariate model, prolonged S-PORT remained independently associated with OS (hazard ratio, 1.39; 95% CI, 1.07-1.80). Conclusions and Relevance:In this multicenter cohort study of patients with oral cavity cancer requiring multimodal therapy, initiation of radiation therapy within 42 days from surgery was associated with improved survival. However, in Canada, only a minority completed S-PORT within the recommended time, whereas most had an appropriate RTI. An interinstitution variation existed in terms of treatment time intervals. Institutions should aim to identify reasons for delays in their respective centers, and efforts and resources should be directed toward achieving timely completion of S-PORT.

The spatial organization of the tumor microenvironment has a profound impact on biology and therapy response. Here, we perform an integrative single-cell and spatial transcriptomic analysis on HPV-negative oral squamous cell carcinoma (OSCC) to comprehensively characterize malignant cells in tumor core (TC) and leading edge (LE) transcriptional architectures. We show that the TC and LE are characterized by unique transcriptional profiles, neighboring cellular compositions, and ligand-receptor interactions. We demonstrate that the gene expression profile associated with the LE is conserved across different cancers while the TC is tissue specific, highlighting common mechanisms underlying tumor progression and invasion. Additionally, we find our LE gene signature is associated with worse clinical outcomes while TC gene signature is associated with improved prognosis across multiple cancer types. Finally, using an in silico modeling approach, we describe spatially-regulated patterns of cell development in OSCC that are predictably associated with drug response. Our work provides pan-cancer insights into TC and LE biology and interactive spatial atlases ( http://www.pboselab.ca/spatial_OSCC/ ; http://www.pboselab.ca/dynamo_OSCC/ ) that can be foundational for developing novel targeted therapies.

Importance The association of primary tumor volume with outcomes in T3 glottic cancers treated with radiotherapy with concurrent chemotherapy remains unclear, with some evidence suggesting worse locoregional control in larger tumors. Objective To evaluate the association of primary tumor volume with oncologic outcomes in patients with T3 N0-N3 M0 glottic cancer treated with primary (chemo)radiotherapy in a large multi-institutional study. Design, Setting, and Participants This multi-institutional retrospective cohort study involved 7 Canadian cancer centers from 2002 to 2018. Tumor volume was measured by expert neuroradiologists on diagnostic imaging. Clinical and outcome data were extracted from electronic medical records. Overall survival (OS) and disease-free survival (DFS) outcomes were assessed with marginal Cox regression. Laryngectomy-free survival (LFS) was modeled as a secondary analysis. Patients diagnosed with cT3 N0-N3 M0 glottic cancers from 2002 to 2018 and treated with curative intent intensity-modulated radiotherapy (IMRT) with or without chemotherapy. Overall, 319 patients met study inclusion criteria. Exposures Tumor volume as measured on diagnostic imaging by expert neuroradiologists. Main Outcomes and Measures Primary outcomes were OS and DFS; LFS was assessed as a secondary analysis, and late toxic effects as an exploratory analysis determined before start of the study. Results The mean (SD) age of participants was 66 (12) years and 279 (88%) were men. Overall, 268 patients (84%) had N0 disease, and 150 (47%) received concurrent systemic therapy. The mean (SD) tumor volume was 4.04 (3.92) cm3. With a mean (SD) follow-up of 3.85 (3.04) years, there were 91 (29%) local, 35 (11%) regional, and 38 (12%) distant failures. Increasing tumor volume (per 1-cm3 increase) was associated with significantly worse adjusted OS (hazard ratio [HR], 1.07; 95% CI, 1.03-1.11) and DFS (HR, 1.04; 95% CI, 1.01-1.07). A total of 62 patients (19%) underwent laryngectomies with 54 (87%) of these within 800 days after treatment. Concurrent systemic therapy was associated with improved LFS (subdistribution HR, 0.63; 95% CI, 0.53-0.76). Conclusions and Relevance Increasing tumor volumes in cT3 glottic cancers was associated with worse OS and DFS, and systemic therapy was associated with improved LFS. In absence of randomized clinical trial evidence, patients with poor pretreatment laryngeal function or those ineligible for systemic therapy may be considered for primary surgical resection with postoperative radiotherapy.

Head and neck cancer (HNC) treatment often consists of major surgery followed by adjuvant therapy, which can result in treatment-related side effects, decreased physical function, and diminished quality of life. Perioperative nutrition interventions and early mobilization improve recovery after HNC treatment. However, there are few studies on prehabilitation that include exercise within the HNC surgical care pathway. We have designed a multiphasic exercise prehabilitation intervention for HNC patients undergoing surgical resection with free flap reconstruction. We will use a hybrid effectiveness-implementation study design guided by the RE-AIM framework to address the following objectives: (1) to evaluate intervention benefits through physical function and patient-reported outcome assessments; (2) to determine the safety and feasibility of the prehabilitation intervention; (3) to evaluate the implementation of exercise within the HNC surgical care pathway; and (4) to establish a post-operative screening and referral pathway to exercise oncology resources. The results of this study will provide evidence for the benefits and costs of a multiphasic exercise prehabilitation intervention embedded within the HNC surgical care pathway. This paper describes the study protocol design, multiphasic exercise prehabilitation intervention, planned analyses, and dissemination of findings. Trial registration: https://clinicaltrials.gov/NCT04598087

The objective of this study was to examine the utility of postoperative radiation for low and intermediate grade cancers of the parotid and submandibular glands.

# 01. Near-peer tutoring: an effective adjunct for virtual anatomy learning {#article-title-2} The start of the COVID-19 pandemic caused a shift in medical education from the classroom to the virtual setting. This abrupt change led to an increase in stress among students. In response, McGill

There are few prognostic biomarkers and targeted therapeutics currently in use for the clinical management of oral squamous cell carcinoma (OSCC) and patient outcomes remain poor in this disease. A majority of mutations in OSCC are loss-of-function events in tumour suppressor genes that are refractory to conventional modes of targeting. Interestingly, the chromosomal segment 3q22-3q29 is amplified in many epithelial cancers, including OSCC. We hypothesized that some of the 468 genes located on 3q22-3q29 might be drivers of oral carcinogenesis and could be exploited as potential prognostic biomarkers and therapeutic targets. Our integrative analysis of copy number variation (CNV), gene expression and clinical data from The Cancer Genome Atlas (TCGA), identified two candidate genes: NCBP2, TFRC , whose expression positively correlates with worse overall survival (OS) in HPV-negative OSCC patients. Expression of NCBP2 and TFRC is significantly higher in tumour cells compared to most normal human tissues. High NCBP2 and TFRC protein abundance is associated with worse overall, disease-specific survival, and progression-free interval in an in-house cohort of HPV-negative OSCC patients. Finally, due to a lack of evidence for the role of NCBP2 in carcinogenesis, we tested if modulating NCBP2 levels in human OSCC cell lines affected their carcinogenic behaviour. We found that NCBP2 depletion reduced OSCC cell proliferation, migration, and invasion. Differential expression analysis revealed the upregulation of several tumour-promoting genes in patients with high NCBP2 expression. We thus propose both NCBP2 and TFRC as novel prognostic and potentially therapeutic biomarkers for HPV-negative OSCC.

Importance:Head and neck oncological resection and reconstruction is a complex process that requires multidisciplinary collaboration and prolonged operative time. Numerous factors are associated with operative time, including a surgeon's experience, team familiarity, and the use of new technologies. It is paramount to evaluate the contribution of these factors and modalities on operative time to facilitate broad adoption of the most effective modalities and reduce complications associated with prolonged operative time. Objective:To examine the association of head and neck cancer resection and reconstruction interventions with operative time. Design, Setting, and Participants:This large cohort study included all patients who underwent head and neck oncologic resection and free flap-based reconstruction in Calgary (Alberta, Canada) between January 1, 2007, and March 31, 2020. Data were analyzed between November 2021 and May2022. Interventions:The interventions that were implemented in the program were classified into team-based strategies and the introduction of new technology. Team-based strategies included introducing a standardized operative team, treatment centralization in a single institution, and introducing a microsurgery fellowship program. New technologies included use of venous coupler anastomosis and virtual surgical planning. Main Outcomes and Measures:The primary outcome was mean operative time difference before and after the implementation of each modality. Secondary outcomes included returns to the operating room within 30 days, reasons for reoperation, returns to the emergency department or readmissions to hospital within 30 days, and 2-year and 5-year disease-specific survival. Multivariate regression analyses were performed to examine the association of each modality with operative time. Results:A total of 578 patients (179 women [30.9%]; mean [SD] age, 60.8 [12.9] years) undergoing 590 procedures met inclusion criteria. During the study period, operative time progressively decreased and reached a 32% reduction during the final years of the study. A significant reduction was observed in mean operative time following the introduction of each intervention. However, a multivariate analysis revealed that team-based strategies, including the use of a standardized nursing team, treatment centralization, and a fellowship program, were significantly associated with a reduction in operative time. Conclusions:The results of this cohort study suggest that among patients with head and neck cancer, use of team-based strategies was associated with significant decreases in operative time without an increase in complications.

PURPOSE:To evaluate the association of primary tumor volume (TV) with overall survival (OS) and disease-free survival (DFS) in T3 N0-3M0 supraglottic cancers treated with intensity-modulated radiotherapy (IMRT). METHODS:This was a retrospective cohort study involving 239 patients diagnosed with T3 N0-3M0 supraglottic cancers between 2002 and 2018 from seven regional cancer centers in Canada. Clinical data were obtained from the patient records. Supraglottic TV was measured by neuroradiologists on diagnostic imaging. Kaplan-Meier method was used for survival probabilities, and a restricted cubic spline Cox proportional hazards regression analysis was used to analyze TV associations with OS and DFS. RESULTS:Mean (SD) of participants was 65.2 (9.4) years; 176 (73.6%) participants were male. 90 (38%) were N0, and 151 (64%) received concurrent systemic therapy. Mean TV (SD) was 11.37 (12.11) cm3 . With mean follow up (SD) of 3.28 (2.60) years, 2-year OS was 72.7% (95% CI 66.9%-78.9%) and DFS was 53.6% (47.4%-60.6%). Increasing TV was associated (per cm3 increase) with worse OS (HR, 1.01, 95% CI 1.00-1.02, p < 0.01) and DFS (HR, 1.01, 95% CI 1.00-1.02, p = 0.02). CONCLUSIONS:Increasing primary tumor volume is associated with worse OS and DFS in T3 supraglottic cancers treated with IMRT, with no clear threshold. The findings suggest that patients with larger tumors and poor baseline laryngeal function may benefit from upfront laryngectomy with adjuvant radiotherapy.