Steven C. Nakoneshny

Individuals with head and neck cancers are living longer than ever before, yet many live with the long-term effects of their cancer and treatment. The purpose of this study was to assess the feasibility of a physiatry assessment clinic (PAC) following neck resection and free flap reconstruction, during which physical function was assessed. Methods: Adult patients participating in a larger prehabilitation study were included. Attendance and the ability to complete the physical function assessment were examined. Exploratory analyses were completed to describe physical function, fitness, shoulder, and neck function among PAC attenders. To further understand PAC feasibility, patient-reported outcomes among PAC attenders and non-attenders were examined over 12 months (QuickDASH, NDII, EAT-10). Results: A total of 36 eligible participants (78.2%) from the larger prehabilitation study were approached to participate in the PAC, and 19 of the 36 attended (52.8%). Participants attended on average 8.6 ± 3.6 weeks post surgery, and 100% were able to complete the functional measures. Exploratory data suggest that those who did not attend (17 of 36 approached) had more advanced disease compared to those who attended (p < 0.05). Patient-reported outcomes suggested better shoulder function and swallow function at 6 months among those who attended the clinic versus those who did not. Conclusions: While recruitment to the PAC and assessment completion demonstrated feasibility, attendance posed challenges for patients. These findings highlight the need for innovative approaches to screening patients and tailoring rehabilitation services based on physical impairment.

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/objectives: Major head and neck oncologic surgeries requiring microvascular reconstruction frequently result in complications such as perioperative blood transfusion (PBT). Not only are blood products overutilized and associated with risks, but preoperative anemia is both a modifiable and predisposing factor for PBT. Our objective was to assess risk factors for PBT and determine a high-risk preoperative hemoglobin to inform transfusion stewardship practices. Methods: Patients that underwent head and neck cancer free flap reconstruction (n = 363) between 2012 and 2019 were included. Univariable and multivariable analyses evaluated predictors of PBT. Results: Overall, 11% of patients were anemic and 19% were transfused. Mean preoperative hemoglobin was significantly lower in the PBT group (128 g/L vs. 145 g/L, p < 0.0001). In our multivariable model, lower preoperative hemoglobin (odds ratio [OR] = 0.94), higher T stage (OR = 2.65), and lower body mass index (BMI) (OR = 0.89) increased the odds of PBT. Adjusting for staging and BMI, the OR of PBT was increased below 120 g/L hemoglobin. Higher mean units of PBT were administered for hemoglobin below 150 g/L with a large inflection below 120 g/L (p < 0.0001). Conclusions: Low preoperative hemoglobin is the strongest predictor of PBT in major head and neck cancer surgery. Recognizing and managing anemia is essential in surgical planning.

(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.

Objective To compare oncologic outcomes of South Asian (SA) patients treated at a regional cancer centre in Canada, for oral squamous cell carcinoma (OSCC), to the general population. Methods Adult patients who underwent primary surgical resection of OSCC +/- adjuvant treatment between 2009 and 2022 (N=697) were included. SA patients were identified using a validated method and compared to non-SA patients. Baseline characteristics, including betel nut consumption, were compared, and disease-specific survival (DSS) and recurrence-free survival (RFS) were evaluated using Kaplan-Meier methods, with median follow-up time of 36.4 months [SD 31.02]. Cox proportional hazard regression models adjusted for potential confounders. A p-value < 0.05 was considered statistically significant. 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. There were no differences in tumor characteristics or the use of adjuvant radiation. 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. Conclusion To our knowledge, this study is the first to compare the oncological outcomes of SA patients with OSCC to non-SA patients. SA patients had significantly worse outcomes, even after controlling for known predictors of recurrence and disease-specific survival. These findings can inform personalized treatment decisions and influence public health policies when managing patients with different ethnic backgrounds.

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.

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.

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- 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(-) OSCC patients. Finally, due to lack of evidence for the role of NCBP2 in carcinogenesis, we tested if modulating NCBP2 levels in human OSCC cell lines affected their carcinogenic behavior. We found that NCBP2 depletion reduced OSCC cell proliferation, migration, and invasion. We thus propose both NCBP2 and TFRC as novel prognostic and potentially therapeutic biomarkers for HPV- OSCC.

Background: Understanding occurrence and timing of second events (recurrence and second primary cancer) is essential for cancer specific survival analysis. However, this information is not readily available in administrative data.Methods: Alberta Cancer Registry, physician claims, and other administrative data were used. Timing of second event was estimated based on our developed algorithm. For validation, the difference, in days between the algorithm estimated and the chart‐reviewed timing of second event. Further, the result of Cox‐regression modeling cancer‐free survival was compared to chart review data.Results: Majority (74.3%) of the patients had a difference between the chart‐reviewed and algorithm‐estimated timing of second event falling within the 0–60 days window. Kaplan–Meier curves generated from the estimated data and chart review data were comparable with a 5‐year second‐event‐free survival rate of 75.4% versus 72.5%.Conclusion: The algorithm provided an estimated timing of second event similar to that of the chart review.

One of the foundational elements of enhanced recovery after surgery (ERAS) guidelines is early postoperative mobilization. For patients undergoing head and neck cancer (HNC) surgery with free flap reconstruction, the ERAS guideline recommends patients be mobilized within 24 h postoperatively. The objective of this study was to evaluate compliance with the ERAS recommendation for early postoperative mobilization in 445 consecutive patients who underwent HNC surgery in the Calgary Head and Neck Enhanced Recovery Program. This retrospective analysis found that recommendation compliance increased by 10% despite a more aggressive target for mobilization (from 48 to 24 h). This resulted in a decrease in postoperative mobilization time and a stark increase in the proportion of patients mobilized within 24 h (from 10% to 64%). There was a significant relationship between compliance with recommended care and time to postoperative mobilization (Spearman’s rho = −0.80; p < 0.001). Hospital length of stay was reduced by a median of 2 days, from 12 (1QR = 9–16) to 10 (1QR = 8–14) days (z = 3.82; p < 0.001) in patients who received guideline-concordant care. Engaging the clinical team and changing the order set to support clinical decision-making resulted in increased adherence to guideline-recommended care for patients undergoing major HNC surgery with free flap reconstruction.