Multiphasic exercise prehabilitation for patients undergoing surgery for head and neck cancer: a hybrid effectiveness-implementation study protocol.

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.

Associations Between Physician Prescribing Behavior and Persistent Postoperative Opioid Use Among Cancer Patients Undergoing Curative-intent Surgery: A Population-based Cohort Study.

OBJECTIVE: This study aimed to evaluate the association between prescribers' opioid prescribing history and persistent postoperative opioid use in cancer patients undergoing curative-intent surgery. BACKGROUND: Study has shown that patients may be over-prescribed analgesics after surgery. However, whether and how the prescriber's opioid prescribing behavior impacts persistent opioid use is unclear. METHODS: All adults with a diagnosis of solid cancers who underwent surgery during the study period (2009-2015) in Alberta, Canada and were opioid-naïve were included. The key exposure was the historical opioid-prescribing pattern of a patient's most responsible prescriber. The primary outcome was "new persistent postoperative opioid user," was defined as a patient who was opioid-naïve before surgery and subsequently filled at least 1 opioid prescription between 60 and 180 days after surgery. RESULTS: We identified 24,500 patients. Of these, 2106 (8.6%) patients became a new persistent opioid user after surgery. Multivariate analysis demonstrated that patients with most responsible prescribers that historically prescribed higher daily doses of opioids (≥50 vs <50 mg oral morphine equivalent) had an increased risk of new persistent opioid use after surgery (odds ratio = 2.41, P < 0.0001). In addition to the provider's prescribing pattern, other factors including younger age, comorbidities, presurgical opioid use, chemotherapy, type of tumor/surgical procedure were also found to be independently associated with new persistent postoperative opioid use. CONCLUSIONS: Our results suggest that prescriber with a history of prescribing a higher opioid dose is an important predictor of persistent postoperative opioid use among cancer patients undergoing curative-intent surgery.

Same-Day Surgery for Mastectomy Patients in Alberta: A Perioperative Care Pathway and Quality Improvement Initiative.

BACKGROUND: Same-day surgery (SDS) following mastectomy is safe and well accepted. Overnight admission in patients fit for discharge is an inefficient use of health resources. In response to a national review highlighting SDS following mastectomy at 1.4% in Alberta, a perioperative pathway was conceived. METHODS: The pathway was implemented across Alberta at 13 hospitals beginning in 2016. A steering committee was assembled, and clinical and administrative leads at each site were identified. Opportunities along the patient care experience whereby action could be taken to promote uptake of SDS were identified. Provincially branded support materials including presentations, order sets, and standard operating procedures were developed. Nurse educators provided in-service teaching such as standardized drain care and discharge teaching. Educational booklets, group classes, and online resources were developed for patients and families. An audit of SDS rates, unscheduled return to the emergency department (ED), and readmission rates was reported to teams quarterly, allowing for iterative modifications. Patient-reported experience measures (PREMs) were collected. RESULTS: SDS following mastectomy increased from 1.7 to 47.8%, releasing an estimated 831 bed days per year. No differences in unexpected return to the ED or readmission to hospital existed between SDS patients and those admitted overnight. A total of 102 patients completed the PREM survey, of whom 90% felt "excellent or good" with the plan to go home, how to care for themselves once home, and who to contact should issues arise. CONCLUSIONS: Implementation of a provincial perioperative pathway improved uptake of SDS following mastectomy and demonstrated favorable PREMs.

Development and validation of case-finding algorithms for recurrence of breast cancer using routinely collected administrative data.

BACKGROUND: Recurrence is not explicitly documented in cancer registry data that are widely used for research. Patterns of events after initial treatment such as oncology visits, re-operation, and receipt of subsequent chemotherapy or radiation may indicate recurrence. This study aimed to develop and validate algorithms for identifying breast cancer recurrence using routinely collected administrative data. METHODS: The study cohort included all young (≤ 40 years) breast cancer patients (2007-2010), and all patients receiving neoadjuvant chemotherapy (2012-2014) in Alberta, Canada. Health events (including mastectomy, chemotherapy, radiation, biopsy and specialist visits) were obtained from provincial administrative data. The algorithms were developed using classification and regression tree (CART) models and validated against primary chart review. RESULTS: Among 598 patients, 121 (20.2%) had recurrence after a median follow-up of 4 years. The high sensitivity algorithm achieved 94.2% (95% CI: 90.1-98.4%) sensitivity, 93.7% (91.5-95.9%) specificity, 79.2% (72.5-85.8%) positive predictive value (PPV), and 98.5% (97.3-99.6%) negative predictive value (NPV). The high PPV algorithm had 75.2% (67.5-82.9%) sensitivity, 98.3% (97.2-99.5%) specificity, 91.9% (86.6-97.3%) PPV, and 94% (91.9-96.1%) NPV. Combining high PPV and high sensitivity algorithms with additional (7.5%) chart review to resolve discordant cases resulted in 94.2% (90.1-98.4%) sensitivity, 98.3% (97.2-99.5%) specificity, 93.4% (89.1-97.8%) PPV, and 98.5% (97.4-99.6%) NPV. CONCLUSION: The proposed algorithms based on routinely collected administrative data achieved favorably high validity for identifying breast cancer recurrences in a universal healthcare system in Canada.

Chronic Postoperative Opioid Use: A Systematic Review.

BACKGROUND: There are a number of studies in the literature that describe the prevalence, causes, and factors associated with chronic postoperative opioid use, but there is a lack of synthesis of the literature to guide clinicians in optimally managing postoperative pain while avoiding opioid dependence. Thus, the goal of this study was to perform a systematic review of the literature to investigate the prevalence of chronic postoperative opioid use and the associated risk factors. MATERIALS AND METHODS: A systematic search was performed using Ovid Medline and Embase according to PRISMA guidelines. Data were collected on the following outcomes of interest: prevalence of opioid use at 3, 6, and 12 months postoperatively, and risk factors associated with chronic postoperative opioid use. RESULTS: Forty-three articles were included in the final analysis. The mean prevalence of chronic postoperative opioid use in all populations at 3, 6, and 12 months postoperatively was 30.5%, 25.6%, and 25.2%, respectively. The prevalence of patients who developed chronic opioid use at 3, 6, and 12 months postoperatively was 10.4%, 8.5%, and 9.8%, respectively. Forty of the articles analyzed risk factors associated with chronic postoperative opioid use. The most common associated risk factor identified was preoperative opioid use with 27 articles demonstrating a significant association with chronic postoperative opioid use. DISCUSSION: The current opioid crisis is in part secondary to the prevalence of chronic opioid use following surgery. This study identified associated risk factors with chronic postoperative opioid use, which may help identify patients at risk for developing chronic postoperative opioid use.

'Driving' Rates Down: A Population-Based Study of Opening New Radiation Therapy Centers on the Use of Mastectomy for Breast Cancer.

BACKGROUND: Two new cancer centers providing radiation therapy opened in Alberta, Canada, in 2010 and 2013, respectively. We aimed to assess whether opening the new RT centers influenced mastectomy rates for breast cancer. METHOD: Breast cancer patients who underwent surgery from 2004 through 2015 were identified from the Alberta Cancer Registry. Mastectomy rates for 64 predefined health status areas (HSAs) were calculated after adjusting for patient and system factors. Variations in mastectomy rates among the HSAs were quantified using weighted coefficient of variation (CV). Multivariable logistic regressions were performed to determine associations between driving time and mastectomy use in the entire cohort and in subgroups. RESULTS: Of the 21,872 patients, the proportion of patients who lived a ≤ 60 min drive from the nearest RT center significantly increased from 68.8% (95% CI 67.7-69.9%) to 80.7% (95% CI 79.5-81.9%) during the study period. Concurrently, the crude provincial mastectomy rate decreased from 56.2% (95% CI 55.3-57.1%) to 45.3% (95% CI 44.1-46.5%). However, variation in adjusted mastectomy rates (weighted CV) across the 64 HSAs increased from 9.5 to 14.6. Factors associated with mastectomy included age, larger tumor size, lymph node involvement, higher tumor grade, molecular subtype, lobular histology type, more comorbidities, academic institution, region, earlier period of diagnosis, and longer driving time to the nearest RT center. CONCLUSIONS: Opening new RT centers in previously underserved regions reduced driving times to the nearest center, and was associated with a reduction in mastectomy rates; however, these reductions among regions across the province were not uniform.

Assessing the performance of a Loop Mediated Isothermal Amplification (LAMP) assay for the detection and subtyping of high-risk suptypes of Human Papilloma Virus (HPV) for Oropharyngeal Squamous Cell Carcinoma (OPSCC) without DNA purification.

BACKGROUND: Oropharyngeal Squamous Cell Carcinoma (OPSCC) is increasing in incidence despite a decline in traditional risk factors. Human Papilloma Virus (HPV), specifically subtypes 16, 18, 31 and 35, has been implicated as the high-risk etiologic agent. HPV positive cancers have a significantly better prognosis than HPV negative cancers of comparable stage, and may benefit from different treatment regimens. Currently, HPV related carcinogenesis is established indirectly through Immunohistochemistry (IHC) staining for p16, a tumour suppressor gene, or polymerase chain reaction (PCR) that directly tests for HPV DNA in biopsied tissue. Loop mediated isothermal amplification (LAMP) is more accurate than IHC, more rapid than PCR and is significantly less costly. In previous work we showed that a subtype specific HPV LAMP assay performed similar to PCR on purified DNA. In this study we examined the performance of this LAMP assay without DNA purification. METHODS: We used LAMP assays using established primers for HPV 16 and 18, and new primers for HPV 31 and 35. LAMP reaction conditions were tested on serial dilutions of plasmid HPV DNA to confirm minimum viral copy number detection thresholds. LAMP was then performed directly on different human cell line samples without DNA purification. RESULTS: Our LAMP assays could detect 105, 103, 104, and 105 copies of plasmid DNA for HPV 16, 18, 31, and 35, respectively. All primer sets were subtype specific, with no cross-amplification. Our LAMP assays also reliably amplified subtype specific HPV DNA from samples without requiring DNA isolation and purification. CONCLUSIONS: The high risk OPSCC HPV subtype specific LAMP primer sets demonstrated, excellent clinically relevant, minimum copy number detection thresholds with an easy readout system. Amplification directly from samples without purification illustrated the robust nature of the assay, and the primers used. This lends further support HPV type specific LAMP assays, and these specific primer sets and assays can be further developed to test for HPV in OPSCC in resource and lab limited settings, or even bedside testing.

Fractal analysis of nuclear histology integrates tumor and stromal features into a single prognostic factor of the oral cancer microenvironment.

BACKGROUND: The lack of prognostic biomarkers in oral squamous cell carcinoma (OSCC) has hampered treatment decision making and survival in OSCC remains poor. Histopathological features are used for prognostication in OSCC and, although useful for predicting risk, manual assessment of histopathology is subjective and labour intensive. In this study, we propose a method that integrates multiple histopathological features of the tumor microenvironment into a single, digital pathology-based biomarker using nuclear fractal dimension (nFD) analysis. METHODS: One hundred and seven consecutive OSCC patients diagnosed between 1998 and 2006 in Calgary, Canada were included in the study. nFD scores were generated from DAPI-stained images of tissue microarray (TMA) cores. Ki67 protein expression was measured in the tumor using fluorescence immunohistochemistry (IHC) and automated quantitative analysis (AQUA®). Lymphocytic infiltration (LI) was measured in the stroma from haematoxylin-eosin (H&E)-stained TMA slides by a pathologist. RESULTS: Twenty-five (23.4%) and 82 (76.6%) patients were classified as high and low nFD, respectively. nFD was significantly associated with pathological tumor-stage (pT-stage; P = 0.01) and radiation treatment (RT; P = 0.01). High nFD of the total tumor microenvironment (stroma plus tumor) was significantly associated with improved disease-specific survival (DSS; P = 0.002). No association with DSS was observed when nFD of either the tumor or the stroma was measured separately. pT-stage (P = 0.01), pathological node status (pN-status; P = 0.02) and RT (P = 0.03) were also significantly associated with DSS. In multivariate analysis, nFD remained significantly associated with DSS [HR 0.12 (95% CI 0.02-0.89, P = 0.04)] in a model adjusted for pT-stage, pN-status and RT. We also found that high nFD was significantly associated with high tumor proliferation (P < 0.0001) and high LI (P < 0.0001), factors that we and others have shown to be associated with improved survival in OSCC. CONCLUSIONS: We provide evidence that nFD analysis integrates known prognostic factors from the tumor microenvironment, such as proliferation and immune infiltration, into a single digital pathology-based biomarker. Prospective validation of our results could establish nFD as a valuable tool for clinical decision making in OSCC.

Head and neck cancer: from anatomy to biology.

The 20th century saw great advances in anatomy-based (surgery and radiotherapy) and chemotherapy approaches for treating head and neck squamous cell carcinoma (HNSCC) and improving quality of life (QoL). However, despite these advances, the survival rate in HNSCC remains at ∼50%. Front-line treatments often cause severe toxicity and debilitating long-term impacts on QoL. In recent decades, dramatic advances have been made in our knowledge of fundamental tumor biology and signaling pathways that contribute to oncogenesis and cancer progression. These insights are presenting unprecedented opportunities to develop more effective and less toxic treatments that are specific to particular molecular targets. This review discusses some of the major, potentially targetable, molecular pathways associated with head and neck carcinogenesis. We present the general mechanism underlying the functional components for each signaling pathway, discuss how these components are aberrantly regulated in HNSCC and describe their potential as therapeutic targets. We have restricted our discussion to "drug-able targets" such as oncogenes including those associated with HPV, tumor hypoxia and microRNAs and present these changes in the context of HNSCC patient care. The specific targeting of these pathways to achieve cancer control/remission and reduce toxicity is now challenging conventional treatment paradigms in HNSCC. This new "biologic era" is transforming our ability to target causal pathways and improve survival outcomes in HNSCC.

Preoperative hemoglobin and perioperative blood transfusion in major head and neck surgery: a systematic review and meta-analysis.

BACKGROUND: There is a growing concern with inappropriate, excessive perioperative blood transfusions. Understanding the influence of low preoperative hemoglobin (Hgb) on perioperative blood transfusion (PBT) in head and neck cancer (HNC) surgery with free flap reconstruction may help guide clinical practice to reduce inappropriate treatment among these patients. The objective is to synthesize evidence regarding the association between preoperative Hgb and PBT among major HNC free flap surgeries. METHODS: Terms and synonyms for HNC surgical procedures, Hgb and PBT were used to search MEDLINE, Embase, CINAHL, Cochrane Central Register of Controlled Trials and Cochrane Database of Reviews from inception to February 2020. Reference lists of included full texts and studies reporting the preoperative Hgb, anemia or hematocrit (exposure) and the PBT (outcome) in major HNC surgery with free flap reconstruction were eligible. Studies examining esophageal, thyroid and parathyroid neoplasms were excluded; as were case reports, case series (n < 20), editorials, reviews, perspectives, viewpoints and responses. Two independent, blinded reviewers screened titles, abstracts and full texts in duplicate. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses was followed. A random-effects model was used to pool reported data. The primary outcome was the proportion of patients who had a PBT. Subgroup analysis examined sources of heterogeneity for perioperative predictors of PBT (age, sex, flap type, flap site and preoperative Hgb). We also examined mean preoperative Hgb in the PBT and no PBT groups. RESULTS: Patients with low preoperative Hgb were transfused more than those with normal Hgb (47.62%, 95% CI = 41.19-54.06, I2 = 0.00% and 13.92%, 95% CI = 10.19-17.65, I2 = 20.69%, respectively). None of the predictor variables explained PBT. The overall pooled mean preoperative Hgb was 12.96 g/dL (95% CI = 11.33-14.59, I2 = 0.00%) and was 13.58 g/dL (95% CI = 11.95-15.21, I2 = 0.00%) in the no PBT group and 12.05 g/dL (95% CI = 10.01 to 14.09, I2 = 0.00%) in the PBT group. CONCLUSIONS: The heterogeneity between studies, especially around the trigger for PBT, highlights the need for additional research to guide clinical practice of preoperative Hgb related to PBT to enhance patient outcomes and improve healthcare stewardship.

Examining the utility of a photorealistic virtual ear in otologic education.

BACKGROUND: Otolaryngology-head and neck surgical (OHNS) trainees' operating exposure is supplemented by a combination of didactic teaching, textbook reading, and cadaveric dissections. Conventional teaching, however, may not adequately equip trainees with an understanding of complex visuospatial relationships of the middle ear. Both face and content validation were assessed of a novel three-dimensional (3D) photorealistic virtual ear simulation tool underwent face and content validation as an educational tool for OHNS trainees. METHODS: A three-dimensional mesh reconstruction of open access imaging was generated using geometric modeling, which underwent global illumination, subsurface scattering, and texturing to create photorealistic virtual reality (VR) ear models were created from open access imaging and comiled into a educational platform. This was compiled into an educational VR platform which was explored to validate the face and content validity questionnaires in a prospective manner. OHNS post-graduate trainees were recruited from University of Toronto and University of Calgary OHNS programs. Participation was on a voluntary basis. RESULTS: Total of 23 OHNS post-graduate trainees from the two universities were included in this study. The mean comfort level of otologic anatomy was rated 4.8 (± 2.2) out of 10. Senior residents possessed more otologic surgical experience (P < 0.001) and higher average comfort when compared to junior residents [6.7 (± 0.7) vs. 3.6 (± 1.9); P = 0.001]. Face and content validities were achieved in all respective domains with no significant difference between the two groups. Overall, respondents believed OtoVIS was a useful tool to learn otologic anatomy with a median score of 10.0 (8.3-10.0) and strongly agreed that OtoVIS should be added to OHNS training with a score of 10.0 (9.3-10.0). CONCLUSIONS: OtoVIS achieved both face and content validity as a photorealistic VR otologic simulator for teaching otologic anatomy in the postgraduate setting. As an immersive learning tool, it may supplement trainees' understanding and residents endorsed its use.

NCBP2 and TFRC are novel prognostic biomarkers in oral squamous cell carcinoma.

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.

Identifying Factors of Operative Efficiency in Head and Neck Free Flap Reconstruction.

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.

Spatial transcriptomics reveals distinct and conserved tumor core and edge architectures that predict survival and targeted therapy response.

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.

Bax expression measured by AQUAnalysis is an independent prognostic marker in oral squamous cell carcinoma.

BACKGROUND: Resistance to apoptosis is a hallmark of cancer and proteins regulating apoptosis have been proposed as prognostic markers in several malignancies. However, the prognostic impact of apoptotic markers has not been consistently demonstrated in oral squamous cell carcinoma (OSCC). This inconsistency in reported associations between apoptotic proteins and prognosis can be partly attributed to the intrinsic low resolution and misclassification associated with manual, semi-quantitative methods of biomarker expression measurement. The aim of this study was to examine the association between apoptosis-regulating proteins and clinical outcomes in oral squamous cell carcinoma (OSCC) using the quantitative fluorescence immunohistochemistry (IHC) based AQUAnalysis technique. METHODS: Sixty-nine OSCC patients diagnosed between 1998-2005 in Calgary, Alberta, Canada were included in the study. Clinical data were obtained from the Alberta Cancer Registry and chart review. Tissue microarrays (TMAs) were assembled from triplicate cores of formalin-fixed paraffin embedded pre-treatment tumour tissue. Bax, Bcl-2 and Bcl-XL protein expression was quantified using fluorescent IHC and AQUA technology in normal oral cavity squamous epithelium (OCSE) and OSCC tumour samples. Survival was analyzed using Kaplan-Meier plots and the Cox proportional hazard model. RESULTS: Bax expression was predominantly nuclear in OCSE and almost exclusively cytoplasmic in OSCC. No similar differences in localization were observed for Bcl-2 or Bcl-XL. Only Bax expression associated with disease-specific survival (DSS), with 5-year survival estimates of 85.7% for high Bax versus 50.3% for low Bax (p = 0.006), in univariate analysis. High Bax expression was also significantly associated with elevated Ki67 expression, indicating that increased proliferation might lead to an improved response to radiotherapy in patients with elevated Bax expression. In multivariate analyses, Bax protein expression remained an independent predictor of DSS in OSCC [HR 0.241 (0.078-0.745), p = 0.013]. CONCLUSIONS: The AQUA technique used in our study eliminates observer bias and provides reliable and reproducible estimates for biomarker expression. AQUA also provides essential measures of quality control that cannot be achieved with manual biomarker scoring techniques. Our results support the use of Bax protein expression as a prognostic marker in conjunction with other clinico-pathological variables when designing personalized treatment strategies for OSCC patients.

Validated algorithms for identifying timing of second event of oropharyngeal squamous cell carcinoma using real-world data.

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.

The feasibility of patient-reported outcomes, physical function, and mobilization in the care pathway for head and neck cancer surgical patients.

BACKGROUND: Head and neck cancer (HNC) patients are an understudied population whose treatment often includes surgery, causing a wide range of side effects. Exercise prehabilitation is a promising tool to optimize patient outcomes and may confer additional benefits as a prehabilitation tool. The primary objective of this study was to assess the feasibility of measuring patient-reported outcomes (PROs), physical function, and in-hospital mobilization across the HNC surgical timeline in advance of a future prehabilitation trial. The secondary objective was to examine potential changes in these outcomes across the surgical timeline. METHODS: HNC patients scheduled to undergo oncologic resection with free-flap reconstruction completed assessments of PROs and physical function at three timepoints across the surgical timeline (baseline, in-hospital, and postsurgical/outpatient). Mobilization was measured during the in-hospital period. The feasibility of recruitment and measurement completion was tracked, as were changes in both PROs and physical function. RESULTS: Of 48 eligible patients, 16 enrolled (recruitment rate of 33%). The baseline and in-hospital PROs were completed by 88% of participants, while the outpatient assessments were completed by 81% of participants. The baseline and in-hospital assessment of physical function were completed by 56% of participants, and 38% completed the outpatient assessment. Measuring in-hospital mobilization was completed for 63% of participants. CONCLUSION: Measuring PROs and in-hospital mobilization is feasible across the surgical timeline in HNC; however, the in-person assessment of physical function prior to surgery was not feasible. A multidisciplinary collaboration between exercise specialists and clinicians supported the development of new clinical workflows in HNC surgical care that will aid in the implementation of a future prehabilitation trial for this patient population.

A Qualitative Study of Patient and Healthcare Provider Perspectives on Building Multiphasic Exercise Prehabilitation into the Surgical Care Pathway for Head and Neck Cancer.

Head and neck cancer (HNC) surgical patients experience a high symptom burden. Multiphasic exercise prehabilitation has the potential to improve patient outcomes, and to implement it into the care pathway, the perspectives of patients and healthcare providers (HCPs) must be considered. The purpose of this study was thus to gather feedback from HNC surgical patients and HCPs on building exercise into the standard HNC surgical care pathway. Methods: Semi-structured interviews were conducted with patients and HCPs as part of a feasibility study assessing patient-reported outcomes, physical function, and in-hospital mobilization. Interview questions included satisfaction with study recruitment, assessment completion, impact on clinical workflow (HCPs), and perceptions of a future multiphasic exercise prehabilitation program. This study followed an interpretive description methodology. Results: Ten patients and ten HCPs participated in this study. Four themes were identified: (1) acceptability and necessity of assessments, (2) the value of exercise, (3) the components of an ideal exercise program, and (4) factors to support implementation. Conclusion: These findings highlight the value of exercise across the HNC surgical timeline from both the patient and the HCP perspective. Results have informed the implementation of a multiphasic exercise prehabilitation trial in HNC surgical patients.

Immune-based classification of HPV-associated oropharyngeal cancer with implications for biomarker-driven treatment de-intensification.

BACKGROUND: There is significant interest in treatment de-escalation for human papillomavirus-associated (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) patients given the generally favourable prognosis. However, 15-30% of patients recur after primary treatment, reflecting a need for improved risk-stratification tools. We sought to develop a molecular test to risk stratify HPV+ OPSCC patients. METHODS: We created an immune score (UWO3) associated with survival outcomes in six independent cohorts comprising 906 patients, including blinded retrospective and prospective external validations. Two aggressive radiation de-escalation cohorts were used to assess the ability of UWO3 to identify patients who recur. Multivariate Cox models were used to assess the associations between the UWO3 immune class and outcomes. FINDINGS: A three-gene immune score classified patients into three immune classes (immune rich, mixed, or immune desert) and was strongly associated with disease-free survival in six datasets, including large retrospective and prospective datasets. Pooled analysis demonstrated that the immune rich group had superior disease-free survival compared to the immune desert (HR = 9.0, 95% CI: 3.2-25.5, P = 3.6 × 10-5) and mixed (HR = 6.4, 95% CI: 2.2-18.7, P = 0.006) groups after adjusting for age, sex, smoking status, and AJCC8 clinical stage. Finally, UWO3 was able to identify patients from two small treatment de-escalation cohorts who remain disease-free after aggressive de-escalation to 30 Gy radiation. INTERPRETATION: With additional prospective validation, the UWO3 score could enable biomarker-driven clinical decision-making for patients with HPV+ OPSCC based on robust outcome prediction across six independent cohorts. Prospective de-escalation and intensification clinical trials are currently being planned. FUNDING: CIHR, European Union, and the NIH.

The impact of close surgical margins on recurrence in oral squamous cell carcinoma.

BACKGROUND: Close margins influence treatment and outcome in patients with oral squamous cell carcinoma (OSCC). This study evaluates 187 cases of surgically treated OSCC regarding the impact of close margins on recurrence-free survival (RFS) and disease-specific survival (DSS). METHODS: Predictors of worsened outcome were identified using Kaplan-Meier analysis and multivariate Cox regression analysis. RESULTS: Tumour size [HR:1.70(0.95-3.08)], nodal status [HR:2.15(1.00-4.64)], presence of extracapsular spread (ECS) [HR:6.36(2.41-16.74)] and smoking history [HR:2.87(1.19-6.86)] were associated with worsened RFS. Similar factors were associated with worsened DSS. Close margins did not influence RFS or DSS. CONCLUSIONS: While most conventional risk factors for OSCC conferred a worsened outcome, close margins did not. One explanation for this would be that close margins (< 5 mm) are equivalent to clear margins and the cutoff definition for a close margin should be re-evaluated. Lack of standardized pathology could also reduce accuracy of reporting of close surgical margins.