Personalized Treatment of Recurrent, Metastatic Head and Neck Cancer Guided by Patient-Derived Xenograft Models.

Recurrent or metastatic head and neck squamous cell carcinoma (RMHNSCC) is associated with a poor prognosis and short survival duration. There is an urgent need to identify personalized predictors of drug response to guide the selection of the most effective therapy for each individual recurrence. We tested the feasibility of patient-derived xenografts (PDX) for guiding their RMHNSCC salvage treatment. Fresh tumor samples from eligible, consented patients were implanted into mice. Established tumors were expanded in mouse PDX cohorts to identify responses to candidate salvage drug treatments in parallel testing. Patients alive and suitable for chemotherapy were treated based on responses determined by PDX testing. Nine patient tumors were successfully engrafted in mice with an average time of 89.2±41.7 days. Four patients' PDX models underwent parallel drug testing. Two patients received PDX-guided therapy. In one of these patients, single agents of cetuximab and paclitaxel demonstrated the best responses in the PDX model, and this patient exhibited sequential partial responses to each drug, including a 17-month clinical response to cetuximab. The main limitation of PDX testing for RMHNSCC was the time delay in obtaining testing results. Despite this, parallel PDX testing may be feasible for a subset of patients and appears to correlate with clinical benefit.

The Ansa Hypoglossi: Quantifying Axonal Density of a Donor Nerve for Facial Reinnervation.

Background: There are a number of nerve grafting options for facial reanimation and the ansa hypoglossi (AH) may be considered in select situations. Objective: To compare axonal density, area, and diameter of AH with other nerves more usually used for facial reanimation. Methods: AH specimens from patients undergoing neck dissections were submitted in formalin. Proximal to distal cross sections, nerve diameters, and the number of axons per nerve, proximally and distally, were measured and counted. Results: Eighteen nerve specimens were analyzed. The average manual axon count for the distal and proximal nerve sections was 1378 ± 333 and 1506 ± 306, respectively. The average QuPath counts for the proximal and distal nerve sections were 1381 ± 325 and 1470 ± 334, respectively. The mean nerve area of the proximal and distal nerve sections was 0.206 ± 0.01 and 0.22 ± 0.064 mm2, respectively. The mean nerve diameter for the proximal and distal nerve sections were 0.498 ± 0.121 and 0.526 ± 0.75 mm, respectively. Conclusion: The histological characteristics of the AH support clinical examination of outcomes as a promising option in facial reanimation.

A comparison of timing and patterns of treatment failure, and survival outcomes after progression between HPV+ and HPV- patients undergoing chemoradiation for oropharyngeal squamous cell carcinomas.

BACKGROUND: We aimed to analyze and compare the timing and patterns of treatment failure, and survival after progression between HPV-positive (HPV+) and HPV-negative (HPV-) patients undergoing chemoradiation for oropharyngeal squamous cell carcinomas (OPSCC). METHODS: A retrospective review was performed of all patients undergoing primary chemoradiation for OPSCC between 2008 and 2021. Demographic and clinical data were collected. Kaplan-Meier estimates for overall survival (OS), and time to recurrence/metastases (TTR) were compared using the log-rank test, with Cox regression used for multivariable modeling comparing HPV+ and HPV- patients. RESULTS: HPV- patients developed recurrence or metastases at earlier time points than HPV+ patients (8.8 vs. 15.2 months, p < 0.05), due to earlier local/locoregional recurrence and distant metastases, but not isolated regional recurrences. HPV- distant metastases exclusively occurred in a single organ, most commonly the lungs or bone, while HPV+ metastases frequently had multi-organ involvement in a wide variety of locations (p < 0.05). Once progression (recurrence/metastases) was diagnosed, HPV+ patients experienced superior survival to HPV- patients on univariate and multivariate analysis, largely due to improved outcomes after treatment of local/locoregional recurrences (p < 0.05). There were no differences in survival after isolated regional recurrences or distant metastases. CONCLUSION: HPV+ OPSCC patients relapse later compared to HPV- patients in local/locoregional and distant sites. HPV+ patients with local/locoregional recurrence experience superior survival after recurrence, which does not hold true for isolated regional recurrences or distant metastases. These data can be useful to inform prognosis and guide treatment decisions in patients with recurrent OPSCC.

"Winged" Eagle's syndrome: neurophysiological findings in a rare cause of spinal accessory nerve palsy. Illustrative cases.

BACKGROUND: Eagle's syndrome (ES) classically describes dysphagia, globus sensation, and otalgia from an elongated and calcified styloid process or stylohyoid ligament. Compression of the spinal accessory nerve (SAN) has not been reported as an associated feature of ES or related variants. OBSERVATIONS: The authors describe two cases of an atypical "winged" variant with SAN palsy resulting from compression by a posteriorly angulated or calcified styloid process. Both patients exhibited lateral scapular winging and atrophy of the trapezius and sternocleidomastoid muscles. Electrophysiological studies demonstrated motor unit preservation; therefore, surgical exploration, styloidectomy, and SAN decompression were performed through a transcervical approach. Postoperatively, both patients had improvements in pain and shoulder mobility, the return of muscle strength, and electrophysiological evidence of trapezius reinnervation. LESSONS: Compression of the SAN, which can be identified both clinically and on electrodiagnostic testing, is an atypical finding that can result from a posteriorly angulated or calcified styloid process. This winged variant of ES should be included in the differential for SAN palsy, and a multidisciplinary approach is recommended for assessment and management.

A sinonasal NUT midline carcinoma in an 84-year-old man undergoing radiation and proton therapy.

NUT midline carcinomas are rare, aggressive, and poorly differentiated tumors that must be considered in the differential diagnosis of midline head and neck tumors. Despite the scarce data, proton therapy could be an option for some patients.

Ultrasound-guided wire localisation: a GPS for hidden head and neck tumours? A case series.

Objectives: Ultrasound-guided wire (USGW) localisation for small non-palpable tumours before a revision head and neck surgery is an attractive pre-operative option to facilitate tumour identification and decrease potential complications. We describe five cases of pre-operative USGW localisation of non-palpable head and neck lesions to facilitate surgical localisation and resection. Methods: All patients undergoing pre-operative USGW localisation for non-palpable tumours of the head and neck region at London Health and Sciences Center, London, Ontario, Canada, were included. All the USGW localisations were performed by the same interventional radiologist, and the surgeries were performed by fellowship trained head and neck surgeons. Results: Five patients were included. All patients were undergoing revision surgery for recurrent or persistent disease. All successfully underwent a pre-operative USGW localisation of the non-palpable lesion before revision surgery. All lesions were localised intra-operatively with no peri-operative complications. Conclusions: USGW localisation is a safe and effective pre-operative technique for the identification of small non-palpable head and neck tumours.

Self-perception of fatigue in individuals diagnosed with head and neck cancer.

PURPOSE: Head and neck cancer (HNCa) presents numerous challenges secondary to treatment. While there is substantial clinical awareness to the range of challenges demonstrated in this population, information on the impact of post-treatment fatigue is limited. This study investigated the degree of perceived fatigue in those treated for HNCa. METHODS: The study was a cross-sectional, self-report, survey design. Adult participants (n = 47) completed a series of three questionnaires; two validated fatigue measures - the Fatigue Screening Inventory (FSI) and the Multidimensional Fatigue Inventory (MFI-20) and a general health-related quality of life measure the European Organisation of Research on the Treatment of Cancer - Quality of Life Questionnaire (EORTC-QLQC30) and the head and neck site specific module (QLQ - H&N 35) were administered. RESULTS: Of the 47 participants, more than half (55%) were identified as having clinically significant self-reported levels of fatigue. Correlational analysis revealed an inverse relationship between fatigue and overall health-related quality of life (HRQOL) implying that as fatigue increases, one's perceived HRQOL decreases. CONCLUSIONS: These data suggest that efforts to proactively screen for and index fatigue and seek anticipatory interventions may benefit both short- and long-term HRQOL outcomes in those diagnosed with HNCa. LEVEL OF EVIDENCE: IV.

Risk Factors for Poor Survival Outcomes in Parotid Metastatic Cutaneous Squamous Cell Carcinoma.

OBJECTIVE: We aimed to analyze risk factors associated with poor survival outcomes for metastatic cutaneous head-and-neck SCC to the parotid. METHODS: All patients undergoing surgery for metastatic cutaneous SCC to the parotid with curative intent between 2011 and 2018, were reviewed. Demographic and clinical characteristics were evaluated. Histopathological data including tumor size and histology, tumor grade, TNM stage, resection margins, lymphovascular invasion, and perineural invasion, were analyzed. Overall survival (OS), disease-specific survival (DSS), and freedom from locoregional recurrence (LRR) were assessed. RESULTS: Ninety patients were included (mean age, 77 years; 75 men [83.3%]). A total parotidectomy was performed in 48 patients (53.3%), and 42 (46.7%) underwent a superficial parotidectomy. Seventy patients (77.8%) underwent adjuvant RT. The median follow-up was 31 months (20-39 months). Tumor volume ≥ 50 cm3 and a shorter RT duration (<20 days) were associated with reduced OS (p = 0.002 and p = 0.01, p = 0.02 and p = 0.009, respectively), and DSS (p = 0.004 and p = 0.02, p = 0.04 and p = 0.02, respectively) on univariable and multivariable analysis, respectively. Only a shorter RT duration was associated with worse freedom from LRR on univariable and multivariable analysis, (p = 0.04 and p < 0.001, respectively). However, with death as a competing risk, a shorter duration of RT was not significantly associated with freedom from LRR. CONCLUSION: A shorter duration of adjuvant RT, and excised tumor volume ≥50 cm3 were predictive factors of reduced OS and DSS, and a shorter duration of RT was also associated with reduced freedom from LRR in patients with metastatic SCC to the parotid gland. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:1163-1168, 2023.

Automated finite element approach to generate anatomical patient-specific biomechanical models of atherosclerotic arteries from virtual histology-intravascular ultrasound.

Despite advancements in early detection and treatment, atherosclerosis remains the leading cause of death across all cardiovascular diseases (CVD). Biomechanical analysis of atherosclerotic lesions has the potential to reveal biomechanically instable or rupture-prone regions. Treatment decisions rarely consider the biomechanics of the stenosed lesion due in-part to difficulties in obtaining this information in a clinical setting. Previous 3D FEA approaches have incompletely incorporated the complex curvature of arterial geometry, material heterogeneity, and use of patient-specific data. To address these limitations and clinical need, herein we present a user-friendly fully automated program to reconstruct and simulate the wall mechanics of patient-specific atherosclerotic coronary arteries. The program enables 3D reconstruction from patient-specific data with heterogenous tissue assignment and complex arterial curvature. Eleven arteries with coronary artery disease (CAD) underwent baseline and 6-month follow-up angiographic and virtual histology-intravascular ultrasound (VH-IVUS) imaging. VH-IVUS images were processed to remove background noise, extract VH plaque material data, and luminal and outer contours. Angiography data was used to orient the artery profiles along the 3D centerlines. The resulting surface mesh is then resampled for uniformity and tetrahedralized to generate the volumetric mesh using TetGen. A mesh convergence study revealed edge lengths between 0.04 mm and 0.2 mm produced constituent volumes that were largely unchanged, hence, to save computational resources, a value of 0.2 mm was used throughout. Materials are assigned and finite element analysis (FEA) is then performed to determine stresses and strains across the artery wall. In a representative artery, the highest average effective stress was in calcium elements with 235 kPa while necrotic elements had the lowest average stress, reaching as low as 0.79 kPa. After applying nodal smoothening, the maximum effective stress across 11 arteries remained below 288 kPa, implying biomechanically stable plaques. Indeed, all atherosclerotic plaques remained unruptured at the 6-month longitudinal follow up diagnosis. These results suggest our automated analysis may facilitate assessment of atherosclerotic plaque stability.

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.

Surgical margins of the oral cavity: is 5 mm really necessary?

BACKGROUND: Squamous cell carcinoma is the most common malignancy of the oral cavity. Primary treatment involves surgical resection of the tumour with a surrounding margin. Historically, the most commonly accepted margin clearance is 5 mm. This distance is controversial, with recent publications suggesting closer margins do not impact local recurrence and survival. The objective of this study is to determine the closest surgical margin that does not impact local recurrence and overall survival. METHODS: A retrospective review of the London Health Sciences Centre Head and Neck Multidisciplinary Clinic between 2010 and 2018 was performed. Demographic data, subsite, tumour staging, treatment modality, margins, and survival outcomes were analyzed. The primary endpoint was local recurrence free survival. Secondary endpoints included recurrence-free survival and overall survival. Descriptive statistics, as well as univariable and multivariable Cox proportional hazards regression modelling were performed for all patients. RESULTS: Four-hundred and twelve patients were included in the study, with a median follow-up of 3.3 years. On univariable analysis, positive margins and margins < 1 mm were associated with significantly worse local recurrence-free survival, recurrence-free survival, and overall survival (p < 0.05), compared to margins > 5 mm. Patients with surgical margins > 1 mm experienced similar outcomes to those with margins > 5 mm. Multivariable analysis identified age of diagnosis, alcohol consumption, pathological tumour and nodal category as predictors of local recurrence free survival. CONCLUSIONS: Although historical margins for head and neck surgery are 5 mm, similar outcomes were observed for margins greater than 1 mm in our cohort. These findings require validation through multi-institutional collaborative efforts.

Bell's palsy misdiagnosis: characteristics of occult tumors causing facial paralysis.

OBJECTIVE: The aim of this study was to report the incidence and clinical course of a series of patients who were misdiagnosed with Bell's palsy and were eventually proven to have occult neoplasms. METHODS: Two hundred forty patients with unilateral facial paralysis who were assessed at the facial nerve reanimation clinic, Victoria Hospital, London Health Science Centre, from 2008 through 2017 were reviewed. Persistent paralysis without recovery was the presenting complaint. RESULTS: Nine patients (3.8%) who were proven to have occult neoplasms initially presented with a diagnosis of Bell's palsy. The mean diagnostic delay was 43.5 months. Four patients were proven to have skin cancers, 3 patients had parotid cancers, and 2 patients had facial nerve schwannomas as a final diagnosis. Initial magnetic resonance imaging (MRI) was performed in all 9 patients and 8 underwent a follow-up MRI. An occult tumor was identified upon review of the original MRI in one patient and at follow-up MRI in 8 patients. The mean time interval between the initial and follow-up imaging was 30.8 months. The disease status at most recent follow-up were no evidence of disease in 2 patients (22%) and alive with disease in 7 patients (78%). An irreversible, progressive pattern of facial paralysis combined with pain, multiple cranial neuropathies or history of skin cancer were predictable risk factors for occult tumors. Seven out of the 9 patients (77.8%) underwent at least one type of facial reanimation surgery, and the final subjective results by the surgeon were available for 5 patients. Three out of the 5 (60%) patients who were available for final subjective analysis were reported as Grade III according to the modified House-Brackmann scale. CONCLUSION: Occult facial nerve neoplasm should be suspected in patients with progressive and irreversible facial paralysis but the diagnosis may only become evident with follow-up imaging. Facial reanimation surgery is a satisfactory option for these patients.

Demographic and pathologic factor regression to a growth rate model of p16-negative oral cavity squamous cell carcinoma.

Objectives: The current study aims to quantify the growth rate of p16-negative oral cavity squamous cell carcinoma, characterize causative relationships between demographic risk factors and tumor growth, and examine pathologic findings associated with the tumor growth rate at a tertiary care institution. It is hypothesized that causative relationships will be drawn between the individual sociodemographic and pathologic factors and oral cavity p16-negative squamous cell carcinoma growth rate. Methods: Prospectively recruited participants, receiving surgical intervention only, were followed from initial staging CT scan to surgical resection. Interval growth was calculated in cm3/week. Demographic information including age, sex, smoking history, alcohol consumption history, previous all-type malignancy, previous chemotherapy treatment, previous head or neck radiation exposure, and time interval elapsed between diagnosis and surgery was collected from each participant, and regression analysis was applied to determine causality. Results: Summary statistics revealed a mean growth rate for the study sample of 1.385cm3/week. Statistically significant regression correlations were detected between tumor growth and alcohol consumption, origination at the retromolar trigone, and clinical nodal stage. Conclusions: Through a small prospective cohort sample, the current study suggests clinical associations between alcohol consumption, origination at the retromolar trigone, and clinical nodal stage with rate of tumor growth. Future work will validate these relationships in a larger patient cohort, and against stronger modeling techniques. Level of Evidence: Prospective non-random cohort design.

Therapeutic potential of vitamin B1 derivative benfotiamine from diabetes to COVID-19.

Benfotiamine (S-benzoylthiamine-O-monophosphate), a unique, lipid-soluble derivative of thiamine, is the most potent allithiamine found in roasted garlic, as well as in other herbs of the genus Allium. In addition to potent antioxidative properties, benfotiamine has also been shown to be a strong anti-inflammatory agent with therapeutic significance to several pathological complications. Specifically, over the past decade or so, benfotiamine has been shown to prevent not only various secondary diabetic complications but also several inflammatory complications such as uveitis and endotoxemia. Recent studies also demonstrate that this compound could be used to prevent the symptoms associated with various infectious diseases such as HIV and COVID-19. In this review article, the authors discuss the significance of benfotiamine in the prevention of various pathological complications.

Thematic Analysis of Canadian Patient-Reported Outcomes in Facial Nerve Paralysis: A Combined Interpretive Description and Modified Delphi Approach.

Background: In facial nerve dysfunction literature, subjective reporting tools lack essential construct validity arising from a patient-driven design process. Objective: Elicit patient-identified themes of importance pertaining to disease course in facial nerve dysfunction from a variety of etiologies. Methods: Twenty participant interviews were conducted from a standardized script and analyzed using a thematic analysis framework. Subsequently, four participants participated in a modified Delphi focus group for consensus of relative theme and domain importance. Results: Upon thematic analysis of 315 codable phrases, 33 codes were sorted into six domains. In descending order: smiling, facial symmetry, surgical access, self-consciousness, eye care, eating, lip movement, eye closure, beverage consumption, speech, chewing, drooling, eyebrow raise, mouth closure, and ptotic vision limitations were identified as the most important aspects of disease course. Care experience, defined as areas of interaction with the health care system in which patients felt strongly about their care or outcome, was the most important domain to participants. Conclusion: Patients with facial nerve dysfunction identified care experience as the highest domain of importance, and value smiling, facial symmetry, and access to surgical treatments.

Assessment of Toxic Effects and Survival in Treatment Deescalation With Radiotherapy vs Transoral Surgery for HPV-Associated Oropharyngeal Squamous Cell Carcinoma: The ORATOR2 Phase 2 Randomized Clinical Trial.

Importance: The optimal approach for treatment deescalation in human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas (OPSCCs) is unknown. Objective: To assess a primary radiotherapy (RT) approach vs a primary transoral surgical (TOS) approach in treatment deescalation for HPV-related OPSCC. Design, Setting, and Participants: This international, multicenter, open-label parallel-group phase 2 randomized clinical trial was conducted at 9 tertiary academic cancer centers in Canada and Australia and enrolled patients with T1-T2N0-2 p16-positive OPSCC between February 13, 2018, and November 17, 2020. Patients had up to 3 years of follow-up. Interventions: Primary RT (consisting of 60 Gy of RT with concurrent weekly cisplatin in node-positive patients) vs TOS and neck dissection (ND) (with adjuvant reduced-dose RT depending on pathologic findings). Main Outcomes and Measures: The primary end point was overall survival (OS) compared with a historical control. Secondary end points included progression-free survival (PFS), quality of life, and toxic effects. Results: Overall, 61 patients were randomized (30 [49.2%] in the RT arm and 31 [50.8%] in the TOS and ND arm; median [IQR] age, 61.9 [57.2-67.9] years; 8 women [13.6%] and 51 men [86.4%]; 31 [50.8%] never smoked). The trial began in February 2018, and accrual was halted in November 2020 because of excessive toxic effects in the TOS and ND arm. Median follow-up was 17 months (IQR, 15-20 months). For the OS end point, there were 3 death events, all in the TOS and ND arm, including the 2 treatment-related deaths (0.7 and 4.3 months after randomization, respectively) and 1 of myocardial infarction at 8.5 months. There were 4 events for the PFS end point, also all in the TOS and ND arm, which included the 3 mortality events and 1 local recurrence. Thus, the OS and PFS data remained immature. Grade 2 to 5 toxic effects occurred in 20 patients (67%) in the RT arm and 22 (71%) in the TOS and ND arm. Mean (SD) MD Anderson Dysphagia Inventory scores at 1 year were similar between arms (85.7 [15.6] and 84.7 [14.5], respectively). Conclusions and Relevance: In this randomized clinical trial, TOS was associated with an unacceptable risk of grade 5 toxic effects, but patients in both trial arms achieved good swallowing outcomes at 1 year. Long-term follow-up is required to assess OS and PFS outcomes. Trial Registration: Clinicaltrials.gov Identifier: NCT03210103.

Routine follow-up care for head and neck cancer after curative treatment: A 3-year experience of measuring patients' self-reported needs, preferences, quality of life and attitudes towards follow-up.

OBJECTIVE: To evaluate and describe attitudes, quality of life (Qol), needs and preferences of patients with head and neck cancer after 3 years of follow-up care. METHODS: This is an exploratory prospective study of recurrence-free patients. Survey results were compared between 1-, 2- and 3-year post-treatment and by disease characteristics. RESULTS: A total of 116 patients were included with 46% oropharyngeal cancer, 66% early stage disease and 41% having had surgery. After 3 years, most patients reported good to excellent health (88%), however expressed uncertainty regarding recurrence (66%), multiple needs (information on prognosis 91%, long-term sequalae 72%) and wanted to continue with follow-up (96%). Few changes were observed over time, with exceptions. Patients with more advanced disease, oral cancer or who had surgery experienced declining Qol (p < 0.050). Women experienced improvements in Qol domains (pain p = 0.028, speech p = 0.009) over time. Attitudes towards communication with oncologists demonstrated improved patient comfort (p = 0.044) over the 3 years; however, patients' beliefs about their prognosis did not (71% vs. 73% vs. 77% did not believe they were cured, p = 0.581). CONCLUSION: Although patients' needs, preferences and attitudes towards follow-up did not change drastically, important needs persist. This work supports identifying individual patient needs and the challenges in addressing prognostic expectations.

The Impact of Surgical Resectability on Outcomes for Patients Undergoing Primary Radiation Treatment for Human Papillomavirus-Related Oropharyngeal Cancer.

PURPOSE: Primary radiation therapy with or without chemotherapy (RT/CRT) is the most common treatment for oropharyngeal squamous cell carcinomas (OPSCC), but there has been an increase in transoral surgery (TOS) for T1-2 tumors. Because only a subset of T1-2 tumors are TOS-favorable, nonrandomized comparisons between RT/CRT and TOS could be confounded by indication. We aimed to compare outcomes of potential TOS-candidates versus non-TOS candidates, among patients who underwent RT/CRT for early T-stage OPSCC. METHODS AND MATERIALS: For patients treated with RT/CRT for early-stage human papilloma virus positive OPSCC between 2014 and 2018, pretreatment imaging was reviewed by 3 head and neck surgeons, blinded to outcomes, to assess primary-site appropriateness for TOS, and extracapsular extension (ECE) was scored by a head and neck neuroradiologist. We compared outcomes based on surgical favorability pertaining to (1) the primary site tumor alone and (2) the primary site and an absence of ECE. Kaplan-Meier estimates for overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) were compared using the log-rank test, with Cox regression used for multivariable modeling. RESULTS: One hundred and forty-three patients were evaluated, of which 121 were male (84.6%), the median age was 59.4 years, and all of them were p16 positive (100%). The primary site was TOS-favorable in 115 of 143 (80.4%). Patients with TOS-favorable primary site experienced superior 5-year OS (89.8% vs 71.2%, P = .017), DSS (90.4% vs 63.4%, P = .022), and RFS (83% vs 49.4%, P = .04) compared with TOS-unfavorable patients. Similarly, patients with a TOS-favorable primary site and no ECE on imaging 101 of 143 (70.6%), had improved OS, DSS, and RFS (P < .05) compared with TOS-unfavorable patients. CONCLUSIONS: In this first study to assess surgical favorability as a prognostic factor among patients with T1/2 p16+ OPSCC, patients with TOS-favorable early-stage OPSCC have better outcomes than TOS-unfavorable patients. This provides valuable prognostic information for patients, and also suggests the risk of confounding by indication in nonrandomized comparisons of treatment modalities.

Introduction and expression of PIK3CAE545K in a papillary thyroid cancer BRAFV600E cell line leads to a dedifferentiated aggressive phenotype.

Anaplastic thyroid cancer (ATC) is a rare, aggressive form of undifferentiated thyroid cancer, which exhibits rapid progression and is almost universally fatal. At least a subset of ATC is thought to arise from pre-existing well-differentiated thyroid cancer, most frequently papillary thyroid cancer (PTC). While PIK3CA mutations are rare in PTC, they are common in ATC and tend to co-occur with BRAF mutations. This provided the rationale for our study to identify the potential role of PIK3CA mutations in the progression from well-differentiated to undifferentiated thyroid cancer. We introduced PIK3CAE545K into the LAM1 PTC cell line, which carries a BRAFV600E mutation. In culture, the engineered cell line (LAM1:PIK3CAE545K) proliferated faster and demonstrated increased clonogenic potential relative to the parental line carrying an empty vector (LAM1EV). Both the LAM1EV and LAM1:PIK3CAE545K edited lines were implanted into hind flanks of athymic nude mice for in vivo determination of disease progression. While tumour weights and volumes were not significantly higher in LAM1:PIK3CAE545K mice, there was a decrease in expression of thyroid differentiation markers TTF-1, thyroglobulin, PAX8 and B-catenin, suggesting that introduction of PIK3CAE545K led to dedifferentiation in vivo. Collectively, this study provides evidence of a role for PIK3CAE545K in driving disease progression from a well-differentiated to an undifferentiated thyroid cancer; however, over-expression was not a determinant of an accelerated growth phenotype in ATC.