Advancing Laryngeal Adductor Reflex Testing Beyond Sensory Threshold Detection.

Flexible endoscopic evaluation of swallowing with sensory testing (FEESST) is a promising clinical tool to assess airway integrity via the laryngeal adductor reflex (LAR). The current clinical protocol relies on sensory threshold detection, as relatively little is known about the motor response of this sensorimotor airway protective reflex. Here, we focused on characterizing normative LAR motion dynamics in 20 healthy young participants using our prototype high-pressure syringe-based air pulse device and analytic software (VFtrack™) that tracks vocal fold (VF) motion in endoscopic videos. Following device bench testing for air pulse stimulus characterization, we evoked and objectively quantified LAR motion dynamics in response to two suprathreshold air pulse stimuli (40 versus 60 mm Hg), delivered to the arytenoid mucosa through a bronchoscope working channel. The higher air pressures generated by our device permitted an approximate 1 cm endoscope working distance for continual visualization of the bilateral VFs throughout the LAR. Post hoc video analysis identified two main findings: (1) there are variant and invariant subcomponents of the LAR motor response, and (2) only a fraction of suprathreshold stimuli evoked complete glottic closure during the LAR. While the clinical relevance of these findings remains to be determined, we have nonetheless demonstrated untapped potential in the current FEESST protocol. Our ongoing efforts may reveal LAR biomarkers to quantify the severity of laryngeal pathology and change over time with natural disease progression, spontaneous recovery, or in response to intervention. The ultimate goal is to facilitate predictive modeling of patients at high risk for dysphagia-related aspiration pneumonia.

Quality of life after segmental mandibulectomy and free flap for mandibular osteonecrosis: Systematic review.

OBJECTIVE: Review QOL outcomes among patients undergoing segmental mandibulectomy and bony free flap reconstruction for ONJ. DATA SOURCES: PubMed was searched for MeSH terms "Quality of life," "Osteonecrosis," "Osteoradionecrosis," "Bisphosphonate-associated osteonecrosis of the jaw," "Free tissue flaps," and "Mandibular reconstruction." REVIEW METHODS: English language studies with QOL outcomes data for patients undergoing free flap reconstruction for advanced ONJ were included. 197 records were initially screened; 18 full texts assessed; 10 full texts included. PRISMA guidelines were followed. RESULTS: Ten studies were included in this systematic review: six retrospective, three retrospective with comparison groups, and one prospective. In studies with comparison groups, ONJ patients have worse self-reported QOL than the general population as well as head and neck cancer patients without ONJ. Nearly all patients with QOL measurements (220/235 patients) had ONJ from prior radiation. Segmental mandibulectomy and bony free flap improved overall QOL in over half of patients, as well as pain associated with ONJ in 70-75 % of patients. Surgery did not improve long-term effects of radiation such as chewing, swallowing, and salivary production. Donor site morbidity rarely affects QOL. CONCLUSIONS: Osteonecrosis of the jaw (ONJ) worsens quality-of-life, and advanced disease often requires segmental mandibulectomy and bony free flap reconstruction. Patients and surgeons may expect improvement in some, but not all, domains of patient-reported QOL by the use of segmental mandibulectomy and reconstruction for advanced ONJ.

Safety of the "incidental" neck dissection or exploration during free tissue transfer after head and neck irradiation.

IMPORTANCE: Patients with either local recurrence of head and neck cancer or osteoradionecrosis after prior radiation treatment often require free tissue transfer for optimal reconstruction. In this setting, neck exploration for vessels is necessary, and an "incidental" neck dissection is often accomplished despite clinically negative cervical lymph nodes. While neck surgery in the post-radiated setting is technically challenging, the safety of post-radiated elective neck dissection or neck exploration for vessels is not well-studied, especially for patients undergoing non-laryngectomy salvage resections. OBJECTIVE: To define intraoperative and postoperative surgical complications for patients undergoing elective neck dissection or exploration with free tissue transfer reconstruction in the post-radiated setting, with attention to complications from neck surgery. DESIGN: Retrospective cohort study. Patient charts from May 2005 to April 2020 were reviewed. SETTING: Tertiary care referral center. PARTICIPANTS: Patients underwent free tissue transfer after prior head and neck irradiation for non-laryngeal local cancer recurrence or second primary, osteoradionecrosis, or for sole reconstructive purposes. Patients with clinically positive neck disease were excluded. MAIN OUTCOMES AND MEASURES: Intraoperative and postoperative complications including unplanned vessel or nerve injury, hematoma, chyle leak, wound dehiscence, wound infection, fistula formation, flap failure, and perioperative medical complications. Neck exploration and neck dissection patient outcomes were compared by Fisher exact test. RESULTS: Seventy-two patients (56 men and 16 women) of average age sixty-one (range 34-89) were identified with average follow-up 25.7 months. Most patients (78%) underwent salvage neck dissection, and the rest underwent neck exploration for vessels only. There were five intraoperative neck complications: three vessel injuries and two nerve injuries. There were twenty-six postoperative surgical complications among eighteen patients. There was no difference in surgical complications whether patients underwent neck dissection or exploration only. Two partial and two complete flap failures occurred. There were nine perioperative medical complications among six patients. CONCLUSIONS AND RELEVANCE: Elective neck dissection or exploration among patients undergoing free tissue transfer in the post-radiated setting carries a risk of both intraoperative and postoperative surgical complications. The present study defines risk of complications and helps to inform patient discussions for risk of complications in the post-radiated setting.

Travel distance is associated with stage at presentation and laryngectomy rates among patients with laryngeal cancer.

BACKGROUND: The impact of travel distance on stage at presentation and management strategies of laryngeal squamous cell carcinoma (SCC) is unknown. We investigated this relationship. METHODS: Retrospective review of patients with laryngeal SCC in the National Cancer Data Base from 2004 to 2016. Multivariate analysis determined relationships between travel distance, sociodemographic, geographic, and hospital factors. Logistic regression determined the influence of travel distance on T-stage and overall stage at presentation, and receipt of total laryngectomy. RESULTS: Sixty thousand four hundred and thirty-nine patients were divided into groups based on distance to treatment: short (<12.5 miles); intermediate (12.5-49.9 miles); and long (>50 miles). Increased travel was associated with T4-stage (intermediate vs. short OR 1.11, CI 1.04-1.18, p = 0.001; long vs. short OR 1.5, CI 1.36-1.65, p < 0.001), and total laryngectomy (intermediate vs. short OR 1.40, CI 1.3-1.5, p ≤ 0.001; long vs. short OR 2.52, CI 2.28-2.79, p ≤ 0.001). In T4 disease, total laryngectomy was associated with improved survival compared to nonsurgical treatment (HR 0.75, CI 0.70-0.80, p < 0.001) regardless of travel distance. CONCLUSION: Longer travel distance to care is associated with increased stage at presentation, rate of laryngectomy, and improved survival in advanced laryngeal SCC. Health policy efforts should be directed towards improving early access to diagnosis and care.

Utility of CT in the workup of adults with sore throat in the emergency department.

OBJECTIVE: The goal of this study was to determine if computed tomography (CT) added any clinical information that was incorporated into the decision regarding treatment for patients who presented to the Emergency Department (ED) with sore throat. METHODS: A retrospective chart review of adult patients who presented to the ED with a chief complaint of sore throat who subsequently underwent CT during that ED visit between 1/1/18 and 12/31/18 at our tertiary academic health center was performed. The association between palatal bulge on Otolaryngology physical exam with successful drainage procedure was examined. The mean Hounsfield units (HU) and maximum dimension of measurable fluid collection on CT were compared between patients who underwent a successful drainage procedure and those who did not undergo a drainage procedure or attempted drainage was unsuccessful. RESULTS: Ninety-four patients met inclusion criteria, with 53% (50/94) men. Of the 22 patients with a palatal bulge on physical examination by Otolaryngology, 86% (19/22) underwent a successful drainage procedure (p < 0.001) when compared to those not undergoing successful drainage. Notably, 56% (53/94) of CT scans were interpreted as normal or tonsillitis. The mean HU was 42.0 in those patients who underwent a successful drainage procedure and 74.1 in those who did not undergo a drainage procedure (p < 0.001). Overall, 21/35 fluid collections had a palatal bulge (p < 0.001). CONCLUSION: Palatal bulge is a reliable finding in identifying patients with a drainable peritonsillar abscess, and CT scans could largely be avoided in patients without physical exam findings suggestive of more extensive deep neck space abscesses. If a CT scan is obtained, HU should be measured and incorporated into the shared decision-making process with the patient.

Tracheotomy Outcomes in the Medical Intensive Care Unit.

This is a retrospective chart review of 161 MICU patients who underwent tracheotomy by the Otolaryngology service at the University of Missouri Hospital from April 2015 through March 2018. The objectives of this study were to describe long term outcomes of patients who underwent tracheotomy, and identify any clinical variables associated with these outcomes. One-year mortality was 37% (50/161), and on multivariate analysis only age (p=0.001) was associated with mortality.

Implementing the Flipped Classroom in a Veterinary Pre-clinical Science Course: Student Engagement, Performance, and Satisfaction.

There has been a recent move toward active learning pedagogies in veterinary education, with increasing use of a blended approach that incorporates both online resources and live classroom sessions. In this study, an established veterinary pre-clinical course in introductory animal health was transitioned from a traditional didactic lecture delivery mode to a flipped classroom approach with core content delivered online. This study compared the experiences of two cohorts of students who studied the same course in the different formats in consecutive years. Online learning resources included short video segments and a variety of short problems and activities. Online materials were complemented with weekly small-group case-based learning classes facilitated by academic staff. A mixed methods evaluation strategy was applied using student grades, surveys, and focus groups to compare student academic performance, satisfaction, and engagement between the two cohorts. The flipped classroom cohort achieved significantly higher grades in the written answer section of the final examination. Student satisfaction with learning resources was also higher in this cohort. However, satisfaction with other aspects of the course was largely the same for both cohorts. This study revealed some of the challenges associated with achieving adequate student preparation for class using online resources. The outcomes of this study have implications for veterinary educators considering the design and development of new online learning resources.

Endothelial dysfunction in an ovine model of collagen-induced arthritis.

BACKGROUND: Rheumatoid arthritis (RA) induces systemic inflammation, producing a range of co-morbidities including cardiovascular disease. An early vascular change is endothelial dysfunction, characterized by reduced endothelium-dependent vasodilation. The aim of this study was to assess endothelial function in isolated coronary and digital arteries using an ovine model of collagen-induced RA. METHODS: Sheep were culled following induction of arthritis, and their endothelial function was compared to that of normal sheep. Paired arterial segments were mounted in a wire myograph and dilated with endothelium-dependent vasodilators [bradykinin, serotonin, carbachol and adenosine diphosphate (ADP); linked to either Gi or Gq signalling pathways] and endothelium-independent dilators (adenosine and sodium nitroprusside) to construct cumulative concentration-response curves. RESULTS: Coronary arteries from arthritic sheep exhibited a significantly greater EC50 value for bradykinin-induced relaxation compared to non-arthritic controls (2.9 × 10(-8) M for arthritic sheep vs. 8.6 × 10(-9) M for controls). Digital arteries from arthritic sheep also exhibited a significantly greater EC50 for relaxation to ADP and a significant decrease in the carbachol maximal response. Responses to sodium nitroprusside were unchanged in both coronary and digital arteries. CONCLUSION: Sheep with RA demonstrated attenuated arterial relaxation to endothelium-dependent vasodilators. This may provide a useful model of endothelial dysfunction in chronic inflammatory conditions. The dysfunction did not appear to be associated with one specific G-protein signalling pathway.

Postoperative Chyle Leak Rate Following Neck Dissection for Squamous Cell Carcinoma Versus Papillary Thyroid Cancer.

OBJECTIVES: Compare the rates of post-operative chyle leak following therapeutic lateral neck dissection during treatment of papillary thyroid carcinoma (PTC) versus squamous cell carcinoma (SCC) of the head and neck. METHODS: A retrospective analysis of 226 consecutive neck dissections in 201 patients who underwent therapeutic neck dissection involving at least levels II-IV with a final pathologic diagnosis of mucosal SCC of the head and neck or PTC from 2010 to 2020. Specific cases of chyle leak were reviewed. Surgical factors associated with chyle leak were analyzed using logistic regression analysis. Duration of chyle leak was assessed by the Kaplan-Meier curve, and time-to-resolution was analyzed by Cox proportional hazard analysis. RESULTS: Postoperative chyle leak was encountered in 15 (6.6%) neck dissections, eight (12.3%) in PTC, and seven (4.3%) in SCC. High-volume chyle leak and chyle leak requiring operative intervention were only encountered in neck dissections performed for PTC. Chyle leak was significantly associated with PTC on univariable analysis (OR 3.08, p = 0.037), but not on multivariable analysis (OR 1.35, p = 0.711). High-volume chyle leak and the need for operative intervention were associated only with PTC patients (OR 23.6, p = 0.006; OR 18.09, p = 0.023 respectively). Median duration of chyle leak was 12.1 days among patients with SCC, and 20.5 days among patients with PTC (p = 0.089). CONCLUSIONS: Among 201 patients undergoing therapeutic neck dissection, chyle leak was associated with PTC pathology on univariable but not multivariable analysis. However, high-volume leaks and leaks requiring operative intervention only occurred among patients with PTC. LEVEL OF EVIDENCE: level III Laryngoscope, 133:2959-2964, 2023.

Going Off Guidelines: An NCDB Analysis of Missed Adjuvant Therapy Among Surgically Treated Oral Cavity Cancer.

OBJECTIVE: Patient factors associated with failure to receive adjuvant therapy after oral cavity cancer resection remain understudied. Here, we identified rates of missed adjuvant therapy, determined factors associated with missed therapy, and assessed associations with survival. STUDY DESIGN: Retrospective cohort. SETTING: National Cancer Database. METHODS: Patients with resected oral cavity squamous cell carcinoma and known adjuvant therapy status were included. T3-4 stage, N2-3 stage, and lymphovascular invasion were considered indications for adjuvant radiation. Extranodal extension or positive margins were considered indications for chemoradiation. Patient factors were examined for associations with missed adjuvant therapy. Overall survival was evaluated by Cox proportional hazard analysis. RESULTS: A total of 53,503 patients were included. 27.5% missed adjuvant therapy altogether, and 26.7% with a documented indication for chemoradiation missed chemotherapy. Factors associated with missed adjuvant therapy were age, white race, low income, metropolitan population, increasing comorbidities, travel distance, lip primary, and treatment at the academic facility. Factors associated with missed chemotherapy were age, female sex, nontongue subsite, and treatment at a nonacademic center. Among patients with indications for adjuvant radiation, missed radiation was associated with worse overall survival (hazard ratio [HR]: 1.42, 95% confidence interval [CI]: 1.31-1.53). Among patients with indications for adjuvant chemoradiation, missed chemotherapy was associated with worse overall survival (HR: 1.19, 95% CI: 1.09-1.29). CONCLUSION: Missed adjuvant therapy occurs frequently after oral cavity resection. Patients treated at academic centers may be at risk of missed therapy related to travel distance, though these patients are more likely to receive adjuvant chemotherapy when indicated. Missed adjuvant therapy is associated with worse survival.

Adjuvant radiotherapy mitigates impact of perineural invasion on oncologic outcomes in early-stage oral cavity squamous cell carcinoma. A multi-institutional analysis of 557 patients.

OBJECTIVES: Understand the prognostic impact of perineural invasion (PNI) in early-stage oral cavity squamous cell carcinoma (OCSCC). Assess the influence of adjuvant radiotherapy on outcomes of patients with PNI-positive early-stage OCSCC. MATERIALS AND METHODS: Retrospective seven-institution cohort study including patients with pathologic T1-2 N0-1 OCSCC who underwent primary surgery with negative margins. Outcomes included disease-free survival (DFS) and locoregional control (LRC). Cox proportional hazards models were used to evaluate oncologic outcomes. Interaction terms were introduced to assess relationships between PNI and adjuvant radiotherapy. RESULTS: Among 557 patients (mean (SD) age 61.0 (13.9), 47.2% female, 66.6% pathologic T1, 93.5% pathologic N0), 93 had PNI-positive tumors, among which 87.1% underwent neck dissection and 39.6% received radiotherapy. On multivariable analysis, PNI was associated with lower DFS and LRC. Adjuvant radiotherapy was not associated with improved outcomes on multivariable analysis of the entire cohort. However, among patients with PNI-positive tumors, adjuvant radiotherapy significantly decreased hazard for DFS. CONCLUSION: Among patients with low-risk, early-stage OCSCC, PNI was associated with worse DFS and LRC. In patients with PNI-positive tumors, adjuvant radiotherapy lowered hazard for DFS on multivariable analysis. These data support using adjuvant radiotherapy for patients with early-stage OCSCC with PNI.

Orocutaneous Fistula After Oral Cavity Resection and Reconstruction: Systematic Review and Meta-Analysis.

OBJECTIVE: Orocutaneous fistula (OCF) after reconstruction for oral cavity resection can lead to prolonged hospitalization and adjuvant treatment delay. Few studies have examined factors leading to OCF after oral cavity resection. Primary objective: evaluate overall incidence and factors associated with OCF after oral cavity reconstruction. DATA SOURCES: Scopus 1960-database was searched for terms: "orocutaneous fistula," "oro cutaneous fistula," "oral cutaneous fistula," "orocervical fistula," "oral cavity salivary fistula." REVIEW METHODS: English language studies with >5 patients undergoing reconstruction after oral cavity cancer resection were included. About 1057 records initially screened; 214 full texts assessed; 78 full-texts included. PRISMA guidelines were followed, and MINORS criteria used to assess risk of bias. Data were pooled using random-effects model. Primary outcome was OCF incidence. Meta-analysis to determine the effect of preoperative radiation on OCF conducted on 12 eligible studies. Pre-collection hypothesis was that prior radiation therapy is associated with increased OCF incidence. Post-collection analyses: free versus pedicled flaps; mandible-sparing versus segmental mandibulectomy. RESULTS: Seventy-eight studies were included in meta-analysis of overall OCF incidence. Pooled effect size showed overall incidence of OCF to be 7.71% (95% CI, 6.28%-9.13%) among 5400 patients. Meta-analysis of preoperative radiation therapy on OCF showed a pooled odds ratio of 1.68 (95% CI, 0.93-3.06). OCF incidence was similar between patients undergoing free versus pedicled reconstruction, or segmental mandibulectomy versus mandible-sparing resection. CONCLUSION: Orocutaneous fistula after oral cavity resection has significant incidence and clinical impact. Risk of OCF persists despite advances in reconstructive options; there is a trend toward higher risk after prior radiation.

Identification of Immuno-Targeted Combination Therapies Using Explanatory Subgroup Discovery for Cancer Patients with EGFR Wild-Type Gene.

(1) Background: Phenotypic and genotypic heterogeneity are characteristic features of cancer patients. To tackle patients' heterogeneity, immune checkpoint inhibitors (ICIs) represent some the most promising therapeutic approaches. However, approximately 50% of cancer patients that are eligible for treatment with ICIs do not respond well, especially patients with no targetable mutations. Over the years, multiple patient stratification techniques have been developed to identify homogenous patient subgroups, although matching a patient subgroup to a treatment option that can improve patients' health outcomes remains a challenging task. (2) Methods: We extended our Subgroup Discovery algorithm to identify patient subpopulations that could potentially benefit from immuno-targeted combination therapies in four cancer types: head and neck squamous carcinoma (HNSC), lung adenocarcinoma (LUAD), lung squamous carcinoma (LUSC), and skin cutaneous melanoma (SKCM). We employed the proportional odds model to identify significant drug targets and the corresponding compounds that increased the likelihood of stable disease versus progressive disease in cancer patients with the EGFR wild-type (WT) gene. (3) Results: Our pipeline identified six significant drug targets and thirteen specific compounds for cancer patients with the EGFR WT gene. Three out of six drug targets-FCGR2B, IGF1R, and KIT-substantially increased the odds of having stable disease versus progressive disease. Progression-free survival (PFS) of more than 6 months was a common feature among the investigated subgroups. (4) Conclusions: Our approach could help to better select responders for immuno-targeted combination therapies and improve health outcomes for cancer patients with no targetable mutations.

The role of matrixmetalloproteinase-2 expression by fibroblasts in perineural invasion by oral cavity squamous cell carcinoma.

OBJECTIVES: The mechanisms of perineural invasion (PNI) in oral cavity squamous cell carcinoma are only partially understood, and no studies have specifically investigated the role of perineural fibroblasts in PNI. Here, we identified fibroblasts within the microenvironment of perineural invasion and assessed their expression of matrix metalloproteinase-2 (MMP-2). MATERIALS AND METHODS: Tumor specimens from 12 patients with oral cavity squamous cell carcinoma and pathologically-confirmed perineural invasion were stained by immunohistochemistry (IHC) for vimentin (positive control) and MMP-2. Scoring was quantified and compared at nerves involved with PNI and nerves uninvolved with PNI. RESULTS: All 12 patients had perineural fibroblasts around involved and uninvolved nerves as marked by vimentin IHC staining. Perineural fibroblasts had detectable MMP-2 expression at areas of perineural invasion in all 12 patients, but no patients had MMP-2 expression by fibroblasts at nerves without PNI. CONCLUSION: MMP-2 is expressed by fibroblasts within the microenvironment of perineural invasion, and MMP-2 expression by fibroblasts is a possible mechanism of perineural invasion by oral cavity squamous cell carcinoma. MMP-2 may be an anti-cancer target among oral cavity squamous cell carcinoma patients with PNI.

Effectiveness of gabapentin in reducing opioid requirements after radiation in head and neck cancer in a single institution.

BACKGROUND: Gabapentin has been shown to reduce opioid use in head and neck cancer patients. Here, we examine the efficacy of prophylactic gabapentin at reducing opioid use in these patients at our institution. METHODS: A retrospective study of patients receiving radiation was performed, using patients from our previous study as controls. Risk factors for opioid use at 3 and 6 months were determined using univariate and multivariate analyses. RESULTS: In total, 53/185 patients were treated with gabapentin, 39.6% of which took opioids at 3 months vs. 58.3% in the non-gabapentin cohort (p = 0.021). Gabapentin was independently associated with less opioid use on multivariate analysis at 3 months (OR 0.47, 95% CI 0.24-0.9). Gastrostomy tube dependence and pretreatment opioid use were associated with chronic opioid use despite gabapentin. CONCLUSIONS: Gabapentin is effective at expediting opioid tapering in head and neck cancer patients who are not gastrostomy tube dependent or taking opioids pretreatment.

Occult Metastases During Salvage Oral Cavity and Oropharyngeal Free Flaps: Oncologic Outcomes.

OBJECTIVES: To define rates of occult metastases in salvage oral cavity and oropharyngeal cancer resection requiring free flap, to examine the location of occult metastases, and to determine associations between occult metastasis and survival. STUDY DESIGN: Retrospective cohort study. SETTING: Two tertiary care referral centers. METHODS: We identified previous cases of irradiation with recurrent or second primary oral cavity or oropharyngeal squamous cell carcinoma that had no evidence of regional metastasis and required free tissue transfer reconstruction of the primary site. Patients who underwent elective neck dissection or exploration were reviewed. The main outcome measures were the presence and location of occult nodal metastasis. Disease-free survival and overall survival were measured. Odds ratios and hazard ratios were used for analysis. RESULTS: A total of 83 patients were included: 52 with oral cavity primary tumors and 31 with oropharynx. An overall 78 (94%) underwent elective salvage neck dissection. Occult metastases were found in 9 (11.5%) patients. The most common nodal station for occult metastasis was level 2. Neither elective neck dissection nor the presence of occult metastasis was significantly associated with regional disease-free or overall survival. Oropharyngeal primary tumors were associated with higher risk of occult metastasis (odds ratio, 1.38; P < .01) and worse overall survival (hazard ratio, 2.09; P = .01). CONCLUSION: There is a low incidence of occult metastasis in postradiated recurrent or second primary oral cavity and oropharyngeal tumors. Elective neck dissection and occult nodal metastases were not associated with regional or overall survival. This series may help surgeons make decisions regarding the extent of neck surgery after prior radiation, especially when free flap reconstruction is required.

Tuft Cells Are Present in Submandibular Glands Across Species.

Tuft cells are bottle-shaped, microvilli-projecting chemosensory cells located in the lining of a variety of epithelial tissues and, following their identification approximately 60 years ago, have been linked to immune system function in a variety of epithelia. Until recently, Tuft cells had not been convincingly demonstrated to be present in salivary glands with their detection by transmission electron microscopy only shown in a handful of earlier studies using rat salivary glands, and no follow-up work has been conducted to verify their presence in salivary glands of other species. Here, we demonstrate that Tuft cells are present in the submandibular glands of various species (i.e., mouse, pig and human) using transmission electron microscopy and confocal immunofluorescent analysis for the POU class 2 homeobox 3 (POU2F3), which is considered to be a master regulator of Tuft cell identity.

Development and Validation of Machine Learning Models for Predicting Occult Nodal Metastasis in Early-Stage Oral Cavity Squamous Cell Carcinoma.

Importance: Given that early-stage oral cavity squamous cell carcinoma (OCSCC) has a high propensity for subclinical nodal metastasis, elective neck dissection has become standard practice for many patients with clinically negative nodes. Unfortunately, for most patients without regional metastasis, this risk-averse treatment paradigm results in unnecessary morbidity. Objectives: To develop and validate predictive models of occult nodal metastasis from clinicopathological variables that were available after surgical extirpation of the primary tumor and to compare predictive performance against depth of invasion (DOI), the currently accepted standard. Design, Setting, and Participants: This diagnostic modeling study collected clinicopathological variables retrospectively from 7 tertiary care academic medical centers across the US. Participants included adult patients with early-stage OCSCC without nodal involvement who underwent primary surgical extirpation with or without upfront elective neck dissection. These patients were initially evaluated between January 1, 2000, and December 31, 2019. Exposures: Largest tumor dimension, tumor thickness, DOI, margin status, lymphovascular invasion, perineural invasion, muscle invasion, submucosal invasion, dysplasia, histological grade, anatomical subsite, age, sex, smoking history, race and ethnicity, and body mass index (calculated as weight in kilograms divided by height in meters squared). Main Outcomes and Measures: Occult nodal metastasis identified either at the time of elective neck dissection or regional recurrence within 2 years of initial surgery. Results: Of the 634 included patients (mean [SD] age, 61.2 [13.6] years; 344 men [54.3%]), 114 (18.0%) had occult nodal metastasis. Patients with occult nodal metastasis had a higher frequency of lymphovascular invasion (26.3% vs 8.1%; P < .001), perineural invasion (40.4% vs 18.5%; P < .001), and margin involvement by invasive tumor (12.3% vs 6.3%; P = .046) compared with those without pathological lymph node metastasis. In addition, patients with vs those without occult nodal metastasis had a higher frequency of poorly differentiated primary tumor (20.2% vs 6.2%; P < .001) and greater DOI (7.0 vs 5.4 mm; P < .001). A predictive model that was built with XGBoost architecture outperformed the commonly used DOI threshold of 4 mm, achieving an area under the curve of 0.84 (95% CI, 0.80-0.88) vs 0.62 (95% CI, 0.57-0.67) with DOI. This model had a sensitivity of 91.7%, specificity of 72.6%, positive predictive value of 39.3%, and negative predictive value of 97.8%. Conclusions and Relevance: Results of this study showed that machine learning models that were developed from multi-institutional clinicopathological data have the potential to not only reduce the number of pathologically node-negative neck dissections but also accurately identify patients with early OCSCC who are at highest risk for nodal metastases.

Assessing Prognostic Value of Quantitative Neck Dissection Quality Measures in Patients With Clinically Node-Negative Oral Cavity Squamous Cell Carcinoma.

Importance: In clinically localized (T1-2) oral cavity squamous cell carcinoma (OCSCC), regional lymph node metastasis is associated with a poor prognosis. Given the high propensity of subclinical nodal disease in these patients, upfront elective neck dissections (END) for patients with clinically node-negative disease are common and associated with better outcomes. Unfortunately, even with this risk-adverse treatment paradigm, disease recurrence still occurs, and our understanding of the factors that modulate this risk and alter survival have yet to be fully elucidated. Objective: To investigate the prognostic value of lymph node yield (LNY), lymph node ratio (LNR), and weighted LNR (wLNR) in patients with clinically node-negative T1-2 OCSCC. Design, Setting, and Participants: In this cohort study, data were collected retrospectively from 7 tertiary care academic medical centers. Overall, 523 patients with cT1-2N0 OCSCC who underwent elective neck dissections after primary surgical extirpation were identified. Exposures: Lymph node yield was defined as the number of lymph nodes recovered from elective neck dissection. Lymph node ratio was defined as the ratio of positive nodes against total LNY. Weighted LNR incorporated information from both LNY and LNR into a single continuous metric. Main Outcomes and Measures: Locoregional control (LRC) and disease-free survival (DFS) were both evaluated using nonparametric Kaplan-Meier estimators and semiparametric Cox regression. Results: On multivariable analysis, LNY less than or equal to 18 lymph nodes was found to be significantly associated with decreased LRC (aHR, 1.53; 95% CI, 1.04-2.24) and DFS (aHR, 1.46; 95% CI, 1.12-1.92) in patients with pN0 disease, but not those with pN-positive disease. Importantly, patients with pN0 disease with LNY less than or equal to 18 and those with pN1 diseasehad nearly identical 5-year LRC (69.7% vs 71.4%) and DFS (58.2% vs 55.7%). For patients with pN-positive disease, LNR greater than 0.06 was significantly associated with decreased LRC (aHR, 2.66; 95% CI, 1.28-5.55) and DFS (aHR, 1.65; 95% CI, 1.07-2.53). Overall, wLNR was a robust prognostic variable across all patients with cN0 disease, regardless of pathologic nodal status. Risk stratification via wLNR thresholds demonstrated greater optimism-corrected concordance compared with American Joint Committee on Cancer (AJCC) 8th edition nodal staging for both LRC (0.61 vs 0.57) and DFS (0.61 vs 0.58). Conclusions and Relevance: Movement toward more robust metrics that incorporate quantitative measures of neck dissection quality and regional disease burden, such as wLNR, could greatly augment prognostication in cT1-2N0 OCSCC by providing more reliable and accurate risk estimations.

Positive Margins in Cutaneous Melanoma of the Head and Neck: Implications for Timing of Reconstruction.

OBJECTIVE: The aim of this study is to identify clinicopathologic features associated with positive margins after surgical treatment of cutaneous melanoma of the head and neck (CMHN). STUDY DESIGN: Retrospective cohort study. SETTING: National Cancer Database. METHODS: A retrospective analysis of the National Cancer Database was performed of patients diagnosed with CMHN between 2004 and 2016. Univariate and multivariate analyses examining the association of clinicopathologic features with positive margins were performed via logistic regression analysis. RESULTS: A total of 101,560 patients met inclusion criteria. The incidence of positive margins was 5.0% (5128/101,560). Patients were significantly more likely to have positive margins with the following: increasing age (P < .001; odds ratio [OR], 1.028; 95% CI, 1.026-1.031), the lip subsite (P < .001; OR, 1.664; 95% CI, 1.286-2.154), the eyelid subsite (P < .001; OR, 2.380; 95% CI, 1.996-2.838), the face subsite (P < .001; OR, 1.215; 95% CI, 1.133-1.302), the lentigo maligna/lentigo maligna melanoma subtype (P = .019; OR, 1.099; 95% CI, 1.016-1.188), the desmoplastic subtype (P < .001; OR, 1.455; 95% CI, 1.261-1.680), the spindle cell subtype (P = .006; OR, 1.276; 95% CI, 1.073-1.516), and advanced pT classification. Patients with male sex (P < .001; OR, 0.733; 95% CI, 0.687-0.782) and without ulceration (P < .001; OR, 0.803; 95% CI, 0.736-0.876) were significantly less likely to have positive margins. CONCLUSION: The following have been identified as clinicopathologic features associated with positive margins after surgical treatment of CMHN: increasing age, female sex, the lip subsite, the eyelid subsite, the face subsite, ulceration, the lentigo maligna/lentigo maligna melanoma subtype, the desmoplastic subtype, the spindle cell subtype, and increasing pT classification.