Defining the Genomic Landscape of Diffuse Sclerosing Papillary Thyroid Carcinoma: Prognostic Implications of RET Fusions.

BACKGROUND: Diffuse sclerosing papillary thyroid carcinoma (DSPTC) is an aggressive histopathologic subtype of papillary thyroid carcinoma. Correlation between genotype and phenotype has not been comprehensively described. This study aimed to describe the genomic landscape of DSPTC comprehensively using next-generation sequencing (NGS), analyze the prognostic implications of different mutations, and identify potential molecular treatment targets. METHODS: Tumor tissue was available for 41 DSPTC patients treated at Memorial Sloan Kettering Cancer Center between 2004 and 2021. After DNA extraction, NGS was performed using the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets platform, which sequences 505 critical cancer genes. Clinicopathologic characteristics were compared using the chi-square test. The Kaplan-Meier method and log-rank statistics were used to compare outcomes. RESULTS: The most common mutation was RET fusion, occurring in 32% (13/41) of the patients. Other oncologic drivers occurred in 68% (28/41) of the patients, including 8 BRAFV600E mutations (20%) and 4 USP8 mutations (10%), which have not been described in thyroid malignancy previously. Patients experienced RET fusion-positive tumors at a younger age than other drivers, with more aggressive histopathologic features and more advanced T stage (p = 0.019). Patients who were RET fusion-positive had a significantly poorer 5-year recurrence-free survival probability than those with other drivers (46% vs 84%; p = 0.003; median follow-up period, 45 months). In multivariable analysis, RET fusion was the only independent risk factor for recurrence (hazard ratio [HR], 7.69; p = 0.017). CONCLUSION: Gene-sequencing should be strongly considered for recurrent DSPTC due to significant prognostic and treatment implications of RET fusion identification. The novel finding of USP8 mutation in DSPTC requires further investigation into its potential as a driver mutation.

Epidemiology and management of oral cavity squamous cell carcinoma in Ireland.

INTRODUCTION: The epidemiology and management of oral cavity cancer have changed considerably in recent decades. This study examines epidemiological and management trends in oral cavity squamous cell carcinoma (OCSCC). METHODS: A retrospective cohort study of data from the National Cancer Registry of Ireland between 1994 and 2014. RESULTS: A total of 2725 patients were identified. The most common subsites were the tongue (34 %, n = 1025), lip (19 %, n = 575), floor of mouth (FOM) (18 %, n = 550), and retromolar trigone (RMT) (6 %, n = 189). The incidence of OCSCC remained largely unchanged (3.14 cases/100000/year) during the study period. 5-year disease-specific survival (DSS) was 58.6 % overall, varying between subsites (lip 85 %, RMT 62.9 %, tongue 54.7 %, and FOM 47.3 %). DSS improved over the study period (p = 0.03), in particular for tongue primaries (p = 0.007). Primary surgery significantly improved DSS versus radiotherapy (HR 0.28, p < 0.0001). Survival of T4 disease managed surgically was superior to that of T1 disease managed with radiotherapy. In node positive patients, chemotherapy improved overall survival (HR 0.8 p = 0.038) but not DSS (HR 0.87 p = 0.215). CONCLUSION: Primary surgery remains the standard of care in the management of OCSCC. Prognosis has improved in line with an increase in the use of primary surgery in the same time frame, though the incidence remains unchanged.

Patient-reported outcomes in human papillomavirus-related oropharyngeal cancer.

This review explores how human papillomavirus-related oropharyngeal cancer affects health-related quality of life (HR-QoL) and the role patient-reported outcomes (PROs) can play in optimizing treatment. PRO measures (PROMs) are comprehensive, subjective assessments of patients' day-to-day HR-QoL. Developed through a scientifically robust, multistage process, PROMs offer insight into patients' symptoms, function, and satisfaction with care. The use of PROMs can increase symptom awareness, stimulate discussion, and enhance shared decision-making between patients and healthcare providers.

Predictors of surgical complications in patients with sinonasal malignancy.

OBJECTIVES: Sinonasal and skull base tumors are rare, making it difficult to identify trends in surgical outcome. This study examines complications in a large cohort of patients undergoing surgery for sinonasal malignancy. METHODS: Following IRB approval, an institutional database was reviewed to identify patients who underwent surgery for sinonasal or skull base malignancies from 1973 to 2016 at our institution. Charlson comorbidity index score and Clavien-Dindo grade were calculated. The main study endpoint was subgroup analysis of Clavien-Dindo Grade 0, Grades 1-2, and Grades 3-5 complications. An ordinal logistic regression model was constructed to assess the association between comorbidities, demographics, tumor characteristics, and surgical complications. RESULTS: In total, 448 patients met inclusion criteria. Perioperative mortality rate at 30 days was 1.6% (n = 7). The rate of severe complications (Clavien-Dindo 3 or higher) was 13.6% (n = 61). Multivariate analysis using an ordinal logistic regression model showed no association between Charlson comorbidity index score and Clavien-Dindo grade of postoperative complication. Advanced T-stage was significantly associated with complications (p = 0.0014; odds ratio: 3.442 [95% confidence interval: 1.615, 7.338]). CONCLUSION: Surgery for sinonasal and skull base tumors is safe with a low mortality rate. Advanced T-stage is associated with postoperative complications. These findings have implications for preoperative risk stratification. Key Points Surgery for sinonasal malignancy is safe with a 30 mortality of 1.6% and rate of severe complications of 12.8%. There is no association between patient comorbidity and post operative complication. On multivariate analysis, only advanced T stage was associated with increased rate of surgical complication.

The effectiveness of neck stretching exercises in alleviating neck pain and self-reported disability after thyroidectomy: A systematic review and meta-analysis of clinical trials.

Thyroidectomy can lead to significant challenges such as neck pain, disability, and limited range of motion. Therefore, our objective is to conduct a systematic review and meta-analysis of clinical trials to investigate the clinical effectiveness of neck stretching exercises in alleviating neck pain and self-reported disability immediately after thyroidectomy. We systematically searched PubMed, CENTRAL, Scopus, and Web of Science from inception until July 28th, 2023. We assessed the selected trials for the risk of bias using both the RoB-2 and ROBINS-I tools. Our specific outcomes were the severity of neck pain and self-reported disability after thyroidectomy. The results were synthesized using risk ratio (RR) and standardized mean differences (SMD) with 95% confidence intervals (CI) in a random-effects model using Stata software. Nine clinical trials, comprising five randomized and four non-randomized trials, were included, with a total of 1026 patients. Neck stretching exercises were significantly associated with improved mean pain scores both after 1 week (n = 625 patients, SMD = -2.43, 95% CI [-4.65, -0.22], p = 0.03, I2 = 98%) and 1 month (n = 545 patients, SMD = -4.11, 95% CI [-8.12, -0.11], p = 0.04, I2 = 99%). Similarly, neck stretching exercises were significantly associated with improved mean self-reported disability scores both after 1 week (n = 298 patients, SMD = -0.70, 95% CI [-1.36, -0.04], p = 0.04, I2 = 87%) and 1 month (n = 298 patients, SMD = -0.42, 95% CI [-0.65, -0.19], p = 0.0004, I2 = 0%). The pooled analysis showed heterogeneity (chi-square p < 0.01, I2 > 80%), except for the mean self-reported neck disability score after 1 month, which showed homogeneity (chi-square p > 0.01, I2 = 0%). This systematic review and meta-analysis, involving 1026 patients, revealed the potential benefits of neck stretching exercises in alleviating neck pain and self-reported disability after thyroidectomy. However, further research is required to address methodological limitations, evaluate long-term outcomes, investigate potential moderators (i.e., the duration or intensity of the exercise program), and explore patients' analgesic consumption.

The association of frailty with morbidity and mortality following major mucosal head and neck surgery.

OBJECTIVES: Frailty refers to a state of reduced physiological reserve and functional decline. We sought to analyse whether frailty, assessed using the 5-item modified frailty index (5mFI), was associated with increased morbidity and mortality following major mucosal head and neck surgery. MATERIALS AND METHODS: We performed a retrospective study of patients undergoing major mucosal head and neck surgical resection over a 2-year period. Potential confounding variables were controlled by way of multivariable regression analysis. RESULTS: There were 310 patients included with 77 (24.8 %) classified as frail. Most patients were male (219/310, 70.7 %), had a history of smoking (246/310, 79.4 %) and 151 patients (48.7 %) were older than 65 at time of surgery. Most surgeries related to oral cavity or oropharyngeal subsites (227/310, 73.2 %) and 150 patients (48.4 %) underwent microvascular free tissue reconstruction. On multivariable analysis, frail patients were more likely to suffer adverse outcomes such as a return to theatre (OR 3.47, 95 % CI 1.82-6.62, p < 0.001), a Clavien-Dindo grade IV complication (OR 6.23, 95 % CI 2.55-15.20, p < 0.001) or medical complications, such as respiratory complications (OR 2.61, 95 % CI 1.45-4.69; p = 0.001) or delirium (OR 5.05, 95 % CI 2.46-10.33; p < 0.001). Additionally, hospital length of stay was increased among frail patients (ß 16.46 days, 95 % CI 9.85-23.07 days; p < 0.001). Neither 90-day nor 1-year post-operative mortality was increased in frail patients. CONCLUSION: Frailty assessed using the 5mFI was associated with greater post-operative morbidity, but not mortality following major mucosal head and neck surgery.

Fatal cerebritis and ventriculitis secondary to tracheoesophageal prosthesis.

Tracheoesophageal puncture and voice prosthesis placement is the preferred method of voice restoration following total laryngectomy. Although this is a safe and effective means of optimizing voice, severe complications can occur. We present the case of a patient who developed cerebritis and ventriculitis secondary to a tracheoesophageal prosthesis eroding his cervical vertebrae 20 years following pharyngo-laryngo-esophagectomy. Despite optimal antimicrobial therapy, he deteriorated and succumbed to his disease. Although tracheoesophageal prostheses are a safe and effective means of voice restoration, life-threatening complications can occur. This case report highlights a rare but severe case of cervical osteomyelitis, epidural abscess, and cerebritis and ventriculitis secondary to tracheoesophageal prosthesis. Clinicians must be aware of this severe complication in postlaryngectomy patients with tracheoesophageal prostheses.

Determining Factors Which Limit Resectability in Advanced Hypopharyngeal Malignancy.

BACKGROUND: Preoperative radiological findings of hypopharyngeal cancers are used to determine suitability for surgical resection. We sought to examine preoperative imaging characteristics to determine how well imaging findings predicted surgical resectability. METHODS: A retrospective case-control study of patients undergoing a pharyngolaryngectomy in a tertiary referral center over a 2-year period was completed. Demographic details, previous treatment, subsite, TNM staging, imaging characteristics, and operative characteristics were collected. RESULTS: A total of 78 patients met initial inclusion criteria, of which 71 patients ultimately underwent successful surgical resection (91.1%). Preoperative images identified suspicion of prevertebral fascia invasion in 24 (30.7%) cases and carotid artery involvement in 14 (17.9%) cases. In cases of suspicion of prevertebral fascia invasion (24), 19 cases (79.2%) were resectable, and in those with carotid artery involvement (14), 11 (78.6%) were resectable. Concern for prevertebral fascia invasion on radiology led to a higher likelihood of a close margin (42% vs. 17%) in those without concerning features (p = 0.088). CONCLUSIONS: The present study demonstrated a high rate of resectability of hypopharyngeal and upper esophageal cancers despite imaging findings suspicious for factors that could limit resectability. In patients with advanced hypopharyngeal, especially in the salvage setting, surgery should be considered.

HPV overtakes smoking as the leading cause of oropharyngeal cancer in Ireland: experience of a head and neck surgery tertiary referral centre.

BACKGROUND: Worldwide, the incidence of oropharyngeal squamous cell carcinoma (OPSCC) caused by human papillomavirus (HPV), a sexually transmitted virus, is increasing. This increase has yet to be demonstrated in an Irish cohort. AIMS: To evaluate the number of OPSCC presentations locally, to stratify cases by HPV status and to estimate if any changes in the patient population had occurred over a 10-year period. METHODS: A STROBE-compliant, retrospective evaluation of patients with OPSCC at St James's Hospital between 2012 and 2022 was performed. Patients with non-SCC histology, undocumented HPV status and residual or recurrent tumours were excluded. RESULTS: We included 294 patients with a mean age of 60.4 years (95% CI 59.2-61.5 years) and 175 (59.5%) patients had HPV+ OPSCC. The number of new OPSCC diagnoses increased from 115 patients (39.1%) between 2012 and 2016 to 179 patients (60.9%) between 2017 and 2021. This was associated with an increased proportion of HPV-linked OPSCC (50.4% 2012-2016 vs. 65.4% 2017-2021, p = 0.011). Over time, more patients had a functionally limiting comorbidity (p = 0.011). The mean age of HPV+ OPSCC cases increased by 3.6 years (p = 0.019). Patients with HPV+ OPSCC had greater 2-year OS (83.9% vs. 54.9%; p < 0.001) and 2-year DFS (73.5% vs. 45.6%; p < 0.001). The 2-year OS and DFS did not change over time for HPV+ or HPV- patients. CONCLUSIONS: In our institution, the number of patients with OPSCC is increasing due to an escalation in cases associated with HPV. Population-level interventions such as vaccination programs may alter the current increase in the incidence of these tumours.

Airway decision making in major head and neck surgery: Irish multicenter, multidisciplinary recommendations.

Major head and neck surgery poses a threat to perioperative airway patency. Adverse airway events are associated with significant morbidity, potentially leading to hypoxic brain injury and even death. Following a review of the literature, recommendations regarding airway management in head and neck surgery were developed with multicenter, multidisciplinary agreement among all Irish head and neck units. Immediate extubation is appropriate in many cases where there is a low risk of adverse airway events. Where a prolonged definitive airway is required, elective tracheostomy provides increased airway security postoperatively while delayed extubation may be appropriate in select cases to reduce postoperative morbidity. Local institutional protocols should be developed to care for a tracheostomy once inserted. We provide guidance on decision making surrounding airway management at time of head and neck surgery. All decisions should be agreed between the operating, anesthetic, and critical care teams.

The role of surgery for anaplastic thyroid carcinoma in the era of targeted therapeutics: A scoping review.

Background: Questions exist regarding patient selection for surgery in anaplastic thyroid carcinoma (ATC), particularly with the advent of neoadjuvant-targeted therapeutics. The present scoping review sought to evaluate what extent of surgical resection should be performed in ATC. Methods: A scoping review was carried out in accordance with Joanna Briggs Institute and the preferred reporting items for systematic reviews and meta-analyses extension for scoping reviews (PRISMA-ScR) protocols. Included studies were required to provide clear description of the surgery performed for ATC. Results: The final search identified 6901 articles. Ultimately only 15 articles including 1484 patients met inclusion criteria. A total of 765 patients (51.5%) underwent attempted curative intent surgery. The approach to resection of adjacent tissues varied between studies. Eight studies considered laryngeal ± pharyngeal resection (8/15, 53.3%), eight studies (53.3%) considered tracheal resection and again eight studies (53.3%) considered esophageal resection. More extensive resections increased morbidity without improving overall survival (OS) (<9 months in the 12 studies using a combination of surgery and chemoradiotherapy). In the three studies utilizing targeted therapy in addition to surgery, OS was notably improved while surgical resection following neoadjuvant therapy was less extensive. Conclusions: There is no clear agreement in the literature regarding the limits of surgical resection in locoregionally advanced ATC. A definition of surgically resectable disease will be required to guide surgical decision making in ATC, particularly with the potential to reduce tumor burden using neoadjuvant targeted treatment in suitable patients. Level of evidence: III.

Surgical management of T1/T2 node-negative papillary thyroid cancer with tall cell histology: Is lobectomy enough?

BACKGROUND: The tall cell variant of papillary thyroid carcinoma has traditionally been treated more aggressively than classic papillary thyroid carcinoma. However, this may not be justified in patients with T1/T2 tall cell variant node-negative tumors. METHODS: We evaluated well-differentiated thyroid cancers treated surgically between 1985 and 2015 at our institution. We compared patients undergoing lobectomy for node-negative T1/T2 tall cell variant tumors with the same cohort with classic papillary thyroid carcinoma. Patients who underwent early planned completion thyroidectomy were excluded. Tall cell variant tumors were defined as those with ≥30% tall cells. Survival and recurrence outcomes were determined by the Kaplan-Meier method and groups compared using the log-rank test. RESULTS: Thyroid lobectomy was performed for T1/T2 N0X disease in 70 (15%) tall cell cases and 429 (23%) classic papillary thyroid carcinoma cases. There was no significant difference in 10-year overall survival (P = .56) or locoregional recurrence-free probability (P = .52). Disease-specific survival and local or central nodal recurrence-free probability were 100% in both groups. In 9 papillary thyroid carcinoma cases, subsequent contralateral lobe tumors developed, and in 5, lateral neck metastases developed. No recurrences were seen in the tall cell group. CONCLUSION: T1 node-negative tumors with tall cell histology can be satisfactorily managed with thyroid lobectomy, with equivalent oncological outcomes to classic papillary thyroid carcinoma.

Nivolumab plus ipilimumab in advanced salivary gland cancer: a phase 2 trial.

Salivary gland cancers (SGCs) are rare, aggressive cancers without effective treatments when metastasized. We conducted a phase 2 trial evaluating nivolumab (nivo, anti-PD-1) and ipilimumab (ipi, anti-CTLA-4) in 64 patients with metastatic SGC enrolled in two histology-based cohorts (32 patients each): adenoid cystic carcinoma (ACC; cohort 1) and other SGCs (cohort 2). The primary efficacy endpoint (≥4 objective responses) was met in cohort 2 (5/32, 16%) but not in cohort 1 (2/32, 6%). Treatment safety/tolerability and progression-free survival (PFS) were secondary endpoints. Treatment-related adverse events grade ≥3 occurred in 24 of 64 (38%) patients across both cohorts, and median PFS was 4.4 months (95% confidence interval (CI): 2.4, 8.3) and 2.2 months (95% CI: 1.8, 5.3) for cohorts 1 and 2, respectively. We present whole-exome, RNA and T cell receptor (TCR) sequencing data from pre-treatment and on-treatment tumors and immune cell flow cytometry and TCR sequencing from peripheral blood at serial timepoints. Responding tumors universally demonstrated clonal expansion of pre-existing T cells and mutational contraction. Responding ACCs harbored neoantigens, including fusion-derived neoepitopes, that induced T cell responses ex vivo. This study shows that nivo+ipi has limited efficacy in ACC, albeit with infrequent, exceptional responses, and that it could be promising for non-ACC SGCs, particularly salivary duct carcinomas. ClinicalTrials.gov identifier: NCT03172624 .

Stimulated Raman Histology for Rapid Intra-Operative Diagnosis of Sinonasal and Skull Base Tumors.

OBJECTIVE: Intra-operative stimulated Raman histology (SRH) is a novel technology that uses laser spectroscopy and color-matching algorithms to create images similar to the formalin-fixed paraffin-embedded (FFPE) section. We aim to assess the accuracy of SRH in a novel range of sinonasal and skull base tumors. METHODS: Select patients undergoing sinonasal and skull base surgery using the Invenio Imaging™ Nio™ Laser Imaging SRH system between June 2020 and September 2021 were assessed. The SRH images were reviewed for pathologic features similar to frozen section (FS) and FFPE. Time taken for results and diagnostic concordance was assessed. RESULTS: Sixty-seven SRH images from 7 tumor types in 12 patients were assessed. Pathologies included squamous cell carcinoma, rhabdomyosarcoma, inverted papilloma, adenoid cystic carcinoma, SMARCB1-deficient sinonasal carcinoma, mucosal melanoma, metastatic colonic adenocarcinoma, and meningioma. Tumor was identified in 100% of lesional specimens, with characteristic diagnostic features readily appreciable on SRH. Median time for diagnosis was significantly faster for SRH (4.3 min) versus FS (44.5 min; p = <.0001). Where SRH sample site matched precisely to FS (n = 32/67, 47.8%), the same diagnosis was confirmed in 93.8%. Sensitivity, specificity, precision, and overall accuracy of SRH were 93.3%, 94.1%, 93.8%, and 93.3%, respectively. Near-perfect concordance was seen between SRH and FS (Cohen's kappa [κ] = 0.89). CONCLUSION: Stimulated Raman histology can rapidly produce images similar to FFPE H&E in sinonasal and skull base tumors. This technology has the potential to act as an adjunct or alternative to standard FS. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:2142-2147, 2022.

Use of Intraoperative Frozen Section to Assess Final Tumor Margin Status in Patients Undergoing Surgery for Oral Cavity Squamous Cell Carcinoma.

Importance: Methods of assessing final margin status in patients undergoing surgery for oral cavity squamous cell carcinoma, such as intraoperative frozen section histopathology (IFSH) taken from the tumor bed, may have limitations in accuracy. Objective: To evaluate the accuracy and implications of using IFSH samples to assess tumor bed margins in patients undergoing surgery for oral cavity squamous cell carcinoma (SCC). Design, Setting, and Participants: This cross-sectional study included 1257 patients who underwent surgery for oral cavity SCC between January 1, 2000, and December 31, 2015, at an academic cancer center. A total of 4821 IFSH samples were examined from 1104 patients (87.8%) who had at least 1 IFSH sample. Institutional practice is to harvest margins for IFSH from the tumor bed. Statistical analysis was performed from August 1, 2021, to April 4, 2022. Main Outcomes and Measures: Sensitivity and specificity were calculated for IFSH samples of margins compared with the permanent pathology samples of the same tissue and for IFSH compared with the final tumor specimen histopathology (FTSH). Results were classified using a binary method, with histopathologic reports interpreted as either negative (including negative or atypia or dysplasia) or positive (including carcinoma in situ, suspicious, or positive). Results: A total of 1257 patients met the inclusion criteria, including 709 men (56.4%), with a median age of 62 years (IQR, 52-73 years); 1104 patients (627 men [56.8%]; median age, 62 years [IQR, 52-72 years]) had IFHS samples. For IFSH relative to permanent sections of the IFSH tissue, sensitivity and specificity of IFSH were high (sensitivity, 76.5% [95% CI, 67.5%-85.5%]; specificity, 99.9% [95% CI, 99.8%-100%]), with discordant results in 24 of 4821 total specimens (0.5%). Final specimen margins were positive in 11.7% of patients (147 of 1257). Compared with FTSH, the sensitivity of IFSH for defining margin status was 10.8% (95% CI, 5.8%-15.8%), and the specificity was 99.1% (95% CI, 98.8%-99.4%). The rate of discordance was 4.0% (171 of 4284 specimens) between IFSH and FTSH. Conclusions and Relevance: The findings of this cross-sectional study suggest that IFSH is accurate compared with permanent pathologic characteristics of the same tissue, but less reliable at assessing final margin status on the tumor specimen. Despite a high specificity, the sensitivity of IFSH compared with FTSH is low, which may be associated with the inherent inability of tumor bed IFSH margin analysis to accurately account for the 3-dimensional association of tumor margins with the periphery of the specimen and the overall low rate of positive final tumor margins. Although tumor bed IFSH is widely used in the management of oral cavity cancer, this study suggests that there are limitations of this modality in assessing the final surgical margin status.

Factors predicting pharyngocutaneous fistula in patients after salvage laryngectomy for laryngeal malignancy - A multicenter collaborative cohort study.

OBJECTIVES: Pharyngocutaneous fistula (PCF) is a major morbidity of salvage total laryngectomy (TL). Understanding the factors predicting PCF is fundamental to managing laryngeal cancer. We aim to assess factors associated with PCF following salvage TL in a multicenter, international retrospective cohort study of academic centers in the US and Canada. RESULTS: In total, 550 patients post-salvage TL were identified (mean [SD; range] age, 64 [10.4; 32-90] years; 465 [85 %] male and 84 [15 %] female) between 2000 and 2014. Rate of PCF was 23 % (n = 127) with median time to PCF of 2.9 weeks. Surgical management of PCF was required in 43 % (n = 54) while 57 % (n = 73) required wound care alone. Rates of PCF differed by primary treatment modality [radiation, 20 % (n = 76); chemoradiation, 27 % (n = 40); not available (n = 6)] and use of vascularized tissue in pharyngeal closure [free/regional flap, 18 % (n = 25); no vascularized tissue/primary closure, 24 % (n = 98); not available (n = 4)]. There was no statistically significant association between PCF and treatment with chemoradiation (HR, 1.32; 95 % CI, 0.91-1.93, p = 0.14) or lack of vascularized tissue reconstruction (HR, 1.41, 95 % CI 0.91-2.18, p = 0.12). Significant association between PCF and advanced stage (T3 or T4), positive margin, close margin (<5mm), lymphovascular invasion and pre-operative tracheostomy were identified on univariable analysis. Positive surgical margin (HR, 1.91; 95 % CI, 1.11 to 3.29) was the only significant association on multivariable analysis. CONCLUSION: We highlight positive surgical margin as the only variable significantly associated with increased risk of PCF following salvage TL on multivariable analysis in a large cohort across several major head and neck oncology centers.

Functional landscapes of POLE and POLD1 mutations in checkpoint blockade-dependent antitumor immunity.

Defects in pathways governing genomic fidelity have been linked to improved response to immune checkpoint blockade therapy (ICB). Pathogenic POLE/POLD1 mutations can cause hypermutation, yet how diverse mutations in POLE/POLD1 influence antitumor immunity following ICB is unclear. Here, we comprehensively determined the effect of POLE/POLD1 mutations in ICB and elucidated the mechanistic impact of these mutations on tumor immunity. Murine syngeneic tumors harboring Pole/Pold1 functional mutations displayed enhanced antitumor immunity and were sensitive to ICB. Patients with POLE/POLD1 mutated tumors harboring telltale mutational signatures respond better to ICB than patients harboring wild-type or signature-negative tumors. A mutant POLE/D1 function-associated signature-based model outperformed several traditional approaches for identifying POLE/POLD1 mutated patients that benefit from ICB. Strikingly, the spectrum of mutational signatures correlates with the biochemical features of neoantigens. Alterations that cause POLE/POLD1 function-associated signatures generate T cell receptor (TCR)-contact residues with increased hydrophobicity, potentially facilitating T cell recognition. Altogether, the functional landscapes of POLE/POLD1 mutations shape immunotherapy efficacy.

Massive vagal schwannoma in an 11-year-old girl.

We describe an unusual case of a young girl presenting with a large vagal schwannoma necessitating a transcervical-mandibulotomy approach for total tumor resection. The presentation is unique due to the size of the lesion, the patient's age, the operative approach, and molecular pathology.

Predictors of distant metastases in sinonasal and skull base cancer patients treated with surgery.

OBJECTIVES: Sinonasal and skull base tumors comprise a heterogeneous group of malignancies with a significant rate of distant recurrence (DR). The aim of this study was to analyze tumor and host factors, including pretreatment neutrophil-to-lymphocyte ratio (NLR), that predict DR in these patients. MATERIALS AND METHODS: We retrospectively reviewed sinonasal tumors and/or tumors involving the skull base treated with surgery between 1973 and 2015 (n = 473). We stratified NLR using the top 5 percentile as cutoff. Factors predictive of outcome were determined by Cox proportional hazards model. RESULTS: Most tumors were primary (81%) and 67% had skull base resection. The most common site was the nasal cavity (37%) and the most common histology was squamous cell carcinoma (34%). Most patients presented with advanced primary tumor stage (pT3/T4; 80%) and most had no regional neck disease (pNx/N0; 93%). A total of 104 patients developed DR. The 5-year overall and disease-specific survival for patients who developed DR were 36.4% and 35.8%, compared to 69.0% and 74.9% for patients who did not. Patients with DR had a higher percentage of NLR-high patients compared patients without DR (11% vs 3%, p = .006). In a multivariable analysis, melanoma histology (HR = 5.469, 95% CI 3.171-9.433), pT3/T4 (HR = 2.686, 95% CI 1.150-6.275), pN+ (HR = 6.864, 95% CI 3.450-13.653), and NLR-high (HR = 3.489, 95% CI 1.593-7.639) were independent predictors of DR. CONCLUSION: Melanoma histology, pT, pN, and high NLR predict DR, suggesting that both tumor and host factors need to be considered. NLR may act as a surrogate marker of the host́s immune system.