Artificial intelligence-based epigenomic, transcriptomic and histologic signatures of tobacco use in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) biomarker studies rarely employ multi-omic biomarker strategies and pertinent clinicopathologic characteristics to predict mortality. In this study we determine for the first time a combined epigenetic, gene expression, and histology signature that differentiates between patients with different tobacco use history (heavy tobacco use with ≥10 pack years vs. no tobacco use). Using The Cancer Genome Atlas (TCGA) cohort (n = 257) and an internal cohort (n = 40), we identify 3 epigenetic markers (GPR15, GNG12, GDNF) and 13 expression markers (IGHA2, SCG5, RPL3L, NTRK1, CD96, BMP6, TFPI2, EFEMP2, RYR3, DMTN, GPD2, BAALC, and FMO3), which are dysregulated in OSCC patients who were never smokers vs. those who have a ≥ 10 pack year history. While mortality risk prediction based on smoking status and clinicopathologic covariates alone is inaccurate (c-statistic = 0.57), the combined epigenetic/expression and histologic signature has a c-statistic = 0.9409 in predicting 5-year mortality in OSCC patients.

Patterns and Trends in Adjuvant Therapy for Major Salivary Gland Cancer.

OBJECTIVE: To investigate adjuvant therapy indications, utilization, and associated survival disparities in major salivary gland cancer (MSGC). STUDY DESIGN: Retrospective cohort study. SETTING: The 2006 to 2017 National Cancer Database. METHODS: Patients with surgically resected MSGC were included (N = 11,398). pT3-4 classification, pN2-3 classification, lymphovascular invasion, pathologic extranodal extension (pENE), and positive surgical margin (PSM) were considered indications for adjuvant radiotherapy (aRT). pENE and PSM were considered possible indications for adjuvant chemotherapy. Multivariable logistic and Cox regression models were implemented. RESULTS: Among 6694 patients with ≥ $\ge $ 1 indication for aRT, 1906 (28.5%) received no further treatment and missed aRT. Age, race, comorbidity status, facility type, and distance to reporting facility were associated with missed aRT (P < .025). Among 4003 patients with ≥1 possible indication for adjuvant chemoradiotherapy (aCRT), 914 (22.8%) received aCRT. Patients with pENE only (38.5%) and both pENE and PSM (44.0%) received aCRT more frequently than those with PSM only (17.0%) (P < .001). Academic facility was associated with aCRT utilization (P < .05). aCRT utilization increased between 2006 and 2017 in both academic (14.8% vs 23.9%) and nonacademic (8.8% vs 13.5%) facilities (P < .05). Among 2691 patients with ≥1 indication for aRT alone, missed aRT portended poorer OS (hazard ratio [HR]: 1.61, 95% confidence interval [CI]: 1.28-2.03, P < .001). Among 4003 patients with ≥1 possible indication for aCRT, aRT alone (HR: 1.02, 95% CI: 0.89-1.18, P = .780) and aCRT were associated with similar OS. CONCLUSION: Missed aRT in MSGC occurs frequently and portends poorer OS. Further studies clarifying indications for aCRT are required.

Adjuvant Radiation and Survival Following Surgical Resection of Sinonasal Adenocarcinoma.

OBJECTIVES: This study aims to investigate the utility of adjuvant radiation in patients who undergo surgical resection for the management of node-negative sinonasal adenocarcinoma (SNAC). STUDY DESIGN: Retrospective database review. METHODS: The 2004-2016 National Cancer Data Base (NCDB) was used to extract patients with surgically resected node-negative SNAC. Kaplan-Meier survival analysis and Cox-Proportional Hazards Modelling were used to analyze the impact of adjuvant radiation on overall survival (OS) following surgery. RESULTS: 349 patients with SNAC underwent surgical resection. Of these patients, 154 (44.1%) received adjuvant radiotherapy (RT). Although there was no significant difference in race, age, or sex of those receiving RT, those receiving RT have more advanced diseases and are more likely to have positive margins. Kaplan Meier analysis showed no significant difference in 5-year OS in patient who received adjuvant RT in comparison to those who underwent surgical resection alone (65.7% vs. 72.6%, respectively; p = 0.378). In addition, when looking at only patients with positive margins, 5-year OS still did not have a significant difference (73.8% vs. 61.6%, respectively; p = 0.101). Only patients with clinical AJCC T4 showed a statistically significant survival benefit with adjuvant RT (56.9% vs. 29.9%, respectively; p = 0.009). CONCLUSIONS: Adjuvant RT does not appear to provide a significant survival benefit in patients with resected SNAC, with the exception of those with clinically AJCC T4 disease. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:2603-2612, 2023.

Prognostic significance of head and neck spindle cell carcinoma.

BACKGROUND: Our study investigates the prognostic significance of spindle cell histology on overall survival (OS) of conventional head and neck squamous cell carcinoma (HNSCC). METHODS: The 2004 to 2017 National Cancer Database was queried for patients with head and neck spindle cell carcinoma (HNSpCC) (n = 1572) or HNSCC (n = 242 697) of the oral cavity, major salivary glands, sinonasal tract, oropharynx, hypopharynx, and larynx treated with curative intent. RESULTS: Patients with HNSpCC presented more frequently with higher-grade tumors and cN0 disease than those with HNSCC (p < 0.001). In the oral cavity, the HR for death for SpCC compared with SCC was 1.33 (p < 0.001). In the oropharynx, the HR for death for SpCC compared with SCC was 1.47 (p = 0.028). CONCLUSIONS: After adjusting for patient, tumor, and treatment characteristics, SpCC histology had an independent adverse prognostic effect on OS in the oral cavity and oropharynx. SpCC histology does not necessarily portend poorer survival in all HNSCC.

Brush swab as a noninvasive surrogate for tissue biopsies in epigenomic profiling of oral cancer.

BACKGROUND: Oral squamous cell carcinoma (OSCC) has poor survival rates. There is a pressing need to develop more precise risk assessment methods to tailor clinical treatment. Epigenome-wide association studies in OSCC have not produced a viable biomarker. These studies have relied on methylation array platforms, which are limited in their ability to profile the methylome. In this study, we use MethylCap-Seq (MC-Seq), a comprehensive methylation quantification technique, and brush swab samples, to develop a noninvasive, readily translatable approach to profile the methylome in OSCC patients. METHODS: Three OSCC patients underwent collection of cancer and contralateral normal tissue and brush swab biopsies, totaling 4 samples for each patient. Epigenome-wide DNA methylation quantification was performed using the SureSelectXT Methyl-Seq platform. DNA quality and methylation site resolution were compared between brush swab and tissue samples. Correlation and methylation value difference were determined for brush swabs vs. tissues for each respective patient and site (i.e., cancer or normal). Correlations were calculated between cancer and normal tissues and brush swab samples for each patient to determine the robustness of DNA methylation marks using brush swabs in clinical biomarker studies. RESULTS: There were no significant differences in DNA yield between tissue and brush swab samples. Mapping efficiency exceeded 90% across all samples, with no differences between tissue and brush swabs. The average number of CpG sites with at least 10x depth of coverage was 2,716,674 for brush swabs and 2,903,261 for tissues. Matched tissue and brush swabs had excellent correlation (r = 0.913 for cancer samples and r = 0.951 for normal samples). The methylation profile of the top 1000 CpGs was significantly different between cancer and normal samples (mean p-value = 0.00021) but not different between tissues and brush swabs (mean p-value = 0.11). CONCLUSIONS: Our results demonstrate that MC-Seq is an efficient platform for epigenome profiling in cancer biomarker studies, with broader methylome coverage than array-based platforms. Brush swab biopsy provides adequate DNA yield for MC-Seq, and taken together, our findings set the stage for development of a non-invasive methylome quantification technique for oral cancer with high translational potential.

The Benefit of Primary Tumor Surgical Resection in Distant Metastatic Carcinomas of the Thyroid.

OBJECTIVES/HYPOTHESIS: Thyroid cancer with distant metastasis (TCDM) at diagnosis has significantly worse survival rates when compared to localized/regional thyroid cancer. This study sought to report on the characteristics of patients presenting with TCDM and the potential survival advantage of surgical resection. STUDY DESIGN: Data were acquired from the Surveillance, Epidemiology, and End Results (SEER) database with cases from 2004 to 2015. METHODS: TCDM cases (n = 2,558) were identified from the SEER database. The Bonferroni correction was applied for multivariate analysis. Kaplan-Meier analysis was utilized to obtain disease-specific survival (DSS) rates. Cox regression analysis was utilized to identify independent factors significantly associated with survival. RESULTS: The average age of diagnosis of TCDM was 62.0 (±17.5) years. Patients were predominantly white (74.6%), female (54.6%), in a relationship (56.0%), and between ages 36 and 80 years (76.4%). Cases consisted of papillary (57.2%), follicular (16.0%), medullary (8.9%), anaplastic (17.9%) TCDM histological variants. Overall 1-, 5-, and 10-year DSS rates were 72.0%, 56.8%, and 43.8%, respectively. Anaplastic and medullary variants had the worst 10-year DSS (0% and 25.5%, respectively). Patients who underwent surgical resection only and surgical resection with radiation were 49% and 59% less likely to die, respectively. Treatment, age, histology, T staging, relationship status, and metastasis site were determined to be significant predictors of survival. CONCLUSIONS: Surgical resection with radiation was found to be a significant predictor of survival after applying the Bonferroni correction for all thyroid cancer variants except medullary. To increase survival, surgical intervention should be recommended in patients who are deemed to be medically tolerant of surgery. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:1026-1034, 2021.

Evaluating the impact of metabolic syndrome on postoperative thyroidectomy outcomes.

OBJECTIVE: Metabolic syndrome (MetS) has previously been linked to increased risk of postoperative morbidity and mortality in other surgical undertakings. Because MetS is a consequence of endocrine dysfunction, and given the thyroid's crucial role in endocrine homeostasis, we sought to evaluate the association between MetS and postoperative outcomes of thyroidectomy. METHODS: Data were acquired from the ACS-NSQIP database from years 2005 to 2017. Patients with obesity, diabetes, and hypertension were defined as having MetS. Odds ratios (OR) were obtained for outcomes to quantify risk with multivariate logistic regression. RESULTS: Outcomes significantly affected by MetS included overall complication (OR: 2.00), extended postoperative stay (OR: 1.52), medical complication (OR: 1.48), surgical complication (OR: 1.62), and mortality (OR: 2.33). CONCLUSIONS: Patients with MetS undergoing thyroidectomy are at increased risk of an increased length of stay, overall complications, and mortality.

Evaluating the impact of smoking on disease-specific survival outcomes in patients with human papillomavirus-associated oropharyngeal cancer treated with transoral robotic surgery.

BACKGROUND: When treated nonsurgically with definitive chemoradiation, smokers with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) have a worse prognosis compared with their nonsmoking counterparts. To the authors' knowledge, the prognostic significance of smoking in surgically treated patients is unknown. METHODS: The current study is a retrospective case series of patients with HPV-positive OPSCC who underwent upfront transoral robotic surgery at a single institution from 2010 through 2017. Exclusion criteria were nonoropharyngeal primary tumors, histology other than SCC, HPV-negative tumors, previous history of head and neck cancer, and/or previous head and neck radiotherapy. Recurrence-free survival (RFS), overall survival, and disease-specific survival were compared using the Kaplan-Meier method and the log-rank test. Smoking history was categorized as never smokers (<1 pack-year), current smokers (smoking at the time of the cancer diagnosis), and former smokers. RESULTS: A total of 258 patients met the study criteria. The average age was 60 years, and approximately 87% of patients were male. A total of 148 patients (57.4%) were smokers whereas 110 (42.6%) reported never smoking. There were 44 active smokers (17.1%) and 104 former smokers (40.3%). The median follow-up was 3.23 years. There were 17 patients of disease recurrence. Smoking pack-year history was not found to be significant for RFS (hazard ratio, 1.01; 95% CI, 0.99-1.03 [P = .45]). There was no significant difference in RFS noted between never and ever smokers (92% vs 89.8%; P = .85) nor was there a difference observed between never, former, and current smokers (92% vs 91.5% vs 86.1%, respectively; P = .69). CONCLUSIONS: A smoking history is common in patients with HPV-positive OPSCC. In the current study, HPV-positive smokers were found to have excellent survival and locoregional control, similar to their nonsmoking counterparts. The results of the current study do not support the exclusion of smokers with early-stage, HPV-positive OPSCC from transoral robotic surgery-based deintensification trials.

Virtual Surgical Planning in Subscapular System Free Flap Reconstruction of Midface Defects.

OBJECTIVES: Reconstruction of the midface has many inherent challenges, including orbital support, skull base reconstruction, optimizing midface projection, separation of the nasal cavity and dental rehabilitation. Subscapular system free flaps (SF) have sufficient bone stock to support complex reconstruction and the option of separate soft tissue components. This study analyzes the effect of virtual surgical planning (VSP) in SF for midface on subsite reconstruction, bone segment contact and anatomic position. MATERIALS AND METHODS: Retrospective cohort of patients with midface defects that underwent SF reconstruction at a single tertiary care institution. RESULTS: Nine cases with VSP were compared to fourteen cases without VSP. VSP was associated with a higher number of successfully reconstructed subunits (5.9 vs 4.2, 95% CI of mean difference 0.31-3.04, p = 0.018), a higher number of successful bony contact between segments (2.2 vs 1.4, 95% CI of mean difference 0.0-1.6, p = 0.050), and a higher percent of segments in anatomic position (100% vs 71%, 95% CI of mean difference 2-55%, p = 0.035). When postoperative bone position after VSP reconstruction was compared to preoperative scans, the difference in anteroposterior, vertical and lateral projection compared to the preoperative 'ideal' bone position was <1 cm in 82% of measurements. There were no flap losses. CONCLUSION: VSP may augment SF reconstruction of the midface by allowing for improved subunit reconstruction, bony segment contact and anatomically correct bone segment positioning. VSP can be a useful adjunct for complex midface reconstruction and the benefits should be weighed against cost.

Survival of oral tongue squamous cell carcinoma in young adults.

BACKGROUND: Small cohort studies have suggested oral tongue squamous cell carcinoma (OTSCC) could be associated with worse prognosis in individuals younger than 40. METHODS: We compared the survival of all OTSCC cases in the National Cancer Database under 40 years old with those older than 40, excluding patients over 70. Cox regression and propensity score matched (PSM) survival analyses were performed. RESULTS: A total of 22 930 OTSCC patients were identified. The under 40 group consisted of 2566 (9.9%) cases; 20664 were 40 to 70 (90.1%). Most were male (13 713, 59.8%), stage I-II (12 754, 72.4%), and treated by surgery alone (13 973, 63.2%). Survival in patients under 40 was higher (79.6% vs 69.5%, P < .001). In PSM analysis (n = 2928) controlling for all 10 significant factors in multivariate regression, patients under 40 had a 9% higher 5-year survival (77.1% vs 68.2%, P < .001). CONCLUSION: Contrary to the prior reports, younger patients with OTSCC did not have worse survival in the National Cancer Database.

Perioperative Management of Total Laryngectomy Patients: A Survey of American Head and Neck Society Surgeons.

OBJECTIVES: Standards of care for total laryngectomy (TL) patients in the postoperative period have not been established. Perioperative care remains highly variable and perhaps primarily anecdotally based. The aim of this study was to survey members of the American Head and Neck Society to capture management practices in the perioperative care of TL patients. METHODS: In this survey study, an electronic survey was distributed to the international attending physician body of the American Head and Neck Society. Forty-five-question electronic surveys were distributed. A total of 777 members were invited to respond, of whom 177 (22.8%) fully completed the survey. The survey elicited information on management preferences in the perioperative care of TL patients. Differences in management on the basis of irradiation status and pharyngeal repair (primary closure vs regional or free flap reconstruction) were ascertained. Main outcomes and measures were time to initiate oral feeding, perioperative antibiotic selection and duration, and estimated pharyngocutaneous fistula rates. These measures were stratified by patient type. RESULTS: Most respondents completed head and neck fellowships (77.0%) and practice at academic tertiary centers (72.3%). Ampicillin/sulbactam was the most preferred perioperative antibiotic (43.2%-49.1% depending on patient type), followed by cefazolin and metronidazole in combination (32.0%-33.7%) and then clindamycin (10.8%-12.6%). Compared with nonirradiated patients, irradiated patients were significantly more likely to have longer durations of antibiotics ( P < .05), longer postoperative times to initiate oral feeding ( P < .05), and higher estimated fistula rates ( P < .05). Additionally, in nonirradiated patients, flap-repaired patients (vs primary repair) were significantly more likely to have longer durations of antibiotics (odds ratio, 1.29; 95% confidence interval, 1.13-1.48) and postoperative times to initiate oral feeding (odds ratio, 2.24; 95% confidence interval, 1.76-2.84). CONCLUSIONS: Perioperative management of TL patients is highly variable. Management of antibiotics and oral feeding are significantly affected by irradiation status and scope of pharyngeal repair. Further studies are needed to standardize perioperative care for this unique patient population.

Tracheal replacement revisited: Use of a vascularized tracheal transplant in a porcine model.

OBJECTIVES/HYPOTHESIS: To determine if a long segment of trachea can be transplanted as a vascularized organ and to determine if a tracheal transplant is a potential surgical option for a long-segment circumferential tracheal defect. STUDY DESIGN: Animal model. METHODS: Four (two donors and two recipients) adult domestic Yorkshire swine were used. Two sets of transplants were performed from a donor to recipient pig. The transplant was placed heterotopically (not in continuity with the airway), and the recipient animals were monitored for 14 days to ensure the transplants were well vascularized. Immunosuppressive therapies included methylprednisolone, cyclosporine, and azathioprine. Gross as well as histological examination of multiple tissues types including mucosa, cartilage, muscle, and blood vessels were performed postsacrifice on day 14. RESULTS: Recipient animal weights ranged from 40 to 42 kilograms. Both recipient pigs survived the full 14 days of study and exhibited normal activity and appetite. Ischemia time of transplanted grafts ranged from 63 to 72 minutes. Transplanted tracheas included a minimum of 15 cartilaginous rings and measured greater than 10 cm in length. Both grafts maintained a robust blood supply throughout the duration of study. CONCLUSIONS: The entire visceral compartment can be reliably transplanted, either as a single component (trachea) or as a chimeric flap with multiple components (trachea, esophagus, larynx, and pharynx). Further studies in the swine model should be considered to study the effects of transplanting the trachea orthotopically into the native airway. Further studies are needed into the reliability of this technique of transplantation in humans. LEVEL OF EVIDENCE: NA Laryngoscope, 128:S1-S9, 2018.

Utilization and Survival of Postoperative Radiation or Chemoradiation for pT1-2N1M0 Head and Neck Cancer.

Objective To analyze the patterns of care and survival for pT1-2N1M0 head and neck cancer based on receipt of surgery alone, surgery + postoperative radiotherapy (S + RT), or surgery + postoperative chemoradiotherapy (S + CRT). Study Design Retrospective analysis. Setting National Cancer Database. Subjects and Methods We queried the database for patients with stage pT1-2N1M0 squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx between 2004 and 2012 who were treated with surgery with negative margins and no extracapsular extension. Logistic regression was used to assess predictors of receipt of postoperative treatment. Overall survival was assessed by the Kaplan-Meier method, and Cox regression analysis identified covariates that affected it. Results There were 1598 patients included in this study: 566 (35.4%) received surgery alone; 726 (45.4%), S + RT; and 306 (19.1%), S + CRT. The 5-year overall survival was 68.8%, 74.0%, and 87.8%, respectively ( P = .009 comparing S + RT and surgery alone, P < .001 for all other comparisons). On multivariable logistic regression, academic centers were associated with a decreased likelihood of S + RT (odds ratio = 0.71) and S + CRT (odds ratio = 0.66). Multivariable Cox regression demonstrated no difference in survival for S + RT over surgery alone (hazard ratio = 0.88, 95% CI = 0.70-1.09, P = .24); however, there was a survival benefit associated with S + CRT (hazard ratio = 0.57, 95% CI = 0.39-0.81, P = .002). Conclusion Nearly 65% of patients with pT1-2N1 head and neck cancer with negative margins and no extracapsular extension received S + RT or S + CRT. Improvement in survival was noted only for patients who received S + CRT.

Multimodality Treatment of Early-Stage Tonsil Cancer.

Objective Compare survival outcomes between unimodality and multimodality treatments for early-stage tonsil squamous cell carcinoma (SCC). Study Design and Setting Review of the National Cancer Database. Subjects and Methods Patients were selected if they were <70 years old with clinical stage I-II SCC of the tonsil, as documented in the National Cancer Database from 1998 to 2011. Palliative and nonstandard treatments were excluded. Propensity score matching was performed, controlling for tumor stage, age, race, comorbidity, insurance status, and year of diagnosis. Overall survival (OS) was compared with the Kaplan-Meier method and log-rank test. Results We identified 3247 patients. Radiotherapy (RT) was delivered in 1295 patients (39.9%), surgery in 824 (25.4%), and surgery + RT in 1128 (34.7%). Patients treated with surgery + RT had the highest 5-year OS (81.1%), followed by surgery (67.4%) and RT (63.4%; P < .001). In a propensity score-matched subpopulation of 2378 patients, the 5-year OS was 78.8% for surgery + RT, 66.7% for surgery, and 64.5% for RT ( P < .001). Among patients who underwent surgical tonsillectomy plus elective neck dissection and/or adjuvant RT, the 5-year OS was equal ( P = .29), and all were superior to RT alone ( P < .001). Conclusion Multimodality treatment is associated with the greatest survival in early-stage tonsil cancer. The addition of tonsillectomy to RT confers a 20% increase in survival. The current guidelines might not offer the most effective treatment. An up-front surgical approach, followed by appropriately selected adjuvant therapy, may result in improved survival for early-stage tonsil SCC. These findings merit investigation in a prospective clinical trial.

Triple-modality treatment in patients with advanced stage tonsil cancer.

BACKGROUND: Concurrent chemoradiation (CCRT) and upfront surgery followed by adjuvant therapy both are recommended treatment options for patients with advanced stage squamous cell carcinoma (SCC) of the tonsil. To the authors' knowledge, the question of whether surgical-based treatments can achieve better survival compared with CCRT has never been compared in a clinical trial. The authors analyzed the National Cancer Data Base to measure the impact of different treatment modalities on overall survival (OS). METHODS: All patients aged ≤70 years diagnosed with clinical stage III to IVB (excluding T4B) SCC of the tonsil from 1998 through 2011 were selected. Analysis was limited to patients receiving CCRT, surgery plus CCRT, or surgery followed by adjuvant radiotherapy (RT). OS was compared using the Kaplan-Meier method and log-rank test. Univariable and multivariable hazards analyses were performed to identify factors significant for survival. Propensity score matching was performed. RESULTS: There were 16,891 patients who met the inclusion criteria. The most common treatment was CCRT (8123 patients; 48.1%), followed by surgery plus CCRT (5249; 31.1%) and surgery plus RT (3519 patients; 20.8%). Patients treated with surgery plus CCRT were found to have the highest 3-year OS rate (88.5%) followed by those treated with surgery plus RT (84%) and CCRT (74.2%) (P<.0001). In a propensity score-matched subpopulation of 4962 patients, the 3-year OS rate was 90.2% for those treated with surgery plus CCRT, 84.9% for those treated with surgery plus RT, and 82.1% for those treated with definitive CCRT (P<.0001). CONCLUSIONS: Patients with advanced stage SCC of the tonsil who underwent surgery followed by CCRT had the greatest OS. Patients undergoing upfront surgery may avoid chemotherapy without jeopardizing survival. Triple-modality therapy may provide a survival benefit for a subset of patients with advanced stage tonsil cancer. Cancer 2017;123:3269-76. © 2017 American Cancer Society.

Causes of dysphagia among different age groups: a systematic review of the literature.

Dysphagia is a common problem that has the potential to result in severe complications such as malnutrition and aspiration pneumonia. Based on the complexity of swallowing, there may be many different causes. This article presents a systematic literature review to assess different comorbid disease associations with dysphagia based on age. The causes of dysphagia are different depending on age, affecting between 1.7% and 11.3% of the general population. Dysphagia can be a symptom representing disorders pertinent to any specialty of medicine. This review can be used to aid in the diagnosis of patients presenting with the complaint of dysphagia.