Targeting STAT3 prevents bile reflux-induced oncogenic molecular events linked to hypopharyngeal carcinogenesis.

The signal transducer and activator of transcription 3 (STAT3) oncogene is a transcription factor with a central role in head and neck cancer. Hypopharyngeal cells (HCs) exposed to acidic bile present aberrant activation of STAT3, possibly contributing to its oncogenic effect. We hypothesized that STAT3 contributes substantially to the bile reflux-induced molecular oncogenic profile, which can be suppressed by STAT3 silencing or pharmacological inhibition. To explore our hypothesis, we targeted the STAT3 pathway, by knocking down STAT3 (STAT3 siRNA), and inhibiting STAT3 phosphorylation (Nifuroxazide) or dimerization (SI3-201; STA-21), in acidic bile (pH 4.0)-exposed human HCs. Immunofluorescence, luciferase assay, Western blot, enzyme-linked immunosorbent assay and qPCR analyses revealed that STAT3 knockdown or pharmacologic inhibition significantly suppressed acidic bile-induced STAT3 activation and its transcriptional activity, Bcl-2 overexpression, transcriptional activation of IL6, TNF-α, BCL2, EGFR, STAT3, RELA(p65), REL and WNT5A, and cell survival. Our novel findings document the important role of STAT3 in bile reflux-related molecular oncogenic events, which can be dramatically prevented by STAT3 silencing. STA-21, SI3-201 or Nifuroxazide effectively inhibited STAT3 and cancer-related inflammatory phenotype, encouraging their single or combined application in preventive or therapeutic strategies of bile reflux-related hypopharyngeal carcinogenesis.

Type of bony involvement predicts genomic subgroup in sphenoid wing meningiomas.

PURPOSE: As sphenoid wing meningiomas (SWMs) are associated with varying degrees of bony involvement, we sought to understand potential relationships between genomic subgroup and this feature. METHODS: Patients treated at Yale-New Haven Hospital for SWM were reviewed. Genomic subgroup was determined via whole exome sequencing, while the extent of bony involvement was radiographically classified as no bone invasion (Type I), hyperostosis only (Type II), tumor invasion only (Type III), or both hyperostosis and tumor invasion (Type IV). Among additional clinical variables collected, a subset of tumors was identified as spheno-orbital meningiomas (SOMs). Machine-learning approaches were used to predict genomic subgroups based on pre-operative clinical features. RESULTS: Among 64 SWMs, 53% had Type-II, 9% had Type-III, and 14% had Type-IV bone involvement; nine SOMs were identified. Tumors with invasion (i.e., Type III or IV) were more likely to be WHO grade II (p: 0.028). Additionally, tumors with invasion were nearly 30 times more likely to harbor NF2 mutations (OR 27.6; p: 0.004), while hyperostosis only were over 4 times more likely to have a TRAF7 mutation (OR 4.5; p: 0.023). SOMs were a significant predictor of underlying TRAF7 mutation (OR 10.21; p: 0.004). CONCLUSIONS: SWMs with invasion into bone tend to be higher grade and are more likely to be NF2 mutated, while SOMs and those with hyperostosis are associated with TRAF7 variants. Pre-operative prediction of molecular subtypes based on radiographic bony characteristics may have significant biological and clinical implications based on known recurrence patterns associated with genomic drivers and grade.

Pepsin Promotes Activation of Epidermal Growth Factor Receptor and Downstream Oncogenic Pathways, at Slightly Acidic and Neutral pH, in Exposed Hypopharyngeal Cells.

Pepsin refluxate is considered a risk factor for laryngopharyngeal carcinogenesis. Non-acidic pepsin was previously linked to an inflammatory and tumorigenic effect on laryngopharyngeal cells in vitro. Yet there is no clear evidence of the pepsin-effect on a specific oncogenic pathway and the importance of pH in this process. We hypothesized that less acidic pepsin triggers the activation of a specific oncogenic factor and related-signalling pathway. To explore the pepsin-effect in vitro, we performed intermittent exposure of 15 min, once per day, for a 5-day period, of human hypopharyngeal primary cells (HCs) to pepsin (1 mg/mL), at a weakly acidic pH of 5.0, a slightly acidic pH of 6.0, and a neutral pH of 7.0. We have documented that the extracellular environment at pH 6.0, and particularly pH 7.0, vs. pH 5.0, promotes the pepsin-effect on HCs, causing increased internalized pepsin and cell viability, a pronounced activation of EGFR accompanied by NF-κB and STAT3 activation, and a significant upregulation of EGFR, AKT1, mTOR, IL1ß, TNF-α, RELA(p65), BCL-2, IL6 and STAT3. We herein provide new evidence of the pepsin-effect on oncogenic EGFR activation and its related-signaling pathway at neutral and slightly acidic pH in HCs, opening a window to further explore the prevention and therapeutic approach of laryngopharyngeal reflux disease.

Results of COVID-minimal Surgical Pathway During Surge-phase of COVID-19 Pandemic.

OBJECTIVE: The outcomes of patients treated on the COVID-minimal pathway were evaluated during a period of surging COVID-19 hospital admissions, to determine the safety of continuing to perform urgent operations during the pandemic. SUMMARY OF BACKGROUND DATA: Crucial treatments were delayed for many patients during the COVID-19 pandemic, over concerns for hospital-acquired COVID-19 infections. To protect cancer patients whose survival depended on timely surgery, a "COVID-minimal pathway" was created. METHODS: Patients who underwent a surgical procedure on the pathway between April and May 2020 were evaluated. The "COVID-minimal surgical pathway" consisted of: (A) evolving best-practices in COVID-19 transmission-reduction, (B) screening patients and staff, (C) preoperative COVID-19 patient testing, (D) isolating pathway patients from COVID-19 patients. Patient status through 2 weeks from discharge was determined as a reflection of hospital-acquired COVID-19 infections. RESULTS: After implementation, pathway screening processes excluded 7 COVID-19-positive people from interacting with pathway (4 staff and 3 patients). Overall, 122 patients underwent 125 procedures on pathway, yielding 83 admissions (42 outpatient procedures). The median age was 64 (56-79) and 57% of patients were female. The most common surgical indications were cancer affecting the uterus, genitourinary tract, colon, lung or head and neck. The median length of admission was 3 days (1-6). Repeat COVID-19 testing performed on 27 patients (all negative), including 9 patients evaluated in an emergency room and 8 readmitted patients. In the postoperative period, no patient developed a COVID-19 infection. CONCLUSIONS: A COVID-minimal pathway comprised of physical space modifications and operational changes may allow urgent cancer treatment to safely continue during the COVID-19 pandemic, even during the surge-phase.

PET/CT radiomics signature of human papilloma virus association in oropharyngeal squamous cell carcinoma.

PURPOSE: To devise, validate, and externally test PET/CT radiomics signatures for human papillomavirus (HPV) association in primary tumors and metastatic cervical lymph nodes of oropharyngeal squamous cell carcinoma (OPSCC). METHODS: We analyzed 435 primary tumors (326 for training, 109 for validation) and 741 metastatic cervical lymph nodes (518 for training, 223 for validation) using FDG-PET and non-contrast CT from a multi-institutional and multi-national cohort. Utilizing 1037 radiomics features per imaging modality and per lesion, we trained, optimized, and independently validated machine-learning classifiers for prediction of HPV association in primary tumors, lymph nodes, and combined "virtual" volumes of interest (VOI). PET-based models were additionally validated in an external cohort. RESULTS: Single-modality PET and CT final models yielded similar classification performance without significant difference in independent validation; however, models combining PET and CT features outperformed single-modality PET- or CT-based models, with receiver operating characteristic area under the curve (AUC) of 0.78, and 0.77 for prediction of HPV association using primary tumor lesion features, in cross-validation and independent validation, respectively. In the external PET-only validation dataset, final models achieved an AUC of 0.83 for a virtual VOI combining primary tumor and lymph nodes, and an AUC of 0.73 for a virtual VOI combining all lymph nodes. CONCLUSION: We found that PET-based radiomics signatures yielded similar classification performance to CT-based models, with potential added value from combining PET- and CT-based radiomics for prediction of HPV status. While our results are promising, radiomics signatures may not yet substitute tissue sampling for clinical decision-making.

Radiation therapy treatment facility and overall survival in the adjuvant setting for locally advanced head and neck squamous cell carcinoma.

BACKGROUND: Treatment at high-volume surgical facilities (HVSFs) provides a survival benefit for patients with head and neck squamous cell carcinomas (HNSCCs); however, it is unknown what role postoperative radiation therapy (PORT) plays in achieving the improved outcomes. METHODS: From the National Cancer Database, 6844 patients with locally advanced invasive HNSCCs of the oral cavity, oropharynx, larynx, and hypopharynx who underwent definitive surgery with PORT between 2004 and 2013 were identified. HVSFs were those in the top percentile for annual case volume during this period. RESULTS: The median follow-up was 54 months. Compared with a lower volume surgical facility (LVSF), an HVSF improved 5-year overall survival (OS; 57.7% at HVSFs vs 52.5% at LVSFs; P = .0003). Overall, 31.6% of the patients changed their radiation therapy (RT) facility after surgery, with this being more common at HVSFs (39.1% vs 28.9% at LVSFs; P < .001). Among those patients undergoing surgery at an HVSF, remaining at the same facility for RT improved 5-year OS (63.1% vs 49.3% with a facility change; P < .0001). A propensity score-matched cohort of patients treated at HVSFs confirmed the improved 5-year OS when patients remained at the treating HVSF for RT (59.2% vs 50.7% with a facility change; P = .005). In a multivariate analysis, treatment at an HVSF and remaining there for RT resulted in a reduced hazard of death (hazard ratio, 0.81; 95% confidence interval, 0.69-0.94; P = .006). CONCLUSIONS: The survival benefit associated with HVSFs persists only when patients remain at the facility for RT, and this suggests that facility specialization and/or high-volume PORT may assist in driving the OS improvement.

Treatment deintensification in human papillomavirus-positive oropharynx cancer: Outcomes from the National Cancer Data Base.

BACKGROUND: The growing epidemic of human papillomavirus-positive (HPV+) oropharyngeal cancer and the favorable prognosis of this disease etiology have led to a call for deintensified treatment for some patients with HPV+ cancers. One of the proposed methods of treatment deintensification is the avoidance of chemotherapy concurrent with definitive/adjuvant radiotherapy. To the authors' knowledge, the safety of this form of treatment de-escalation is unknown and the current literature in this area is sparse. The authors investigated outcomes after various treatment combinations stratified by American Joint Committee on Cancer (AJCC) eighth edition disease stage using patients from the National Cancer Data Base. METHODS: A retrospective study of 4443 patients with HPV+ oropharyngeal cancer in the National Cancer Data Base was conducted. Patients were stratified into AJCC eighth edition disease stage groups. Multivariate Cox regressions as well as univariate Kaplan-Meier analyses were conducted. RESULTS: For patients with stage I disease, treatment with definitive radiotherapy was associated with diminished survival compared with chemoradiotherapy (hazard ratio [HR], 1.798; P = .029), surgery with adjuvant radiotherapy (HR, 2.563; P = .002), or surgery with adjuvant chemoradiotherapy (HR, 2.427; P = .001). For patients with stage II disease, compared with treatment with chemoradiotherapy, patients treated with a single-modality (either surgery [HR, 2.539; P = .009] or radiotherapy [HR, 2.200; P = .030]) were found to have poorer survival. Among patients with stage III disease, triple-modality therapy was associated with improved survival (HR, 0.518; P = .024) compared with treatment with chemoradiotherapy. CONCLUSIONS: Deintensification of treatment from chemoradiotherapy to radiotherapy or surgery alone in cases of HPV+ AJCC eighth edition stage I or stage II disease may compromise patient safety. Treatment intensification to triple-modality therapy for patients with stage III disease may improve survival in this group. Cancer 2018;124:717-26. © 2017 American Cancer Society.

Smoking, cessation, and cessation counseling in patients with cancer: A population-based analysis.

BACKGROUND: Smoking is known to be carcinogenic and an important factor in the outcome of cancer treatment. However, to the authors' knowledge, smoking habits and smoking cessation counseling in patients with cancer have been poorly studied. The authors sought to analyze smoking habits among Americans diagnosed with cancer in a nationally representative dataset. METHODS: The cancer supplement of the National Health Interview Survey (NHIS) in 2010 was used to obtain information regarding self-reported smoking behavior in a representative sample of the US population. Cancer history, smoking history, quitting behavior, cessation counseling, cessation approaches, and sociodemographic variables were analyzed. RESULTS: A total of 27,157 individuals were interviewed for the NHIS in 2010, representing 216,052,891 individuals, 7,058,135 of whom had ever smoked and 13,188,875 of whom had been told that they had cancer. Approximately 51.7% of individuals diagnosed with cancer and who were active smokers reported being counseled to quit smoking by a health professional within the previous 12 months. Cancer survivors were no more likely to quit smoking than individuals in the general population. Those diagnosed with a tobacco-related cancer were found to be no more likely to report quitting smoking than those with other types of cancers. Rates of quitting did not appear to vary based on the type of smoking cessation method used (P = .50). CONCLUSIONS: Patients with cancer, including those diagnosed with a tobacco-related cancer, do not appear to be more likely to quit smoking than the general population. Only approximately one-half of patients with cancer who smoke are counseled to quit. Smoking cessation in patients with cancer is an important area for intervention and investigation.

Treatment trends and survival effects of chemotherapy for hypopharyngeal cancer: Analysis of the National Cancer Data Base.

BACKGROUND: The current study was performed to characterize trends and survival outcomes for chemotherapy in the definitive and adjuvant treatment of hypopharyngeal cancer in the United States. METHODS: A total of 16,248 adult patients diagnosed with primary hypopharyngeal cancer without distant metastases between 1998 and 2011 were identified in the National Cancer Data Base. The association between treatment modality and overall survival was analyzed using Kaplan-Meier survival curves and 5-year survival rates. A multivariate Cox regression analysis was performed on a subset of 3357 cases to determine the treatment modalities that predict improved survival when controlling for demographic and clinical factors. RESULTS: There was a significant increase in the use of chemotherapy with radiotherapy both as definitive treatment (P<.001) and as adjuvant chemoradiotherapy with surgery (P=.001). This was accompanied by a decrease in total laryngectomy/pharyngectomy rates (P<.001). Chemoradiotherapy was associated with improved 5-year survival compared with radiotherapy alone in the definitive setting (31.8% vs 25.2%; log rank P<.001). Similarly, in multivariateanalysis, definitive radiotherapy was found to be associated with compromised survival compared with definitive chemoradiotherapy (hazard ratio, 1.51; P<.001). CONCLUSIONS: Survival analysis revealed that overall 5-year survival rates were higher for chemoradiotherapy compared with radiotherapy alone in the definitive setting, but were comparable between surgery with chemoradiotherapy and surgery with radiotherapy. Cancer 2016;122:1853-60. © 2016 American Cancer Society.

Proposing prognostic thresholds for lymph node yield in clinically lymph node-negative and lymph node-positive cancers of the oral cavity.

BACKGROUND: Prognostic lymph node yield thresholds have been identified and incorporated into treatment guidelines for multiple cancer sites, but not for oral cancer. The objective of this study was to identify optimal thresholds in elective and therapeutic neck dissection for oral cavity cancers. METHODS: Patients with oral cavity cancers in the National Cancer Database (NCDB) were stratified into clinically lymph node-negative (cN0) and clinically lymph node-positive (cN+) cohorts to reflect the differing surgical management for these diseases. Univariate and multivariate analyses were performed to assess the relation between lymph node yield and overall survival, adjusting for other prognostic factors. Thresholds derived from the NCDB were validated in the Surveillance, Epidemiology, and End Results database. RESULTS: In patients with cN0 cancers of the oral cavity from the NCDB, those who had <16 lymph nodes had significantly decreased survival. The proportion of positive lymph nodes was higher for patients who had ≥16 lymph nodes (27.2% vs 16.3% for < 16 lymph nodes; P < .001). This threshold was validated in 2715 lymph node-negative cancers from SEER, with a mortality hazard ratio of 0.825 for ≥ 16 lymph nodes (95% confidence interval, 0.764-0.950; P = .004). In patients with cN + oral cavity cancers from the NCDB, groups with <26 lymph nodes had significantly decreased survival. This threshold was validated in 1903 lymph node-positive cancers from SEER, with a mortality hazard ratio of 0.791 (95% confidence interval, 0.692-0.903; P = .001). Academic centers, higher volume centers, and geographic location predicted higher lymph node yields. CONCLUSIONS: More extensive neck dissection (≥16 lymph nodes in cN0, ≥ 26 lymph nodes in cN+) was associated with better survival. Further evaluation of practice patterns in lymph node yield may represent an opportunity for improved quality of care. Cancer 2016;122:3624-31. © 2016 American Cancer Society.

Trends and variations in the use of adjuvant therapy for patients with head and neck cancer.

BACKGROUND: The National Comprehensive Cancer Network guidelines recommend that patients with surgically resected head and neck cancers that have adverse pathologic features should receive adjuvant therapy in the form of radiotherapy (RT) or chemoradiation (CRT). To the authors' knowledge, the current study is the first analysis of temporal trends and use patterns of adjuvant therapy for these patients. METHODS: Patients with head and neck cancer and adverse pathologic features were identified in the National Cancer Data Base (1998-2011). Data were analyzed using chi-square, Student t, and log-rank tests; multivariate logistic regression; and Cox multivariate regression. RESULTS: A total of 73,088 patients were identified: 41.5% had received adjuvant RT, 33.5% had received adjuvant CRT, and 25.0% did not receive any adjuvant therapy. From 1998 to 2011, the increase in the use of adjuvant CRT was greatest for patients with oral cavity (6-fold) and laryngeal (5-fold) cancers. Multivariate analysis demonstrated that Medicare/Medicaid insurance (odds ratio [OR], 1.05; 95% confidence interval [95% CI], 1.01-1.11), distance ≥34 miles from the cancer center (OR, 1.66; 95% CI, 1.59-1.74), and academic (OR, 1.26; 95% CI, 1.20-1.31) and high-volume (OR, 1.10; 95% CI, 1.05-1.15) centers were independently associated with patients not receiving adjuvant therapy. Receipt of adjuvant therapy was found to be independently associated with improved overall survival (hazard ratio, 0.84; 95% CI, 0.81-0.86). CONCLUSIONS: Approximately 25% of patients are not receiving National Comprehensive Cancer Network guideline-directed adjuvant therapy. Patient-level and hospital-level factors are associated with variations in the receipt of adjuvant therapy. Further evaluation of these differences in practice patterns is needed to standardize practice and potentially improve the quality of care. Cancer 2014;120:3353-3360. © 2014 American Cancer Society.

Novel non-invasive molecular signatures for oral cavity cancer, by whole transcriptome and small non-coding RNA sequencing analyses: Predicted association with PI3K/AKT/mTOR pathway.

INTRODUCTION: Identification of molecular biomarkers in the saliva and serum of oral cavity cancer patients represents a first step in the development of essential and efficient clinical tools for early detection and post-treatment monitoring. We hypothesized that molecular analyses of paired saliva and serum samples from an individual would likely yield better results than analyses of either serum or saliva alone. MATERIALS AND METHODS: We performed whole-transcriptome and small non-coding RNA sequencing analyses on 32 samples of saliva and serum collected from the same patients with oral squamous cell carcinoma (OSCC) and healthy controls (HC). RESULTS: We identified 12 novel saliva and serum miRNAs and a panel of unique miRNA and mRNA signatures, significantly differentially expressed in OSCC patients relative to HC (log2 fold change: 2.6-26.8; DE: 0.02-0.000001). We utilized a combined panel of the 10 top-deregulated miRNAs and mRNAs and evaluated their putative diagnostic potential (>87% sensitivity; 100% specificity), recommending seven of them for further validation. We also identified unique saliva and serum miRNAs associated with OSCC and smoking history (OSCC smokers vs. never-smokers or HC: log2 fold change: 22-23; DE: 0.00003-0.000000001). Functional and pathway analyses indicated interactions between the discovered OSCC-related non-invasive miRNAs and mRNAs and their targets, through PI3K/AKT/mTOR signaling. CONCLUSION: Our data support our hypothesis that using paired saliva and serum from the same individuals and deep sequencing analyses can provide unique combined mRNA and miRNA signatures associated with canonical pathways that may have a diagnostic advantage relative to saliva or serum alone and may be useful for clinical testing. We believe this data will contribute to effective preventive care by post-treatment monitoring of patients, as well as suggesting potential targets for therapeutic approaches.

Identifying Opportunities to Deliver High-Quality Cancer Care Across a Health System: A Clinical Responsibility.

OBJECTIVE: We examined process-related quality metrics for oral squamous cell carcinoma (OSCC) depending on treating facility type across a health system and region. STUDY DESIGN: Retrospective in accordance with Strengthening the Reporting of Observational Studies in Epidemiology guidelines. SETTING: Single health system and region. METHODS: Patients with OSCC diagnosed between 2012 and 2018 were identified from tumor registries of 6 hospitals (1 academic and 5 community) within a single health system. Patients were categorized into 3 care groups: (1) solely at the academic center, (2) solely at community facilities, and (3) combined care at academic and community facilities. Primary outcome measures were process-related quality metrics: positive surgical margin rate, lymph node yield (LNY), adjuvant treatment initiation ≤6 weeks, National Comprehensive Cancer Network (NCCN)-guideline adherence. RESULTS: A total of 499 patients were included: 307 (61.5%) patients in the academic-only group, 101 (20.2%) in the community-only group, and 91 (18.2%) in the combined group. Surgery at community hospitals was associated with increased odds of positive surgical margins (11.9% vs 2.5%, odds ratio [OR]: 47.73, 95% confidence interval [CI]: 11.2-275.86, P < .001) and lower odds of LNY ≥ 18 (52.8% vs 85.9%, OR: 0.15, 95% CI: 0.07-0.33, P < .001) relative to the academic center. Compared with the academic-only group, odds of adjuvant treatment initiation ≤6 weeks were lower for the combined group (OR: 0.30, 95% CI: 0.13-0.64, P = .002) and odds of NCCN guideline-adherent treatment were lower in the community only group (OR: 0.35, 95% CI: 0.18-0.70, P = .003). CONCLUSION: Quality of oral cancer care across the health system and region is comparable to or better-than national standards, indicating good baseline quality of care. Differences by facility type and fragmentation of care present an opportunity for bringing best in-class cancer care across an entire region.

Association of Medical School Gap Year Research and Degree Programs With Otolaryngology Interview and Match Outcomes.

OBJECTIVE: To investigate whether a gap year for either research or a master's degree is associated with interview offers or match outcomes among otolaryngology applicants. METHODS: Using the Texas Seeking Transparency in Application to Residency (Texas STAR) database, we conducted a cross-sectional analysis of otolaryngology applicants from 2018 to 2022. Applicants were stratified based on the presence and type of gap year during medical school. Applicant characteristics, signaling, research productivity, and application costs were analyzed, with primary outcomes including number of interview offers and match status. RESULTS: Among 564 otolaryngology applicant respondents to the Texas STAR survey, 160 (28%) reported a gap year, including 64 (40%) applicants participating in a research year, 65 (41%) completing a Master of Public Health or Science (MPH and MSc), and 31 (19%) completing a Master of Business Administration, Education, or other degree (MBA and MEd). Gap-year applicants who completed a research year or MPH/MSc degree received more interview offers (P < .01) than MBA, MEd applicants, or those without a gap year. Applicants with a research year had the most publications, oral presentations, abstracts, posters, and research experiences (all P < .01). When controlling for USMLE scores, clerkship honors, and applications submitted, applicants completing a research year or an MPH/MSc-degree received increased interview offers (P < .01). No significant differences were seen in expenditures or match rates. CONCLUSIONS: Research and MPH/MSc gap years were associated with increased residency interview offers but not increased match success. Further longitudinal studies are needed to assess how yearlong experiences affect long-term career outcomes.

Impact of 18F-FDG PET Intensity Normalization on Radiomic Features of Oropharyngeal Squamous Cell Carcinomas and Machine Learning-Generated Biomarkers.

We aimed to investigate the effects of 18F-FDG PET voxel intensity normalization on radiomic features of oropharyngeal squamous cell carcinoma (OPSCC) and machine learning-generated radiomic biomarkers. Methods: We extracted 1,037 18F-FDG PET radiomic features quantifying the shape, intensity, and texture of 430 OPSCC primary tumors. The reproducibility of individual features across 3 intensity-normalized images (body-weight SUV, reference tissue activity ratio to lentiform nucleus of brain and cerebellum) and the raw PET data was assessed using an intraclass correlation coefficient (ICC). We investigated the effects of intensity normalization on the features' utility in predicting the human papillomavirus (HPV) status of OPSCCs in univariate logistic regression, receiver-operating-characteristic analysis, and extreme-gradient-boosting (XGBoost) machine-learning classifiers. Results: Of 1,037 features, a high (ICC ≥ 0.90), medium (0.90 > ICC ≥ 0.75), and low (ICC < 0.75) degree of reproducibility across normalization methods was attained in 356 (34.3%), 608 (58.6%), and 73 (7%) features, respectively. In univariate analysis, features from the PET normalized to the lentiform nucleus had the strongest association with HPV status, with 865 of 1,037 (83.4%) significant features after multiple testing corrections and a median area under the receiver-operating-characteristic curve (AUC) of 0.65 (interquartile range, 0.62-0.68). Similar tendencies were observed in XGBoost models, with the lentiform nucleus-normalized model achieving the numerically highest average AUC of 0.72 (SD, 0.07) in the cross validation within the training cohort. The model generalized well to the validation cohorts, attaining an AUC of 0.73 (95% CI, 0.60-0.85) in independent validation and 0.76 (95% CI, 0.58-0.95) in external validation. The AUCs of the XGBoost models were not significantly different. Conclusion: Only one third of the features demonstrated a high degree of reproducibility across intensity-normalization techniques, making uniform normalization a prerequisite for interindividual comparability of radiomic markers. The choice of normalization technique may affect the radiomic features' predictive value with respect to HPV. Our results show trends that normalization to the lentiform nucleus may improve model performance, although more evidence is needed to draw a firm conclusion.

Promoting safe swallowing when puree is swallowed without aspiration but thin liquid is aspirated: nectar is enough.

The use of thickened liquids is a common compensatory strategy to improve swallow safety. The purpose of this study was to determine the optimal liquid viscosity to use to promote successful swallowing in a specific subset of dysphagic patients who swallow puree without aspiration but thin liquid with aspiration. A referral-based sample of 84 consecutive inpatients from a large, urban, tertiary-care teaching hospital who met the study criteria was analyzed prospectively. Inclusion criteria were no preexisting dysphagia, a successful pharyngeal swallow without aspiration with puree consistency but pharyngeal dysphagia with aspiration of thin liquid consistency, and stable medical, surgical, and neurological status at the time of transnasal fiberoptic swallow testing and up to 24 h after recommendations for oral alimentation with a modified diet consisting of nectar-like and honey-like thickened liquids. Success with ingesting both nectar-like and honey-like thickened liquids and clinically evident aspiration events were recorded. Care providers were blinded to the study's purpose. All 84 patients were successfully ingesting nectar-like and honey-like thickened liquids at the time of swallow testing and up to 24 h after testing. A specific subset of dysphagic patients who swallowed puree without aspiration but aspirated thin liquid demonstrated 100 % successful swallowing of both nectar-like and honey-like thickened liquids. Therefore, a nectar-like thickened liquid appears to be adequate to promote safe swallowing in these patients and, because of patient preference for the least thick liquid, may enhance compliance and potentially contribute to maintenance of adequate hydration requirements.

The Role of PARP-1 and NF-κB in Bile-Induced DNA Damage and Oncogenic Profile in Hypopharyngeal Cells.

OBJECTIVES/HYPOTHESIS: We recently documented that acidic bile, a gastroesophageal reflux content, can cause invasive hypopharyngeal squamous cell carcinoma, by inducing widespread DNA damage and promoting nuclear factor kappa B (NF-κB)-related oncogenic molecular events. Poly or adenosine diphosphate (ADP)-ribose polymerase-1 (PARP-1), a sensitive sensor of DNA damage, may interact with NF-κB. We hypothesized that PARP-1 is activated in hypopharyngeal cells (HCs) with marked DNA damage caused by acidic bile, hence there is an association between PARP-1 and NF-κB activation or its related oncogenic profile, in this process. STUDY DESIGN: In vitro study. METHODS: We targeted PARP-1 and NF-κB(p65), using pharmacologic inhibitors, 1.0 µM Rucaparib (AG014699) and 10 µM BAY 11-7082 {3-[4=methylphenyl)sulfonyl]-(2E)-propenenitrile}, respectively, or silencing their gene expression (siRNAs) and used immunofluorescence, luciferase, cell viability, direct enzyme-linked immunosorbent assays, and qPCR analysis to detect the effect of targeting PARP-1 or NF-κB in acidic bile-induced DNA damage, PARP-1, p-NF-κB, and B-cell lymphoma 2 (Bcl-2) expression, as well as NF-κB transcriptional activity, cell survival, and mRNA oncogenic phenotype in HCs. RESULTS: We showed that (i) PARP-1 is overexpressed by acidic bile, (ii) targeting NF-κB adequately prevents the acidic bile-induced DNA double-strand breaks (DSBs) by gamma H2A histone family member X (γH2AX), oxidative DNA/RNA damage, PARP-1 overexpression, anti-apoptotic mRNA phenotype, and cell survival, whereas (iii) targeting PARP-1 preserves elevated DNA damage, NF-κB activation, and anti-apoptotic phenotype. CONCLUSION: We document for the first time that the activation of PARP-1 is an early event during bile reflux-related head and neck carcinogenesis and that NF-κB can mediate DNA damage and PARP-1 activation. Our data encourage further investigation into how acidic bile-induced activated NF-κB mediates DNA damage in hypopharyngeal carcinogenesis. LEVEL OF EVIDENCE: NA Laryngoscope, 133:1146-1155, 2023.

Prognostic value of absolute lymphocyte count in oral cavity squamous cell carcinoma.

Objectives: Absolute lymphocyte count (ALC) has been shown to be a prognostic indicator in other solid tumors. Given this, we aimed to evaluate the prognostic value of ALC in oral cavity squamous cell carcinoma (OSCC). Methods: Using our institutional tumor registry data, we identified patients ≥18 years old who were diagnosed with OSCC between 2012 and 2018. Preoperative ALC values within 30 days of surgery were collected through retrospective chart review. American Joint Committee on Cancer, 7th-edition best stage was used to categorize cancers as early stage (stages 1 and 2) or late-stage (stages 3 and 4). Primary outcomes were likelihood of recurrence and survival rates after 3 years. Results: Of the 412 patients identified, 262 patients had available ALC data and met inclusion criteria. Early stage cancer patients who had lymphopenia did not have any significant difference in their rate of death ([OR], 1.71, CI: 0.54-5.45, p = .36) or likelihood recurrence ([OR], 0.60, CI: 0.06-5.87, p = .66) after controlling for age, tobacco use, alcohol use, positive margins, and adjuvant therapy. Late-stage cancer patients who had lymphopenia also showed no difference in their rate of death ([OR], 2.74, CI: 0.65-11.6, p = .17) or likelihood of recurrence ([OR], 0.38, CI: 0.04-3.36, p = .38). Conclusions and Relevance: This study evaluates the prognostic value of ALC in oral cavity cancers. Our findings demonstrate that pretreatment ALC is not significantly associated with recurrence and survival outcomes patients with OSCC. Level of Evidence: III. Lay Summary: Absolute lymphocyte count (ALC) has been associated with prognosis in several cancers. We found that preoperative ALC was not associated with likelihood of survival or recurrence in patients with early stage or late-stage oral cavity cancer.

Association of Age and Frailty With 30-Day Outcomes Among Patients Undergoing Oral Cavity Cancer Surgery.

OBJECTIVE: To evaluate the impact of age and frailty on 30-day outcomes following surgery for oral squamous cavity carcinoma (OSCC). STUDY DESIGN: Retrospective cross-sectional analysis. SETTING: American College of Surgeons' National Quality Improvement Program (NSQIP) database. METHODS: Patients who underwent OSCC resection were queried via NSQIP (2015-2020). Cases were stratified by age (18-65, 65-75, and older than 75) as well as by modified frailty index scores (mFI 0, mFI 1, and mFI 2+) for comparative analyses. Univariate and multivariable analyses were conducted to examine demographics, perioperative outcomes, and 30-day postoperative adverse events. RESULTS: A total of 3238 patients who underwent OSCC surgery were identified and categorized as nongeriatric ("NGA," age 18-65), younger geriatric ("YGA," age 65-75), and older geriatric ("OGA," age >75) adults. Compared to NGA, geriatric patients had higher the American Society of Anesthesiologists classification, higher modified frailty index scores, and more comorbidities such as hypertension, congestive heart failure, chronic obstructive disease, and diabetes (p < .001). YGAs and OGAs were also less likely to undergo neck dissection (p < .001), composite resection (p = .006), and free flap reconstruction compared to NGAs (p < .001). When controlling for confounders, age was not independently associated with an increased risk of poor outcomes. On the other hand, frailty was found to be independently associated with a higher risk of adverse events (odds ratio: 1.40 [1.15-1.70], p < .001 for mFI 1, odds ratio: 1.45 [1.04-2.02], p = .027 for mFI 2+). CONCLUSION: A higher mFI score, not older age, is associated with an increased risk of 30-day complications following OSCC surgery.

A Novel Saliva and Serum miRNA Panel as a Potential Useful Index for Oral Cancer and the Association of miR-21 with Smoking History: a Pilot Study.

Tobacco use is implicated in the carcinogenesis of oral squamous cell carcinoma (OSCC), which is associated with poor survival if not diagnosed early. Identification of novel noninvasive, highly sensitive, and cost-effective diagnostic and risk assessment methods for OSCC would improve early detection. Here, we report a pilot study assessing salivary and serum miRNAs associated with OSCC and stratified by smoking status. Saliva and paired serum samples were collected from 23 patients with OSCC and 21 healthy volunteers, with an equal number of smokers and nonsmokers in each group. Twenty head and neck cancer-related miRNAs were quantified by qPCR (dual-labeled LNA probes) and analyzed by Welch t test (95% confidence interval). Four saliva miRNAs, miR-21, miR-136, miR-3928, and miR-29B, showed statistically significant overexpression in OSCC versus healthy controls (P < 0.05). miR-21 was statistically significantly overexpressed in OSCC smokers versus nonsmokers (P = 0.006). Salivary miR-21, miR-136, and miR-3928, and serum miR-21 and miR-136, showed statistically significant differential expression in early-stage tumors versus controls (P < 0.05), particularly miR-21 in smokers (P < 0.005). This pilot study provides a novel panel of saliva and serum miRNAs associated with oral cancer. Further validation as a potential useful index of oral cancer, particularly miR-21 in smokers and early-stage OSCC is warranted. PREVENTION RELEVANCE: Saliva and serum miR-21, miR-136, miR-3928, and miR-29B, are potentially associated with oral cancer even at an early stage, especially miR-21 in individuals with a smoking history, a further validation in a larger cohort of subjects with premalignant and early malignant lesions need to confirm.