Polygenic risk score-based phenome-wide association study of head and neck cancer across two large biobanks.

BACKGROUND: Numerous observational studies have highlighted associations of genetic predisposition of head and neck squamous cell carcinoma (HNSCC) with diverse risk factors, but these findings are constrained by design limitations of observational studies. In this study, we utilized a phenome-wide association study (PheWAS) approach, incorporating a polygenic risk score (PRS) derived from a wide array of genomic variants, to systematically investigate phenotypes associated with genetic predisposition to HNSCC. Furthermore, we validated our findings across heterogeneous cohorts, enhancing the robustness and generalizability of our results. METHODS: We derived PRSs for HNSCC and its subgroups, oropharyngeal cancer and oral cancer, using large-scale genome-wide association study summary statistics from the Genetic Associations and Mechanisms in Oncology Network. We conducted a comprehensive investigation, leveraging genotyping data and electronic health records from 308,492 individuals in the UK Biobank and 38,401 individuals in the Penn Medicine Biobank (PMBB), and subsequently performed PheWAS to elucidate the associations between PRS and a wide spectrum of phenotypes. RESULTS: We revealed the HNSCC PRS showed significant association with phenotypes related to tobacco use disorder (OR, 1.06; 95% CI, 1.05-1.08; P = 3.50 × 10-15), alcoholism (OR, 1.06; 95% CI, 1.04-1.09; P = 6.14 × 10-9), alcohol-related disorders (OR, 1.08; 95% CI, 1.05-1.11; P = 1.09 × 10-8), emphysema (OR, 1.11; 95% CI, 1.06-1.16; P = 5.48 × 10-6), chronic airway obstruction (OR, 1.05; 95% CI, 1.03-1.07; P = 2.64 × 10-5), and cancer of bronchus (OR, 1.08; 95% CI, 1.04-1.13; P = 4.68 × 10-5). These findings were replicated in the PMBB cohort, and sensitivity analyses, including the exclusion of HNSCC cases and the major histocompatibility complex locus, confirmed the robustness of these associations. Additionally, we identified significant associations between HNSCC PRS and lifestyle factors related to smoking and alcohol consumption. CONCLUSIONS: The study demonstrated the potential of PRS-based PheWAS in revealing associations between genetic risk factors for HNSCC and various phenotypic traits. The findings emphasized the importance of considering genetic susceptibility in understanding HNSCC and highlighted shared genetic bases between HNSCC and other health conditions and lifestyles.

Utilizing the AJCC 8th Staging to Discriminate Survival Outcomes in HPV-associated Oropharyngeal Squamous Cell Carcinoma.

BACKGROUND/AIM: The American Joint Committee on Cancer (AJCC) staging 8th edition introduced major changes in the TNM staging of oropharyngeal squamous cell carcinoma (OPSCC) based on the human papillomavirus (HPV) status. This study aimed to observe how well the AJCC staging 8th edition precisely discriminates survival outcomes in patients with HPV-associated OPSCC using a large population database. MATERIALS AND METHODS: Using the Surveillance, Epidemiology, and End Results database between 2010 and 2016, 7,448 patients with HPV-associated OPSCC were enrolled. Patients diagnosed with OPSCC and tested positive for HPV with information on the TNM staging according to the AJCC staging 7th edition were selected. Next, T-, N-, and clinical staging were reconstructed based on the AJCC staging 8th edition. Survival probabilities in both AJCC staging 7th and 8th editions were estimated and compared. RESULTS: Most patients (93.44%) were down-staged from the 7th to the 8th edition. The AJCC staging 8th edition showed more discriminatory power in predicting survival of patients with HPV-associated OPSCC than the AJCC staging 7th edition, regardless of the primary subsites. Additionally, clinical stage I patients with HPV-associated OPSCC according to the AJCC 8th edition showed better prognosis in case of high T staging than high N staging. Clinical staging according to the AJCC 8th edition compared to that of the 7th edition was an independent prognostic factor in patients with HPV-associated OPSCC. CONCLUSION: This study emphasizes the advantages of the new classification system for discriminating survival in HPV-associated OPSCC according to various factors.

Determination of pepsin in human saliva using pepsin-susceptible peptide reporter and colorimetric dipstick assay: a prospective, cross-sectional study.

A simple and effective pepsin detection assay is reported based on a pepsin-susceptible peptide (PSP) reporter degradation strategy. PSP, which can be specifically cleaved by pepsin, was modified with fluorescein isothiocyanate (FITC) and biotin at the N- and C-terminals to be used as a reporter for colorimetric detection of dipsticks. A universal lateral flow dipstick consisting of a streptavidin test line for biotin binding and a sample pad immobilized with a gold-labeled polyclonal (rabbit) anti-FITC antibody was used to verify PSP-based pepsin detection. When the PSP reporter reacts with pepsin in a tube, it cleaves into two fragments, and the cleaved fragments do not display any color on the test line. Therefore, the higher the concentration of pepsin is, the greater is the decrease in test line intensity (IT-line) and the higher is the control line intensity (IC-line). First, the PSP cleavage and dipstick assay conditions for pepsin detection was optimized. The ratio of color intensity (IT-line/IC-line) of PSP-based dipstick assay showed a linear relationship with log concentration of pepsin ranging between 4 and 500 ng/mL (R2 = 0.98, n = 6), with a limit of detection of 1.4 ng/mL. It also exhibited high specificity and good reproducibility. Finally, pepsin levels were quantified in saliva samples from healthy controls (n = 34) and patients with laryngopharyngeal reflux (LPR, n = 61). Salivary pepsin levels were higher in patients with LPR than in healthy controls. The salivary pepsin levels correlated with those measured using a conventional enzyme-linked immunosorbent assay kit. Therefore, this PSP-based dipstick assay is a convenient tool for assessing salivary pepsin levels.

Cell Death Induced by the Combination of Ephedra sinica Extract and Radiation in HNSCC is Positively Related to BAX and p-MLKL Expression.

BACKGROUND: Numerous studies have proven the efficacy and safety of natural products, and are widely used as attractive cancer treatments. The investigation of effective natural products for improving cancer treatment is a promising strategy. Combination treatment with radiosensitizers and radiotherapy (RT) is considered necessary for therapeutic improvement in head and neck squamous cell carcinoma(HNSCC). OBJECTIVE: This study aims to investigate whether Ephedra sinica (ES) extract could induce selective cell death in cancer cells and serve as a radiosensitizer for HNSCC. METHODS: HNSCC cells were pretreated with ES extract before radiation, and the radiosensitizing activity was assessed using a colony formation assay. Radiation-induced cell death was evaluated using an annexinV-FITC assay. Western blotting was performed to confirm cell death-related gene expression, including apoptosis and necrosis markers. RESULTS: ES extract significantly inhibited HNSCC cell viability (FaDu and SNU1076), while having minimal effect on normal HaCaT cells. When HNSCC cells were irradiated with 2, 4, or 8 Gy and cultured with ES extract (25 µg/mL), they exhibited increased radiation sensitivity compared to non-treated cells. The combination of ES extract and radiation resulted in increased cell death compared to non-treated, ES-treated, or irradiated cells. The apoptosis marker BAX and necrosis marker p-MLKL expression levels were also elevated following the combination treatment. CONCLUSION: ES extract demonstrated significant cytotoxic potential in HNSCC cells without affecting normal cells. It enhanced the radiosensitivity of HNSCC cells by upregulating BAX and p-MLKL expression, leading to increased cell death. These results suggest ES extract exhibits a potential radiosensitizing capacity in HNSCC.

The Dubai Definition and Diagnostic Criteria of Laryngopharyngeal Reflux: The IFOS Consensus.

OBJECTIVE: The objective of this work was to gather an international consensus group to propose a global definition and diagnostic approach of laryngopharyngeal reflux (LPR) to guide primary care and specialist physicians in the management of LPR. METHODS: Forty-eight international experts (otolaryngologists, gastroenterologists, surgeons, and physiologists) were included in a modified Delphi process to revise 48 statements about definition, clinical presentation, and diagnostic approaches to LPR. Three voting rounds determined a consensus statement to be acceptable when 80% of experts agreed with a rating of at least 8/10. Votes were anonymous and the analyses of voting rounds were performed by an independent statistician. RESULTS: After the third round, 79.2% of statements (N = 38/48) were approved. LPR was defined as a disease of the upper aerodigestive tract resulting from the direct and/or indirect effects of gastroduodenal content reflux, inducing morphological and/or neurological changes in the upper aerodigestive tract. LPR is associated with recognized non-specific laryngeal and extra-laryngeal symptoms and signs that can be evaluated with validated patient-reported outcome questionnaires and clinical instruments. The hypopharyngeal-esophageal multichannel intraluminal impedance-pH testing can suggest the diagnosis of LPR when there is >1 acid, weakly acid or nonacid hypopharyngeal reflux event in 24 h. CONCLUSION: A global consensus definition for LPR is presented to improve detection and diagnosis of the disease for otolaryngologists, pulmonologists, gastroenterologists, surgeons, and primary care practitioners. The approved statements are offered to improve collaborative research by adopting common and validated diagnostic approaches to LPR. LEVEL OF EVIDENCE: 5 Laryngoscope, 134:1614-1624, 2024.

Prognostic significance of senescence-related tumor microenvironment genes in head and neck squamous cell carcinoma.

The impact of the senescence related microenvironment on cancer prognosis and therapeutic response remains poorly understood. In this study, we investigated the prognostic significance of senescence related tumor microenvironment genes (PSTGs) and their potential implications for immunotherapy response. Using the Cancer Genome Atlas- head and neck squamous cell carcinoma (HNSC) data, we identified two subtypes based on the expression of PSTGs, acquired from tumor-associated senescence genes, tumor microenvironment (TME)-related genes, and immune-related genes, using consensus clustering. Using the LASSO, we constructed a risk model consisting of senescence related TME core genes (STCGs). The two subtypes exhibited significant differences in prognosis, genetic alterations, methylation patterns, and enriched pathways, and immune infiltration. Our risk model stratified patients into high-risk and low-risk groups and validated in independent cohorts. The high-risk group showed poorer prognosis and immune inactivation, suggesting reduced responsiveness to immunotherapy. Additionally, we observed a significant enrichment of STCGs in stromal cells using single-cell RNA transcriptome data. Our findings highlight the importance of the senescence related TME in HNSC prognosis and response to immunotherapy. This study contributes to a deeper understanding of the complex interplay between senescence and the TME, with potential implications for precision medicine and personalized treatment approaches in HNSC.

Effect of statin use on head and neck cancer prognosis in a multicenter study using a Common Data Model.

Few studies have found an association between statin use and head and neck cancer (HNC) outcomes. We examined the effect of statin use on HNC recurrence using the converted Observational Medical Outcome Partnership (OMOP) Common Data Model (CDM) in seven hospitals between 1986 and 2022. Among the 9,473,551 eligible patients, we identified 4669 patients with HNC, of whom 398 were included in the target cohort, and 4271 were included in the control cohort after propensity score matching. A Cox proportional regression model was used. Of the 4669 patients included, 398 (8.52%) previously received statin prescriptions. Statin use was associated with a reduced rate of 3- and 5-year HNC recurrence compared to propensity score-matched controls (risk ratio [RR], 0.79; 95% confidence interval [CI], 0.61-1.03; and RR 0.89; 95% CI 0.70-1.12, respectively). Nevertheless, the association between statin use and HNC recurrence was not statistically significant. A meta-analysis of recurrence based on subgroups, including age subgroups, showed similar trends. The results of this propensity-matched cohort study may not provide a statistically significant association between statin use and a lower risk of HNC recurrence. Further retrospective studies using nationwide claims data and prospective studies are warranted.

Somatic anxiety in patients with laryngopharyngeal reflux.

Objective: This study aimed to evaluate the relationship between laryngopharyngeal reflux (LPR) and anxiety in patients with LPR. Design: Prospective, case-control study. Setting: This study was conducted at a tertiary care center. Participants: Sixty-four patients with LPR and 60 healthy controls. Methods: Patients with LPR and healthy individuals (N = 64 and N = 60) were enrolled in this study. The Beck Anxiety Inventory (BAI) and reflux symptom index (RSI) were used to evaluate anxiety and reflux-related symptoms, respectively. The BAI can be classified into somatic and subjective symptom scales. The prevalence of anxiety was compared between patients with LPR and healthy individuals. This study evaluated the relationship between BAI and RSI scores. Results: No statistical difference was found in the prevalence of anxiety between patients with LPR and healthy individuals (42.2% vs. 33.3%). However, the somatic anxiety symptom score was statistically higher in patients with LPR than in healthy individuals (p = .047). We observed a correlation between RSI and somatic anxiety scores of BAI in patients with LPR (rho = 0.286, p = .021). Conclusion: Patients with LPR had more severe somatic anxiety symptoms, and somatic anxiety was associated with their LPR-related symptoms.

Association between Metabolic Syndrome and Risk of Hypopharyngeal Cancer: A Nationwide Cohort Study from Korea.

This study evaluated the relationship between metabolic syndrome (MS) and the risk of hypopharyngeal cancer. This retrospective cohort study used data from the Korean National Health Insurance Research Database. A total of 4,567,890 participants who underwent a health checkup in 2008 were enrolled. The participants were followed until 2019, and the incidence of hypopharyngeal cancer was analyzed. We evaluated the risk of hypopharyngeal cancer according to the presence of MS, including obesity, dyslipidemia, hypertension, and diabetes, using a multivariate Cox proportional hazards model adjusted for age, sex, alcohol consumption, and smoking. During the follow-up period, 821 were newly diagnosed with hypopharyngeal cancer. MS was inversely associated with the risk of hypopharyngeal cancer (hazard ratio (HR), 0.83 [95% confidence interval (CI), 0.708-0.971]). Large waist circumference and high triglyceride levels among MS elements were both inversely related to the risk of hypopharyngeal cancer (HR: 0.82 [95% CI, 0.711-0.945] and 0.83 [95% CI, 0.703-0.978], respectively). The risk of hypopharyngeal cancer decreased with increasing comorbidity of MS in women (N = 0 vs. N = 1-2 vs. N ≥ 3; HR = 1 vs. HR = 0.511 [95% CI, 0.274-0.952] vs. HR = 0.295 [95% CI, 0.132-0.66]), but not in men. This study may improve our etiological understanding of hypopharyngeal cancer.

Clinically conserved genomic subtypes of gastric adenocarcinoma.

Gastric adenocarcinoma (GAC) is a lethal disease characterized by genomic and clinical heterogeneity. By integrating 8 previously established genomic signatures for GAC subtypes, we identified 6 clinically and molecularly distinct genomic consensus subtypes (CGSs). CGS1 have the poorest prognosis, very high stem cell characteristics, and high IGF1 expression, but low genomic alterations. CGS2 is enriched with canonical epithelial gene expression. CGS3 and CGS4 have high copy number alterations and low immune reactivity. However, CGS3 and CGS4 differ in that CGS3 has high HER2 activation, while CGS4 has high SALL4 and KRAS activation. CGS5 has the high mutation burden and moderately high immune reactivity that are characteristic of microsatellite instable tumors. Most CGS6 tumors are positive for Epstein Barr virus and show extremely high levels of methylation and high immune reactivity. In a systematic analysis of genomic and proteomic data, we estimated the potential response rate of each consensus subtype to standard and experimental treatments such as radiation therapy, targeted therapy, and immunotherapy. Interestingly, CGS3 was significantly associated with a benefit from chemoradiation therapy owing to its high basal level of ferroptosis. In addition, we also identified potential therapeutic targets for each consensus subtype. Thus, the consensus subtypes produced a robust classification and provide for additional characterizations for subtype-based customized interventions.

Acute, Recurrent, and Chronic Laryngopharyngeal Reflux: The IFOS Classification.

OBJECTIVE: To investigate the clinical patterns and disease evolution of laryngopharyngeal reflux (LPR) patients. METHODS: Patients with LPR diagnosed by hypopharyngeal-esophageal impedance-pH monitoring were prospectively followed in three medical centers. Symptoms and findings were assessed with reflux symptom score (RSS) and reflux sign assessment (RSA). Patients were treated with 3-to 9-month diet and combination of proton pump inhibitors, alginate or magaldrate. Patients were followed for 3 years to determine the clinical evolution of symptoms over time. LPR that did not recur was defined as acute. Recurrent LPR consisted of reflux with one or several recurrences yearly despite successful treatment. Chronic LPR was reflux with a chronic course of symptoms. Predictive indicators of clinical evolution were investigated. RESULTS: One hundred forty patients and 82 healthy individuals completed the evaluations. Among patients, 41 (29.3%), 57 (40.7%), and 42 (30.0%) had acute, recurrent, or chronic LPR respectively. Baseline quality of life-RSS (QoL-RSS) and RSS total scores were significantly higher in chronic LPR patients. The post-treatment decrease of QoL-RSS and RSS of acute LPR patients were significantly faster as compared to recurrent and chronic patients. QoL-RSS >5 reported adequate sensitivity (94.2) and specificity (75.3). QoL-RSS thresholds defined acute (QoL-RSS = 6-25), recurrent (QoL-RSS = 26-38), and chronic (QoL-RSS > 38) LPR. CONCLUSION: Baseline QoL-RSS may predict the clinical course of LPR patients: acute, recurrent, or chronic. A novel classification system that groups patients according to the longevity, severity, and therapeutic response of symptoms was proposed: the International Federation of Otorhinolaryngological Societies Classification of LPR. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:1073-1080, 2023.

Gene signature predicting recurrence in oral squamous cell carcinoma is characterized by increased oxidative phosphorylation.

Although numerous studies have used systemic approaches to identify prognostic predictors in oral squamous cell carcinoma (OSCC), the effectiveness of these approaches has not been assessed clinically. Further, the mechanism underlying malignant behaviors in OSCC is poorly characterized. This study aimed to develop and verify accurate prognostic predictors for OSCC patients and assess the associated biology. We identified an OSCC-recurrence-related gene signature (ORGS) using a Cox regression analysis. Functional enrichment analysis was used to identify enriched pathways and biological processes to reveal the underlying mechanism of OSCC malignant behavior. The ORGS successfully divided OSCC patients into low- and high-risk groups with significantly different overall survivals. Pathway analysis revealed oxidative phosphorylation (OXPHOS) as a signaling pathway associated with the ORGS in OSCC. Interestingly, high OXPHOS status was strongly associated with poor overall survival in OSCC patients. Mediator complex subunit 30 (MED30) was a predicted upstream regulator of OXPHOS, and knockdown of MED30 reduced histone acetylation. We identified that the ORGS was strongly correlated with OXPHOS regulatory processes, suggesting OXPHOS as a key mechanism leading to poor prognosis in OSCC.

The key timing of pharyngeal reflux in patients with laryngopharyngeal reflux.

OBJECTIVE: To analyze the incidence of pharyngeal reflux in laryngopharyngeal reflux patients over a 24-hour period and find out the key timing of pharyngeal reflux. METHODS: We reviewed 69 patients who visited our clinic with LPR-related symptoms and were proven to have pharyngeal reflux via 24-hour multichannel intraluminal impedance-pH (24hr MII-pH) monitoring. Quantitative analysis was conducted for the LPR profiles, such as the acidity of reflux, nighttime reflux, and positional reflux. The time series of pharyngeal reflux episodes and mealtimes were analyzed over a 24-hour period. Also, we recruited 26 normal controls. We compared the timing of pharyngeal reflux between LPR patients and asymptomatic controls. RESULTS: The quantitative analysis revealed that pharyngeal reflux occurred 4.88 ± 4.59 times over 24 hours. Weakly acidic pharyngeal reflux was more abundant than acidic or weakly alkaline reflux. Pharyngeal reflux occurred mainly during daytime in the upright position. The most frequent timing of pharyngeal reflux episodes was within 2 hours after meals. Additionally, there was no significant difference of the timing of post-prandial reflux between LPR patients and asymptomatic controls. CONCLUSION: The key timing of pharyngeal reflux in patients with LPR was post-prandial 2 hours.

Association between oral cavity cancer and metabolic syndrome.

PURPOSE: Few studies have been conducted on the association between oral cavity cancer and metabolic diseases. This study aimed to investigate the relationship between oral cavity cancer and metabolic diseases. METHODS: This cohort study used the database of the Korean National Health Insurance Service, which contains medical data of 97% of the Korean population. Oral cavity cancer occurred in a total of 2718 patients. Metabolic syndrome was defined according to IDF criteria. The Cox proportional hazard regression model was used. RESULTS: The HR for oral cavity cancer in patients with metabolic syndrome was 1.113(95% CI 1.006-1.232), which was significantly higher than that in normal patients, especially in males (p = 0.0386). When the number of metabolic syndrome factors was ≥ 3, the HR of oral cavity cancer was 1.191(95% CI 1.026-1.383), which was significantly higher than that of 0 metabolic syndrome factors, especially in males (p = 0.0218). When the number of metabolic syndrome factors was ≥ 3, the HR for oral cavity cancer was 1.439(95% CI 1.066-1.942), which was significantly higher than that of 0 metabolic syndrome factors, especially in males aged < 50 years (p = 0.0173). CONCLUSION: Metabolic syndrome increases the risk of oral cavity cancer only in males. In addition, the incidence of oral cavity cancer increased as the number of factors constituting metabolic syndrome increased, only in young males aged < 50 years. Thus, metabolic syndrome is an important risk factor for oral cavity cancer, particularly in young males.

Association between cancer stem cell gene expression signatures and prognosis in head and neck squamous cell carcinoma.

BACKGROUND: Various cancer stem cell (CSC) biomarkers and the genes encoding them in head and neck squamous cell carcinoma (HNSCC) have been identified and evaluated. However, the validity of these factors in the prognosis of HNSCC has been questioned and remains unclear. In this study, we examined the clinical significance of CSC biomarker genes in HNSCC, using five publicly available HNSCC cohorts. METHODS: To predict the prognosis of patients with HNSCC, we developed and validated the expression signatures of CSC biomarker genes whose mRNA expression levels correlated with at least one of the four CSC genes (CD44, MET, ALDH1A1, and BMI1). RESULTS: Patients in The Cancer Genome Atlas (TCGA) HNSCC cohort were classified into CSC gene expression-associated high-risk (CSC-HR; n = 285) and CSC gene expression-associated low-risk (CSC-LR; n = 281) subgroups. The 5-year overall survival and recurrence-free survival rates were significantly lower in the CSC-HR subgroup than in the CSC-LR subgroup (p = 0.04 and 0.02, respectively). The clinical significance of the CSC gene expression signature was validated using four independent cohorts. Analysis using Cox proportional hazards models showed that the CSC gene expression signature was an independent prognostic factor of non-oropharyngeal HNSCC which mostly indicates HPV (-) status. Furthermore, the CSC gene expression signature was associated with the prognosis of HNSCC patients who received radiotherapy. CONCLUSION: The CSC gene expression signature is associated with the prognosis of HNSCC and may help in personalized treatments for patients with HNSCC, especially in cases with HPV (-) status who were classified in more detail.

Differences in Diagnostic Rates After Hypopharyngeal-esophageal Impedance-pH Monitoring of Laryngopharyngeal Reflux Patients by Age and Sex.

PURPOSE: To evaluate the differences in diagnostic rates according to the age and sex of patients with suspected laryngopharyngeal reflux (LPR) symptoms and completed the 24-hour hypopharyngeal-esophageal multichannel intraluminal impedance-pH (24h-HEMII-pH) monitoring. METHODS: Patients with LPR symptoms underwent the 24h-HEMII-pH monitoring. We compared the diagnostic rates of LPR in patients with LPR symptoms according to age and sex. The number of reflux episodes and type of reflux were compared among patients who were confirmed to have LPR according to age and sex. RESULTS: A total of 249 patients with suspected LPR symptoms who completed 24h-HEMII-pH monitoring were analyzed. A total of 170 patients (68.3%) were diagnosed with LPR after 24h-HEMII-pH monitoring. There were 57 (67.1%) men and 113 (68.9%) women. The old age group (older than 55 years) showed a statistically significant higher diagnostic rate than the young age group (73.5%, 60.8%, p=0.034). Women's diagnostic rate was statistically higher in the old age group than that in the young age group (75% vs. 58.3%, p=0.026). There were no specific differences in the number of refluxes in the diagnosed patients between the age groups, and there were no differences in the initial reflux symptom index. CONCLUSIONS: Among those who visited the clinic with suspected LPR symptoms and performed 24h-HEMII-pH monitoring, the diagnostic rate of LPR was higher in the older age group than that in the younger age group.

Prediction of survival in oropharyngeal squamous cell carcinoma using machine learning algorithms: A study based on the surveillance, epidemiology, and end results database.

Background: We determined appropriate survival prediction machine learning models for patients with oropharyngeal squamous cell carcinoma (OPSCC) using the "Surveillance, Epidemiology, and End Results" (SEER) database. Methods: In total, 4039 patients diagnosed with OPSCC between 2004 and 2016 were enrolled in this study. In particular, 13 variables were selected and analyzed: age, sex, tumor grade, tumor size, neck dissection, radiation therapy, cancer directed surgery, chemotherapy, T stage, N stage, M stage, clinical stage, and human papillomavirus (HPV) status. The T-, N-, and clinical staging were reconstructed based on the American Joint Committee on Cancer (AJCC) Staging Manual, 8th Edition. The patients were randomly assigned to a development or test dataset at a 7:3 ratio. The extremely randomized survival tree (EST), conditional survival forest (CSF), and DeepSurv models were used to predict the overall and disease-specific survival in patients with OPSCC. A 10-fold cross-validation on a development dataset was used to build the training and internal validation data for all models. We evaluated the predictive performance of each model using test datasets. Results: A higher c-index value and lower integrated Brier score (IBS), root mean square error (RMSE), and mean absolute error (MAE) indicate a better performance from a machine learning model. The C-index was the highest for the DeepSurv model (0.77). The IBS was also the lowest in the DeepSurv model (0.08). However, the RMSE and RAE were the lowest for the CSF model. Conclusions: We demonstrated various machine-learning-based survival prediction models. The CSF model showed a better performance in predicting the survival of patients with OPSCC in terms of the RMSE and RAE. In this context, machine learning models based on personalized survival predictions can be used to stratify various complex risk factors. This could help in designing personalized treatments and predicting prognoses for patients.

Prognostic Significance of the BIRC2-BIRC3 Gene Signature in Head and Neck Squamous Cell Carcinoma.

BACKGROUND/AIM: Head and neck squamous cell carcinoma (HNSCC) has poor prognosis, with survival rates that have not significantly improved over the past several decades. Therefore, prediction of HNSCC prognosis is of clinical importance. Baculoviral IAP Repeat containing 2 (BIRC2) and Baculoviral IAP Repeat containing 3 (BIRC3) are involved in oncogenic activity by modulating cell proliferation, apoptosis and invasion in HNSCC. This study aimed to develop and validate a predictive gene signature for BIRC2 and BIRC3. MATERIALS AND METHODS: The genomic copy number and gene expression for BIRC2 and BIRC3 were systematically explored in patients with HNSCC to investigate the clinical relevance of BIRC2 and BIRC3 activation. A prognostic signature was developed based on correlations associated with BIRC2 and BIRC3 mRNA expression and copy number alterations. Hierarchical clustering was used to classify the clusters (Clusters 1 and 2). Moreover, independent validation of the BIRC2-BIRC3 gene signature was performed using the Leipzig, MDACC, FHCRC, and KHU datasets. To explore the biological functions of the BIRC2-BIRC3 gene signature, string analysis and pathway annotation were also performed. RESULTS: BIRC2-BIRC3 gene signature-derived cluster 2 patients exhibited significantly poor survival. This signature also predicted survival in three independent cohorts. Interestingly, the BIRC2-BIRC3 gene signature additionally permitted the identification of survival in advanced tumor stages with excellent accuracy in all three cohorts. Multivariate Cox regression analysis identified that the BIRC2-BIRC3 signature was an independent predictor associated with the survival of patients with HNSCC. Moreover, Inhibition of BIRC2 modulated the NF-B signaling pathway via upregulation of CBR1 expression. CONCLUSION: The BIRC2-BIRC3 gene signature was found to be associated with the prognosis of HNSCC. Thus, BIRC2 and BIRC3 could be potential targets for improving HNSCC prognosis.

Metabolic Diseases and Risk of Head and Neck Cancer: A Cohort Study Analyzing Nationwide Population-Based Data.

The aim of the study was to investigate the association between metabolic diseases and the risk of head and neck cancer (HNC) using nationwide population-based big data. This retrospective cohort study was conducted using the Korean National Health Insurance Service health checkup database. A total of 4,575,818 participants aged >40 years who received a health checkup in 2008 were enrolled, and we studied the incidence of HNC until 2019. We analyzed the risk of HNC according to the presence of metabolic diseases, such as obesity, dyslipidemia, hypertension, and diabetes. Although metabolic syndrome itself was not associated with HNC, each component of metabolic syndrome was associated with HNC. Underweight and diabetes were risk factors for HNC (HR: 1.694). High total cholesterol and high low-density lipoprotein cholesterol levels were factors that decreased the risk (HR 0.910 and 0.839). When we analyzed men and women separately, low total cholesterol level, low low-density lipoprotein cholesterol level, and hypertension were risk factors only in men. In addition, pre-obesity, obesity, and central obesity decreased the risk only in men. Each metabolic disease affects HNC in different ways. Underweight and diabetes increased the risk of HNC, whereas high total cholesterol and high low-density lipoprotein cholesterol levels decreased the risk of HNC.