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Background To cure advanced hypopharyngeal squamous cell carcinoma (HPSCC), primary operation followed by adjuvant (chemo-)radiotherapy (OP-CRT) or definitive chemoradiation (CCRT) are the two primary options. This study aimed to compare the failure patterns and long-term survival outcomes of HPSCC patients treated with these two strategies. Patients and Methods From 2007 to 2015, 198 pathologically confirmed HPSCC patients receiving either OP-CRT or CCRT were retrospectively reviewed. Failure patterns and survival outcomes stratified by the 7th American Joint Committee on Cancer staging system and treatment modalities were compared. Results One hundred and eighty-nine patients (95.4%) were stage III/IV and 62 patients (31.3%) received OP-CRT. Median follow-up duration was 4.9 years. Compared with CCRT, OP-CRT provided better 3-year local relapse-free survival for T3 (93 vs 48%, p < 0.0001), T4a (88 vs 37%, p = 0.0005) and better 3-year regional relapse-free survival for N2b+2c (93 vs 60%, p < 0.0001). Of note, for stage IVA subjects, OP-CRT provided better 3-year loco-regional relapse-free survival (85 vs 37%, p < 0.0001), marginal poor 3-year distant metastasis-free survival (62 vs 79%, p = 0.06), but comparable 3-year OS (52 vs 44%, p = 0.37) and 5-year OS (44 vs 31%, p = 0.15) compared with CCRT. Conclusions For patients with advanced HPSCC, although OP-CRT and CCRT provided similar overall survival, failure patterns were distinct. OP-CRT provided better loco-regional control but was more likely to encounter distant metastases than CCRT. The detailed analysis of failure patterns will pave the way to improve this devastating disease.

Purpose Although YAP1 and TAZ are believed to be equivalent downstream effectors of the Hippo pathway, differential expression of YAP1 or TAZ suggests distinct functions during cancer progression. The exact role of YAP1 and TAZ in esophageal cancer, the 6th leading cancer-related mortality in the world, remains elusive. Methods Following single or double manipulation of YAP1 or TAZ expression, we subjected these manipulated cells to proliferation, migration, invasion, and xenograft tumorigenesis assays. We used RT-qPCR and Western blotting to examine their expression in the manipulated cells with or without inhibition of transcription or translation. We also examined the impact of YAP1 or TAZ deregulation on clinical outcome of esophageal cancer patients from the TCGA database. Results We found that YAP1 functions as a tumor suppressor whereas TAZ exerts pro-tumor functions in esophageal cancer cells. We also found a significant increase in TAZ mRNA expression upon YAP1 depletion, but not vice versa, despite the downregulation of CTGF and CYR61, shared targets of YAP1 and TAZ, in xenografted tissue cells. In addition to transcriptional regulation, YAP1-mediated TAZ expression was found to occur via protein synthesis. Restored TAZ expression mitigated YAP1-mediated suppression of cellular behavior. By contrast, TAZ silencing reduced the promoting effect exerted by YAP1 depletion on cellular behaviors. The observed anti-tumor function of YAP1 was further supported by a better overall survival among esophageal cancer patients with a high YAP1 expression. Conclusion From our data we conclude that YAP1 functions as a suppressor and negatively regulates pro-tumor TAZ expression via transcriptional and translational control in esophageal cancer.

Supplementary Figure Legends 1-2 from Endoplasmic Reticulum Stress Triggers XBP-1–Mediated Up-regulation of an EBV Oncoprotein in Nasopharyngeal Carcinoma

Supplementary Figure 1 from Endoplasmic Reticulum Stress Triggers XBP-1–Mediated Up-regulation of an EBV Oncoprotein in Nasopharyngeal Carcinoma

Endoplasmic reticulum (ER) stress-activated unfolded protein response (UPR) plays multiple roles in cancer development, but its specific roles for virus-associated cancers have not been fully understood. It is still unknown whether ER stress/UPR occurs in and contributes to nasopharyngeal carcinoma (NPC), an epithelial malignancy closely associated with EBV. Here, we report that UPR proteins are frequently detected in NPC biopsies. In addition, we reveal that, in EBV-infected NPC cells, ER stress inducers up-regulate a potent EBV oncoprotein latent membrane protein 1 (LMP1), and the ER stress-induced LMP1 enhances production of interleukin-8. ER stress triggers LMP1 expression at a transcriptional level, activating a distal LMP1 promoter TR-L1. TR-L1 contains an ER stress-responsive element, which is targeted by an UPR protein XBP-1. Ectopic expression of XBP-1 induces LMP1 expression, and knockdown of XBP-1 blocks ER stress-triggered up-regulation of LMP1 in NPC cells. Furthermore, XBP-1 significantly correlates with LMP1 expression in NPC tumor biopsies. Therefore, this study not only provides a novel clue linking ER stress/UPR to EBV-associated NPC but also suggests that ER stress/UPR can promote virus-associated cancer in a unique way by driving expression of a viral oncogene. [Cancer Res 2009;69(10):4461–7]

Supplementary Information. Include supplementary material, methods, table title and figure legends

Supplementary Tables S1-S4. Supplementary Table S1: Clinicopathological characteristics of 40 pairs of OSCC specimens and their corresponding non-tumorous epithelia. Supplementary Table S2: A list of deregulated miRNA in 40 pairs of OSCC specimens and their corresponding non-tumorous epithelia. Supplementary Table S3: Characteristics of 83 OSCC patients for Wnt-7b IHC study. Supplementary Table S4: Top ten of enriched transcriptional factors in miRNA overexpression.

Supplementary Figure 2 from Endoplasmic Reticulum Stress Triggers XBP-1–Mediated Up-regulation of an EBV Oncoprotein in Nasopharyngeal Carcinoma

Supplementary Figures S1-S7. Supplementary Figure S1: Genome-wide profiling of chromosome 14q32.2 miRNA on OSCC tissues. Supplementary Figure S2: Mi-RNA level in miR-PM overexpressed OEC-M1 and SCC-15 cells. Supplementary Figure S3: Effect of miR-329 and miR-410 on Wnt/β-catenin signaling pathway. Supplementary Figure S4: The effects of miR-329 and miR-410 on tumor cell proliferation. Supplementary Figure S5: Expression level of miRNA in xenograft tumor tissue. Supplementary Figure S6: Effects of miR-329 and -410 on tumorigenicity. Supplementary Figure S7: Effects of arecoline on Wnt/β-catenin signaling pathway.

For patients with glottic insufficiency disease, injection laryngoplasty is a rapid and efficient management option that complements voice therapy. Some studies have indicated that respiratory muscle training may also show promise in patients with voice disorders. However, the effect of respiratory muscle training in patients with glottic insufficiency was reported to be limited, and whether it provides additional benefit after standard management requires further evaluation. We aimed to investigate the effectiveness of inspiratory muscle training on glottis closure and patient-reported voice quality in glottic insufficiency patients who had been treated with hyaluronic acid injection.Retrospective observational study.We included 46 patients with glottic insufficiency who had undergone hyaluronic acid injection. Twenty of them had undergone inspiratory muscle training during three months. We measured patients' changes in glottic status according to the normalized glottal gap area and bowing index, as well as voice quality of life according to the voice handicap index 10 and the voice outcome survey, before and after training.Patients who underwent inspiratory muscle training had higher odds of experiencing better improvement in all scores. The range of odds ratios ranged from 2.5 to 6.3 for changes in scores, and from 3.8 to 22.2 for changes in score percentages. Of note, the effect of training on percentage changes in the normalized glottal gap area score was significant (P= 0.0127) after adjustment for the duration of vocal disease, body mass index and BMI, and history of gastroesophageal reflux disease.Inspiratory muscle training can improve the glottal gap after injection laryngoplasty, and may be applied in clinical practice.

Many studies have reported a positive association between lower socioeconomic status (SES) and higher head and neck cancer (HNC) risk. Fewer studies have examined the impact of SES on the association between alcohol or cigarette use and HNC risk. The current case‐control study (1104 HNC cases and 1363 controls) investigated the influence of education, a SES indicator, on the association between HNC and the use of alcohol, cigarettes, or betel quids in Taiwan, a country with universal health care. Our results showed a larger increase in HNC risk associated with alcohol among those with lower educational level (odds ratio [OR] = 2.07; 95% confidence interval [CI], 1.53‐2.80) than those with higher educational level (OR = 1.38; 95% CI, 1.04‐1.85) (heterogeneity‐P = .03). Educational level had an influence on the association between alcohol use and HNC risk among those with genetic susceptibility (ALDH2‐deficient) to the carcinogenic effect of alcohol. The association between cigarette or betel quid use and HNC risk was similar between the high and low educational groups. National policies and social interventions have led to the decline in the prevalence of cigarette and betel quid users in Taiwan. In contrast, due to the lack of adequate alcohol control policies, alcohol consumption in Taiwan has continued to rise. A higher impact of alcohol on HNC risk among lower SES individuals even with universal health care could be the result of insufficient alcohol control policies in Taiwan.

We evaluated objective and subjective swallowing function outcomes in patients with dysphagia treated for head and neck cancer (HNC) and identified risk factors for poor swallowing outcomes. Patients undergoing videofluoroscopic swallowing studies (VFSS) between January 2016 and March 2021 were divided into four groups according to primary tumor sites; post-treatment dysphagia was assessed. The penetration–aspiration scale (PAS) and bolus residue scale (BRS) were used to objectively assess swallowing function through VFSS. The Functional Oral Intake Scale (FOIS) was used for subjective analyses of swallowing statuses. To account for potential confounding, important covariates were adjusted for in logistic regression models. Oropharyngeal tumors were significantly more likely to have poor PAS and BRS scores than oral cavity tumors, and the patients with nasopharyngeal tumors were significantly less likely to have poor FOIS scores. Old age, having multiple HNCs, and a history of radiotherapy were associated with an increased odds of poor PAS scores (for all types of swallows), poor BRS scores (for semiliquid and solid swallows), and poor FOIS scores, respectively. This indicates using only subjective assessments may not allow for accurate evaluations of swallowing function in patients treated for HNC. Using both objective and subjective assessments may allow for comprehensive evaluations.

Dysphagia affects 60-75% of patients treated for head and neck cancer (HNC). We aimed to evaluate the association between residue severity and airway invasion severity using a videofluoroscopic swallowing study and identify risk factors for poor penetration-aspiration outcomes in patients with dysphagia treated for HNC. Penetration-Aspiration Scale (PAS) was used to assess airway invasion severity, while residue severity was assessed using both the Bolus Residue Scale (BRS) for residue location and the Normalized Residue Ratio Scale (NRRS) for residue amount. Relevant covariates were adjusted in the logistic regression models to account for potential confounding. Significantly higher abnormal PAS was reported for increased piriform sinus NRRS (NRRSp) [odds ratio (OR), 4.81; p = 0.042] with liquid swallowing and increased BRS value (OR, 1.52; p = 0.014) for semi-liquid swallowing in multivariate analysis. Tumor location, older age, and poorer Functional Oral Intake Scale (FOIS) were significant factors for abnormal PAS in both texture swallowings. After adjusting for confounding factors (sex, age, and FOIS score), NRRS model in liquid swallowing (area under the curve [AUC], 0.83; standard error = 0.04, 95% confidence interval [CI]: 0.75, 0.91) and BRS in semi-liquid swallowing (AUC, 0.83; SE = 0.04; 95% CI: 0.76, 0.91) predicted abnormal PAS. The results indicate that while assessing residue and swallowing aspiration in patients with HNC, it is important to consider age, tumor location, and functional swallowing status. The good predictability of abnormal PAS with BRS and NRRS indicated that residue location and amount were both related to the aspiration event in patients with HNC.

Poor oral hygiene is an established risk factor of head and neck cancer (HNC); however, its role in the survival of HNC patients is unclear. This study evaluated the association between oral hygiene habits, including regular dental visits, frequency of tooth brushing, and use of dental floss, and the overall survival (OS) of HNC patients using interview data collected from 740 HNC patients. In addition, the interactions between oral hygiene and the polymorphisms of TLR2 and TLR4 on the OS of HNC patients were assessed. The analysis indicated that poor oral hygiene was significantly associated with poorer OS of HNC patients (hazard ratio (HR) = 1.38, 95% confidence interval (CI): 1.03‐1.86). This association was modified by a single nucleotide polymorphism, rs11536889, of TLR4. A significant association between poor oral hygiene and worse survival of HNC was observed among those with the CG or CC genotype (HR = 2.32, 95% CI: 1.41‐3.82) but not among those with the GG genotype (HR = 0.95, 95% CI: 0.65‐1.40). Our results suggested that poor oral hygiene is not only a risk factor but may also be a prognostic factor of HNC., Poor oral hygiene was associated with a worse survival of head and neck cancer. TLR4 affected the survival of head and neck cancer due to poor oral hygiene. Poor oral hygiene is both a risk and a prognostic factor of head and neck cancer

Objectives We assess the incremental cost-effectiveness ratio (ICER) of the oral cancer (OC) screening program in Taiwan. Materials and methods We interlinked the Cancer Registry, Mortality Registry, National Vital Statistics, reimbursement database of National Health Insurance, and the National Oral Cancer Screening database of Taiwan. A total of 40,092 pathologically verified OC patients were identified and followed during 2002–2014. After stratification by stages, lifetime survival curves were estimated by a rolling extrapolation algorithm to obtain life expectancy (LE), expected years of life lost (EYLL), and lifetime medical costs (LMC). Results The LE for stages I-IV were 19.5, 14.0, 11.9, and 7.7 life-years, respectively, while those of EYLL were 7.3, 12.2, 15.4, and 18.7 life-years, respectively. The LMC for stages I-IV were US$ 65,752, 60,086, 53,675, and 47,570, respectively. We assumed no life loss for stage 0 with LMC of US$ 5380 spent for the first year after diagnosis. During 2010–2013, 967 out of the 28,018 cases detected with abnormal oral pathology by screening were found to develop OC. The ICER of the screening program was US$ 28,516 per life-year saved, which could be improved to US$ 5579 per life-year saved if all cancers transformed from abnormal oral pathology were detected before stage I. Conclusion The ICER of the current OC screening program in Taiwan slightly exceeds 1 GDP (gross domestic product) per capita per life-year saved. Intensive follow-up and treatment for all patients with abnormal oral pathology would improve screening efficiency and effectiveness of prevention.

Background The prognosis of advanced oral squamous cell carcinoma is poor. We investigated the effect of cetuximab-based sequential therapy as a primary treatment. Methods Forty-seven treatment-naive patients with advanced tumors originating from the oral cavity or oropharynx were enrolled. Neoadjuvant cetuximab, paclitaxel, and cisplatin were administered, followed by cetuximab-based radiotherapy. Immunohistochemical staining was applied to study the tissues. Results The best overall response rate was 70.2%, including 4 patients with a complete response and 29 with a partial response. The median progression-free and overall survival rates were 10.3 and 15.2 months, respectively. Patients with more than 50% tumor reduction with neoadjuvant therapy had better survival outcomes. Twenty-two patients had severe adverse events with mostly dermatological complications. Of the 16 patients who received operations, 9 had increased PD-L1 staining compared to pretreatment biopsy in the post hoc study. Conclusion The regimen was effective in selected patients. Increased PD-L1 suggested altered tumor features.

Human papillomavirus (HPV) is recognized as a major cause of oropharyngeal cancer (OPC) in Western countries. Less is known regarding its contribution to the OPC occurring in Asia. The current study aimed to investigate the association between antibody responses to HPV16 E7 and head and neck cancer (HNC) risk in a hospital‐based case–control study conducted in Taiwan with 693 HNC cases and 1,035 controls. A positive association was observed between seropositivity to HPV16 E7 and OPC risk, whereas no significant association was found in the non‐OPC cases. The increased OPC risk associated with seropositivity to HPV16 E7 was more significant among nonbetel quid or noncigarette users. Seropositivity to HPV16 E7 showed moderate agreement with P16 expression in OPC. OPC patients that were seropositive to HPV16 E7 or p16 positive were more highly educated and less likely to use alcohol, betel quids, and cigarettes compared to HPV16 E7 seronegative or p16 negative OPC patients. Furthermore, patients with p16 positive OPC were more likely to be women compared to patients with p16 negative OPC, likely owing to the low prevalence of alcohol, betel quid, and cigarette users among women. Overall, this study suggested that similar to Western countries, HPV may also be an important risk factor of OPC in Taiwan. With the declining consumption of betel quids and cigarettes in Taiwan, a higher percentage of OPC cases in Taiwan will be attributed to HPV in the future. Public health measures, including HPV vaccination, need to be implemented to prevent the occurrence of HPV‐positive OPC., The current study found a a positive association between seropositivity to HPV16 E7 and oropharyngeal cancer risk. This study suggested that similar to Western countries, HPV may also be an important risk factor of OPC in Taiwan.

Background and purpose Concurrent chemoradiotherapy is the established treatment for locally advanced nasopharyngeal carcinoma (NPC). However, there is no evidence supporting routine adjuvant chemotherapy. We aimed to demonstrate the effect of adjuvant chemotherapy on survival and distant metastasis in high-risk N3 NPC patients. Materials and methods We linked the Taiwan Cancer Registry and Cause of Death database to obtain data. Clinical N3 NPC patients were divided as those receiving definitive concurrent chemoradiotherapy (CCRT) with adjuvant 5-fluorouracil and platinum (PF) chemotherapy and those receiving no chemotherapy after CCRT. Patients receiving neoadjuvant chemotherapy were excluded. We compared overall survival, disease-free survival, local control, and distant metastasis in both groups using Cox proportional hazards regression analysis. Results We included 431 patients (152 and 279 patients in the adjuvant PF and observation groups, respectively). Median follow-up was 4.3 years. The 5-year overall survival were 69.1% and 57.4% in the adjuvant PF chemotherapy and observation groups, respectively (p = 0.02). Adjuvant PF chemotherapy was associated with a lower risk of death (hazard ratio [HR] = 0.61, 95% confidence interval [CI]: 0.43–0.84; p = 0.003), even after adjusting for baseline prognostic factors (HR = 0.61, 95% CI: 0.43–0.86; p = 0.005). Distant metastasis-free survival at 12 months was higher in the adjuvant PF chemotherapy group than in the observation group (98% vs 84.8%; p p = 0.003). Conclusion Prospective evaluation of adjuvant PF chemotherapy in N3 NPC patients treated with definitive CCRT is warranted because adjuvant PF chemotherapy was associated with improved overall survival and decreased risk of distant metastasis.

Concurrent chemoradiotherapy is the established treatment for locally advanced nasopharyngeal carcinoma (NPC). However, there is no evidence supporting routine adjuvant chemotherapy. We aimed to demonstrate the effect of adjuvant chemotherapy on survival and distant metastasis in high-risk N3 NPC patients. We linked the Taiwan Cancer Registry and Cause of Death database to obtain data. Clinical N3 NPC patients were divided as those receiving definitive concurrent chemoradiotherapy (CCRT) with adjuvant 5-fluorouracil and platinum (PF) chemotherapy and those receiving no chemotherapy after CCRT. Patients receiving neoadjuvant chemotherapy were excluded. We compared overall survival, disease-free survival, local control, and distant metastasis in both groups using Cox proportional hazards regression analysis. Propensity-score matching was also performed to evaluate the independent effect of adjuvant PF in a matched cohort with similar baseline characteristics. We included 431 patients (152 and 279 patients in the adjuvant PF and observation groups, respectively). Median follow-up was 4.3 years. The 5-year overall survival were 69.1% and 57.4% in the adjuvant PF chemotherapy and observation groups, respectively (p = 0.02). Adjuvant PF chemotherapy was associated with a lower risk of death (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.43–0.84; p = 0.003), even after adjusting for baseline prognostic factors (HR 0.61, 95% CI 0.43–0.86; p = 0.005). Distant metastasis-free survival at 12 months was higher in the adjuvant PF chemotherapy group than in the observation group (98% vs 84.8%; p p = 0.003). Adjuvant chemotherapy was also associated with a decreased risk of death (HR 0.59, 95% CI 0.41–0.85, p = 0.004) in a propensity score-matched cohort. Prospective evaluation of adjuvant PF chemotherapy in N3 NPC patients treated with definitive CCRT is warranted because adjuvant PF chemotherapy was associated with improved overall survival and decreased risk of distant metastasis.

We sought to compare the clinical outcomes of Taiwanese patients with resected oral cavity squamous cell carcinoma (OCSCC) who underwent reconstruction with free versus local flaps.From 2011 to 2017, we examined 8646 patients with first primary OCSCC who received surgery either with or without adjuvant therapy. Of these patients, 7297 and 1349 received free and local flap reconstruction, respectively. Two propensity score-matched groups of patients who underwent free versus local flap (n = 1268 each) reconstructions were examined. Margin status was not included as a propensity score-matched variable.Compared with local flaps, patients who received free flaps had a higher prevalence of the following variables: male sex, age 65 years, pT3-4, pN1-3, p-Stage III-IV, depth ≥ 10 mm, margin 4 mm, extranodal extension (ENE), and adjuvant therapy (all p 0.0001). Multivariable analysis identified the reconstruction method (local vs. free flaps, only overall survival [OS]), age ≥ 65 years, pT3-4, pN1-3, p-Stage III-IV, depth ≥ 10 mm (only OS), margins ≤ 4 mm, and ENE as independent adverse prognosticators for disease-specific survival (DSS) and OS. The results of propensity score-matched analyses revealed that, compared with free flaps, patients who underwent local flap reconstruction showed less favorable 5-year DSS (hazard ratio [HR] 1.26, 82%/77%; p = 0.0100) and OS (HR 1.21, 73%/68%; p = 0.0079).After adjusting for covariates using multivariate models, and also by propensity score modeling, OCSCC patients who underwent free flap reconstruction showed a higher frequency of clear margins and a significant survival advantage compared with those who received local flaps.

Conduct an accurate risk assessment of resected oral cavity squamous cell carcinoma (OSCC) patients by accessing a nationwide systemic investigation is pivotal to improve treatment outcomes. In this article, we tried to determine the impact of different prognostic factors for OSCC patients who received adjuvant radiotherapy (RT) after curative surgery, using Taiwan's national cancer registry database (TCR). A nationwide, large population‐based study was conducted using TCR with patients identified from 2007 to 2015. The study variables included age, gender, cancer subsites, stage, histology grade, margin and extra‐nodal extension (ENE) status, treatment type, surgery to RT interval (ORI), total RT treatment time (RTT), and RT dose. Univariate and multivariate analysis were performed to identify predictors of the variables associated with overall survival (OS), cause‐specific survival (CSS), local‐regional relapse‐free survival (LRFS), and distant metastasis‐free survival (DMFS). 8986 OSCC patients treated with surgery and adjuvant RT were analyzed. In multivariate analysis, worse outcomes were associated with males, older age, subsite in the oral tongue, advanced stage, higher histologic grade, involved margin, and positive ENE. ORI only showed an adverse trend in LRFS, when exceeding 7 weeks (P = .06). RTT >8 weeks was a significant poor predictor in OS, CSS and LRFS (P 70 Gy or ≤50 Gy) also demonstrated an adverse impact on the outcomes. Prolonged RT treatment time and extreme RT doses were identified as significantly poor prognostic predictors in OSCC patients who received adjuvant RT after curative surgery.

Background Margin status and lymph node metastasis are the most important prognostic factors for oral cancers. However, while adequate surgical resection is crucial for local control and prognosis, the definition of clear margins has long been a subject of debate. In this study, we analyzed data from a nationwide population-based cancer registry database and evaluated the impact of surgical margins on cancer-specific survival (CSS) and overall survival (OS) as well as the optimal cutoff of adequate surgical margins. Methods This analysis included all cases of oral cancer diagnosed from 2011 to 2017 that were reported to the Taiwan Cancer Registry database. The staging system was converted from American Joint Committee on Cancer (AJCC) version 7 to AJCC version 8. Kaplan–Meier analysis and Cox proportional-hazards regression were performed to identify covariates that were significantly associated with CSS and OS. Results Between 2011 and 2017, 15,654 of a total of 36,091 cases diagnosed with oral cancers were included in the final analyses. Advanced N stage, positive margins, and advanced T stage are the leading risk factors for poor CSS and OS. When surgical margins were subdivided into 1-mm intervals from 5 mm to positive margin, we found that surgical margins Conclusions This is the first nationwide, population-based cohort to revisit the question of the adequate surgical margins for oral cancers. We conclude that surgical margins ≥4 mm and ≥5 mm are adequate for good CSS and OS, respectively.

// Chan-Chi Chang 1, 2, * , Wei-Ting Lee 1, 2, * , Yao-Chou Lee 2, 3 , Cheng-Chih Huang 1 , Chun-Yen Ou 1 , Yu-Hsuan Lin 1 , Jehn-Shyun Huang 4 , Tung-Yiu Wong 4 , Ken-Chung Chen 4 , Jenn-Ren Hsiao 1, 2 , Yu-Cheng Lu 1 , Sen-Tien Tsai 1 , Yu-Hsuan Lai 2, 5 , Yuan-Hua Wu 5 , Wei-Ting Hsueh 5 , Chia-Jui Yen 6 , Shang-Yin Wu 2, 6 , Jang-Yang Chang 6, 7 , Sheen-Yie Fang 1 , Jiunn-Liang Wu 1 , Chen-Lin Lin 8 , Ya-Ling Weng 7 , Han-Chien Yang 7 , Yu-Shan Chen 1 and Jeffrey S. Chang 7 1 Department of Otolaryngology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70456, Taiwan 2 Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 70456, Taiwan 3 Division of Plastic and Reconstructive Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70456, Taiwan 4 Department of Stomatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70456, Taiwan 5 Department of Radiation Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70456, Taiwan 6 Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70456, Taiwan 7 National Institute of Cancer Research, National Health Research Institutes, Tainan 70456, Taiwan 8 Department of Nursing, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70456, Taiwan * These authors have contributed equally to this work Correspondence to: Jeffrey S. Chang, email: jeffreychang@nhri.org.tw Keywords: head and neck cancer, diet, vegetables and fruits, risk factor, Taiwan Abbreviations: confidence interval (CI); head and neck cancer (HNC); Nutrition and Heath Surveys in Taiwan (NAHSIT); OR (odds ratio); upper aerodigestive tract (UADT) Received: July 23, 2017 Accepted: September 30, 2017 Published: October 24, 2017 ABSTRACT Most studies reporting an inverse association between the consumption of vegetables and fruits and head and neck cancer (HNC) risk were conducted in Western populations and only a few included East Asians. The current case-control study investigated the association between diet and HNC risk using data of 838 HNC cases and 998 controls from a case-control study of HNC conducted in Taiwan. Each participant was asked about their consumption of fresh vegetables, pickled vegetables, fresh fruits, citrus fruits, meat, processed meat, fish, egg, and dairy products. Unconditional logistic regression was performed to estimate the odds ratio (OR) and 95% confidence interval (CI) of HNC risk associated with each food category, adjusted for sex, age, education, and use of alcohol, betel quid and cigarette. An inverse association was observed between HNC risk and daily intake of fresh vegetables (OR = 0.44, 95% CI: 0.20-0.95, p -trend = 0.002) or fruits (OR = 0.55, 95% CI: 0.43-0.72, p -trend = 0.00001). Individuals who did not consume fresh fruits and vegetables daily had more than double the risk of HNC compared to those with daily intake of vegetables and fruits (OR= 2.24, 95% CI: 1.54-3.25). The results of the current study supported an inverse association between the consumption of fresh vegetables and fruits and HNC risk. In addition to cessation of cigarette smoking and betel quid chewing and reduction of alcohol drinking, a public health campaign for preventing the occurrence of HNC should promote a healthy diet that contains plenty of fresh vegetables and fruits.

Although patients with buccal squamous cell carcinoma (SCC) usually show acceptable outcomes, local control and survival rates are generally lower than those observed for tongue SCC. This study was designed to compare the clinical outcomes of Taiwanese patients with these two common oral cavity malignancies.Patients with first primary buccal or tongue SCC who were included in the Taiwanese Cancer Registry Database between 2004 and 2012 were eligible. The study sample consisted of 16,379 patients (7870 buccal SCC and 8509 tongue SCC) who received surgery with or without adjuvant therapy. The 5-year disease-specific survival (DSS) and overall survival (OS) rates served as the outcome measures.Compared with tongue SCC, patients with buccal SCC had a higher prevalence of males (95.7% vs. 86.4%, p0.0001), pT4 disease (21.4% vs. 12.7%, p0.0001), and p-Stage IV (30.4% vs. 24.8%, p0.0001) but a lower frequency of pN2 disease (15.2% vs. 18.5%, p0.0001). The 5-year DSS and OS rates of buccal SCC patients were slightly higher than those of tongue SCC (78% vs. 77%, p=0.0297; and 71% vs. 69%, p=0.0231, respectively). Multivariate analysis identified tumor site (tongue vs. buccal SCC), sex (male vs. female), age (≥65 vs.65years), pT classification (T4/T3/T2 vs. T1), and pN classification (N3/N2/N1vs. N0) as independent prognostic factors in the entire study cohort.The survival advantage of buccal SCC over tongue SCC appears significant in large clinical samples, despite a higher prevalence of p-Stage IV disease in the former.

Oral cancer, a subtype of head and neck cancer, is characterized by increased infiltrating regulatory T cells (Treg); however, the pathological significance of the increase in Tregs in disease prognosis and progression and their underlying mechanism remain unestablished. C‐C motif chemokine ligand 22 (CCL22) has been implicated in the recruitment of Tregs. We used RT‐qPCR to determine CCL22 mRNA expression in clinical specimens and cultured cells. Loss‐of‐function and gain‐of‐function studies were carried out to analyze the effects of CCL22 modulations on cell proliferation, migration, invasion, and tumorigenesis and the mechanism involved in the deregulation of CCL22. In oral cancer specimens, CCL22 mRNA was upregulated. The increase was not only associated with reduced disease‐free survival but also strongly correlated with an increase in FOXP3 mRNA, a master regulator of Treg development and functions. Silencing CCL22 expression reduced cell proliferation, migration, and invasion, whereas ectopic overexpression showed opposite effects. Manipulation of CCL22 expression in cancer cells altered tumorigenesis in both immune‐compromised and ‐competent mice, supporting both autonomous and non‐autonomous actions of CCL22. Release of interleukin 1β (IL‐1β) from cancer‐associated fibroblasts (CAF) induces CCL22 mRNA expression in oral cancer cells by activating transcription factor nuclear factor kappa B (NF‐κB). Our data support a model in which CAF‐derived IL‐1β, CCL22, and its receptor CCR4 foster a protumor environment by promoting cell transformation and Treg infiltration. Intervention of the IL‐1β‐CCL22‐CCR4 signaling axis may offer a novel therapeutic strategy for oral cancer treatment.

BACKGROUND Carriers of the ALDH2*2 allele have impaired alcohol metabolism and are more susceptible to the development of alcohol-related cancers, including head and neck cancer (HNC). Screening for ALDH2*2 allele may identify high-risk individuals for alcohol health education. Although genotyping of ALDH2 is the most accurate way to identify ALDH2 deficiency, it may not be practical due to the cost and requirement for genotyping service. METHODS This study evaluated the accuracy of the alcohol flushing questionnaire to identify ALDH2 deficiency in a case-control study of HNC conducted in Taiwan using data collected from 904 patients with HNC and 1,078 controls. RESULTS Overall, alcohol flushing questionnaire had a high sensitivity (89%) of identifying ALDH2*2 carriers among the control subjects and a good sensitivity (79%) among the patients with HNC. The sensitivity of the alcohol flushing questionnaire in identifying ALDH2*2 carriers was affected by alcohol use, with a lower sensitivity among individuals who consumed alcohol, particularly among current regular (drinking alcohol once per week or more) alcohol drinkers. CONCLUSIONS The current validation study showed that the alcohol flushing questionnaire may be a reasonable method to identify ALDH2-deficient individuals. However, current regular users of alcohol who reported no alcohol flushing may need to undergo genotyping of ALDH2 for a more accurate assessment of the ALDH2 status.

Background Frey syndrome is a common complication after parotidectomy. This study aimed to investigate the potential predictors for developing severe Frey syndrome after parotidectomy and to identify patients who may benefit from additional preventive maneuvers. Methods A total of 485 patients received parotidectomy because of parotid tumors at the Otolaryngology Department of the National Cheng Kung University Hospital, from July 2009 to November 2015. Only 115 of 485 patients were included in this study and to fill in a questionnaire to determine the occurrence and severity of Frey syndrome. Results A total of 115 parotidectomies were identified. 84 (73%, 84/115) patients were aware of the discomfort and were thus considered symptomatic. 39 (34%, 39/115) patients considered the symptoms apparently affected their quality of life. MSI tests showed that 56 (49%, 56/115) patients had a positive MSI test. By combining the results from symptom questionnaire and MSI test, 23 patients (20%, 23/115) had a severe form of Frey syndrome. Among all clinicopathological variables, the resected specimen size was the only significant predictor of the severe Frey syndrome group (P = 0.04). Disease pathology, tumor size, and adjuvant radiotherapy did not correlate with the severe Frey syndrome. Using receiver operating curve analysis, the best cutoff value of the resected specimen size (in largest dimension) for predicting severe Frey syndrome was 40 mm(sensitivity: 71.7%, specificity: 42.0%; area under the curve = 0.6483). The odds ratio of severe Frey syndrome with every 10 mm increase in the largest diameter of resected specimen was 1.30 (95% confidence interval, 1.01-1.68; P = 0.04). Conclusions Resected specimen size is the only significant predictor of developing severe Frey syndrome after parotidectomy. Preventive interventions may have to be considered in high-risk patients whose resected specimen size (in largest dimension) is greater than 40 mm.

Background: Although alcohol drinking is an established risk factor of head and neck cancer (HNC), less is known about its role in the prognosis of HNC. The current study investigated the association between pretreatment alcohol consumption and the overall survival (OS) of HNC patients. Methods: Cox proportional hazards models were performed to evaluate the association between prediagnosis alcohol drinking and the OS of HNC patients. In addition, the influence of the polymorphisms of two ethanol-metabolizing genes, ADH1B and ALDH2, on this relationship was also evaluated. Results: The results showed a significant positive dose–response relationship between prediagnosis alcohol use and worse OS of HNC patients. This association was more significant for oropharyngeal cancer, hypopharyngeal cancer, and laryngeal cancer than for oral cancer. The association between alcohol use and the poorer OS of HNC patients was mainly through its association with a higher stage of HNC at diagnosis. The worst OS associated with alcohol use was observed among HNC patients with the fast ADH1B and the slow/nonfunctional ALDH2 genotype combination. Conclusions: Our analysis showed a significant positive dose–response relationship between prediagnosis alcohol use and a worse OS of HNC. This association was mainly due to the higher stage of HNC among alcohol drinkers. In addition, the polymorphisms of the ethanol-metabolizing genes, ADH1B and ALDH2, modified the relationship between prediagnosis alcohol use and the OS of HNC patients. Impact: Prediagnosis alcohol use may be a prognostic indicator of HNC.

The S100A2 protein is an important regulator of keratinocyte differentiation, but its role in wound healing remains unknown. We establish epithelial-specific S100A2 transgenic (TG) mice and study its role in wound repair using punch biopsy wounding assays. In line with the observed increase in proliferation and migration of S100A2-depleted human keratinocytes, mice expressing human S100A2 exhibit delayed cutaneous wound repair. This was accompanied by the reduction of re-epithelialization as well as a slow, attenuated response of Mcp1, Il6, Il1β, Cox2, and Tnf mRNA expression in the early phase. We also observed delayed Vegfa mRNA induction, a delayed enhancement of the Tgfβ1-mediated alpha smooth muscle actin (α-Sma) axis and a differential expression of collagen type 1 and 3. The stress-activated p53 tumor suppressor protein plays an important role in cutaneous wound healing and is an S100A2 inducer. Notably, S100A2 complexes with p53, potentiates p53-mediated transcription and increases p53 expression both transcriptionally and posttranscriptionally. Consistent with a role of p53 in repressing NF-κB-mediated transcriptional activation, S100A2 enhanced p53-mediated promoter suppression of Cox2, an early inducible NF-κB target gene upon wound injury. Our study thus supports a model in which the p53-S100A2 positive feedback loop regulates wound repair process.

Poor oral hygiene may lead to overgrowth of pathogenic oral bacteria, which may induce chronic inflammation to promote the oncogenesis of oral squamous cell carcinoma (OSCC). This study investigated the association between oral bacterial profile and OSCC risk in a case-control study of 138 OSCC cases and 151 controls (88 cases and 90 controls for the discovery group and 50 cases and 61 controls for the validation group). Oral bacterial profiles were characterized by targeted sequencing of the 16S rRNA gene. Three species of periodontopathogenic bacteria, Prevotella tannerae, Fusobacterium nucleatum, and Prevotella intermedia, were associated with an increased OSCC risk. This association was modified by the genetic polymorphisms of TLR2 and TLR4. Use of alcohol, betel quids and cigarettes and poor oral hygiene were associated with a higher percentage of oral periodontopathogenic bacteria. The association between alcohol and periodontopathogenic bacteria was modified by the genetic polymorphism of ALDH2, with a stronger positive association observed among the ALDH2-deficient individuals. The percentage of periodontopathogenic bacteria was positively correlated with the level of salivary IL1β, an inflammatory cytokine. Overall, our results showed a positive association between periodontopathogenic bacteria and OSCC risk and this relationship may be influenced by lifestyle and genetic factors. Our results provided further biological support for the established association between poor oral hygiene and OSCC risk. This suggested that improving oral hygiene may reduce OSCC risk and should be part of a public health campaign to prevent the occurrence of OSCC.

S100A9 is a calcium-binding protein with two EF-hands and frequently deregulated in several cancer types, however, with no clear role in oral cancer. In this report, the expression of S100A9 in cancer and adjacent tissues from 79 early-stage oral cancer patients was detected by immunohistochemical staining. Although S100A9 protein was present in both tumor and stromal cells, only the early-stage oral cancer patients with high stromal expression had reduced recurrence-free survival. High stromal S100A9 expression was also significantly associated with non-well differentiation and recurrence. In addition to increasing cell migration and invasion, ectopic S100A9 expression in tumor cells promoted xenograft tumorigenesis as well as the dominant expression of myeloid cell markers and pro-inflammatory IL-6. The expression of S100A9 in one stromal component, monocytes, stimulated the aggressiveness of co-cultured oral cancer cells. We also detected the elevation of serum S100A9 levels in early-stage oral cancer patients of a separate cohort of 73 oral cancer patients. The release of S100A9 protein into extracellular milieu enhanced tumor cell invasion, transendothelial monocyte migration and angiogenic activity. S100A9-mediated release of IL-6 requires the crosstalk of tumor cells with monocytes through the activation of NF-κB and STAT-3. Early-stage oral cancer patients with both high S100A9 expression and high CD68+ immune infiltrates in stroma had shortest recurrence-free survival, suggesting the use of both S100A9 and CD68 as poor prognostic markers for oral cancer. Together, both intracellular and extracellular S100A9 exerts a tumor-promoting action through the activation of oral cancer cells and their associated stroma in oral carcinogenesis.

Although Sistrunk operation is the standard method to treat thyroglossal duct cyst, the reported recurrence rates after a "classic" or "modified" Sistrunk procedure still varied from 0 to 15.8 %, indicating the existence of some technical uncertainties. While simple cystectomy has been recognized as the most important prognostic factor predicting thyroglossal duct cyst recurrence, whether other clinico-pathological parameters also affect disease recurrence has not been well studied. We retrospectively reviewed the medical records of all patients who underwent thyroglossal duct cyst surgery between June 1998 and June 2014 at our institution. Among the 180 primary patients, 160 patients received a "conservative" Sistrunk operation, while the remaining 20 patients received simple cystectomy only. Five patients (2.8 %, 5/180) had recurrence. Four of them received simple cystectomy while 1 had "conservative" Sistrunk operation. In univariable analysis, age (p = 0.02), history of previous infection (p = 0.004) and the type of resection (p = 0.001) were significantly correlated with disease recurrence. In multivariable analysis, the type of resection turned out to be the most important factor (p = 0.03) related to recurrence. In the most parsimonious model selected by backward elimination, both history of infection (p = 0.048) and the type of resection (p = 0.02) were important predictors of postoperative recurrence. Our results demonstrated that a "conservative" Sistrunk approach could provide a comparably low recurrence rate (0.6 %, 1/160) in dealing with primary thyroglossal dust cysts. Routine dissection of suprahyoid tissue may not be imperative. Overall, the type of resection and history of infection are the most important predictors of recurrence for thyroglossal duct cyst.

microRNA (miRNA) dysregulation contributes widely to human cancer but has not been fully assessed in oral cancers. In this study, we conducted a global microarray analysis of miRNA expression in 40 pairs of betel quid–associated oral squamous cell carcinoma (OSCC) specimens and their matched nontumorous epithelial counterparts. Eighty-four miRNAs were differentially expressed in the OSCC specimens compared with the matched tissue. Among these downregulated miRNAs, 19 miRNAs were found and mapped to the chromosome 14q32.2 miRNA cluster region, which resides within a parentally imprinted region designated as Dlk-Dio3 and known to be important in development and growth. Bioinformatic analysis predicted two miRNAs from the cluster region, miR329 and miR410, which could potentially target Wnt-7b, an activator of the Wnt–β-catenin pathway, thereby attenuating the Wnt–β-catenin signaling pathway in OSCC. Stable ectopic expression of Wnt-7b in OSCC cells overexpressing miR329 or miR410 restored proliferation and invasion capabilities abolished by these miRNA. Combining a demethylation agent and a histone deacetylase inhibitor was sufficient to reexpress miR329, miR410, and Meg3, consistent with epigenetic regulation of these miRNA in human OSCC. Specifically, arecoline, a major betel nut alkaloid, reduced miR329, miR410, and Meg3 gene expression. Overall, our results provide novel molecular insights into how betel quid contributes to oral carcinogenesis through epigenetic silencing of tumor-suppressor miRNA that targets Wnt–β-catenin signaling. Cancer Res; 74(24); 7560–72. ©2014 AACR.

Although alcohol is an established risk factor of head and neck cancer (HNC), insufficiencies exist in the literature in several aspects. We analyzed detailed alcohol consumption data (amount and type of alcoholic beverage) of 811 HNC patients and 940 controls to evaluate the association between alcohol and HNC by HNC sites and by genotypes of ADH1B and ALDH2. Alcohol was associated with an increased HNC risk in a dose-response relationship, with the highest risk observed for hypopharyngeal cancer, followed by oropharyngeal and laryngeal cancers. Liquor showed a stronger positive association with HNC than beer and wine. The highest HNC risk occurred in individuals with the slow ADH1B and slow/non-functional ALDH2 genotype combination. In our study population, 21.8% of HNCs, 55.7% of oropharyngeal cancers, and 89.1% of hypopharyngeal cancers could be attributed to alcohol. Alcohol accounted for 47.3% of HNCs among individuals with the slow ADH1B and slow/non-functional ALDH2 genotype combination. The HNC risk associated with alcohol became comparable to that of never/occasional drinkers after ten or more years of cessation from regular alcohol drinking. In conclusion, alcohol use is associated with an increased HNC risk, particularly for individuals with slow ethanol metabolism. HNC incidence may be reduced by alcohol cessation.

Questionnaire. Physical activity questions. This file contains questions used to collect physical activity data (DOC 29Â kb)

The association between regular recreational physical activity and cancers of tonsil and tongue base and other pharyngeal cancers. This supplementary table examines the association between regular recreational physical activity and head and neck cancer sites by the association with human papillomavirus. (DOC 75Â kb)

Objective Previous studies examining the association between genetic variations in prostaglandin pathway and risk of head and neck cancer (HNC) have only included polymorphisms in the PTGS2 (COX2) gene. This study investigated the association between genetic polymorphisms of six prostaglandin pathway genes (PGDS, PTGDS, PTGES, PTGIS, PTGS1 and PTGS2), and risk of HNC. Methods Interviews regarding the consumption of alcohol, betel quid, and cigarette were conducted with 222 HNC cases and 214 controls. Genotyping was performed for 48 tag and functional single-nucleotide polymorphisms (SNPs). Results Two tag SNPs of PTGIS showed a significant association with HNC risk [rs522962: log-additive odds ratio (OR) = 1.42, 95% confidence interval (CI): 1.01–1.99 and dominant OR = 1.58, 95% CI: 1.02–2.47; rs6125671: log-additive OR = 1.49, 95% CI: 1.08–2.05 and dominant OR = 1.96, 95% CI: 1.16–3.32]. In addition, a region in PTGIS tagged by rs927068 and rs6019902 was significantly associated with risk of HNC (global P = 0.007). Finally, several SNPs interacted with betel quid and cigarette to influence the risk of HNC. Conclusions Genetic variations in prostaglandin pathway genes are associated with risk of HNC and may modify the relationship between use of betel quid or cigarette and development of HNC.

Alcohol consumption is an established risk factor for head and neck cancer (HNC). The major carcinogen from alcohol is acetaldehyde, which may be produced by humans or by oral microorganisms through the metabolism of ethanol. To account for the different sources of acetaldehyde production, the current study examined the interplay between alcohol consumption, oral hygiene (as a proxy measure for the growth of oral microorganisms), and alcohol-metabolizing genes (ADH1B and ALDH2) in the risk of HNC. We found that both the fast (*2/*2) and the slow (*1/*1 + *1/*2) ADH1B genotypes increased the risk of HNC due to alcohol consumption, and this association differed according to the slow/non-functional ALDH2 genotypes (*1/*2 + *2/*2) or poor oral hygiene. In persons with the fast ADH1B genotype, the HNC risk associated with alcohol drinking was increased for those with the slow/non-functional ALDH2 genotypes. For those with the slow ADH1B genotypes, oral hygiene appeared to play an important role; the highest magnitude of an increased HNC risk in alcohol drinkers occurred among those with the worst oral hygiene. This is the first study to show that the association between alcohol drinking and HNC risk may be modified by the interplay between genetic polymorphisms of ADH1B and ALDH2 and oral hygiene. Although it is important to promote abstinence from or reduction of alcohol drinking to decrease the occurrence of HNC, improving oral hygiene practices may provide additional benefit.

This analysis examined the association between oral hygiene and head and neck cancer (HNC) and whether this association differed by the consumption of alcohol, betel quid, or cigarette and by the genetic polymorphisms of inflammation-related genes.Interviews regarding dental care and oral health were conducted with 317 HNC cases and 296 controls. Genotyping was performed for 6 single nucleotide polymorphisms in IL6, IL10 and PTGS2.A positive association was observed between HNC and no regular dental visits (odds ratio (OR)=2.86, 95% confidence interval (CI): 1.47-5.57), brushing teeth2times/day (OR=1.51, 95% CI: 1.02-2.23), frequent gum bleeding (OR=3.15, 95% CI: 1.36-7.28), and loss of20 teeth (OR=2.31, 95% CI: 1.05-5.07). Analysis with dental care score (range: 0-4, 4=worst dental care), which combined regular dental visits, toothbrushing, and use of dental floss and mouthwash, showed a positive trend with HNC risk, particularly among alcohol drinkers and cigarette smokers. Multifactor dimensionality reduction analysis divided the study subjects into high- and low-risk group based on combinations of dental care score and IL6 rs1800796 genotypes. Compared to the low-risk group, the high-risk group had an OR of HNC=2.16 (95% CI: 1.44-3.25).This study observed a positive association between poor oral hygiene and HNC, which appeared to differ by alcohol or cigarette consumption and the genotypes of IL6 rs1800796. Further investigations are needed to determine whether poor oral hygiene is a cause for HNC or a surrogatemarker of an unhealthy lifestyle that increases the risk of HNC.