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Background: The efficacy of adjuvant sublingual immunotherapy (SLIT) in correcting structural problems in patients with allergic rhinitis (AR) caused by mite who have undergone septomeatoplasty (SMP) has not been studied., Methods: This non-randomized controlled study recruited patients with AR (caused by mite) and concurrent septal deviation and inferior turbinate hypertrophy, at a tertiary hospital in Taiwan. SMP was performed on all patients as a surgical intervention. The patients were then divided into two groups: the control group, which underwent surgery only, and the experimental group, which received SLIT as an adjuvant treatment. Demographic data and rhinitis control assessment test (RCAT) results were analyzed., Results: A total of 96 patients were enrolled in the study (SMP + SLIT group, n = 52; SMP only group, n = 44). No significant differences were observed in any of the variables between the two groups before and one month after surgery. However, during evaluations at the third and sixth month, the SMP + SLIT group showed significant improvement in the total RCAT scores compared to the SMP only group (28.6 ± 1.56 vs. 24.5 ± 3.66, p < 0.001; 27.1 ± 2.87 vs. 19.9 ± 5.56, p < 0.001). In addition, significantly better control of all RCAT sub-categories was observed in the SMP + SLIT group at the third and sixth month evaluations., Conclusions: SLIT may serve as an ideal adjuvant therapy after SMP in patients with AR., Level of Evidence: 3 Laryngoscope, 134:3073-3079, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

This is a retrospective longitudinal study that uses data from the National Health Insurance Research Database (NHIRD) of Taiwan of which hypothyroid patients who received a diagnosis between 2000 and 2010 were selected and followed up until 2011. The primary outcome of this study was the occurrence of tinnitus (ICD-9-CM code 388.3). The relevant comorbidities were selected as potential confounders according to the literature, which included vertigo (ICD-9-CM code 386), insomnia (ICD-9-CM code 780), anxiety (ICD-9-CM code 300.00), and hearing loss (ICD-9-CM code 388-389). The overall incidence of tinnitus was significantly higher in the hypothyroidism cohort than in the non-hypothyroidism cohort (9.49 vs. 6.03 per 1000 person-years), with an adjusted HR of 1.35 (95% CI 1.18-1.54) after adjusting potential confounders. The incidences of tinnitus, as stratified by gender, age, comorbidity, and follow-up time, were all significantly higher in the hypothyroidism cohort than those in the non-hypothyroidism cohort. The incidence of tinnitus significantly increased with age (aHR = 1.01, 95% CI 1.01-1.02). In conclusion, we report the relationship between hypothyroidism and the increased risk for tinnitus. We also found that hypothyroidism patients are at increased risk of developing tinnitus when associated with comorbidities including vertigo, hearing loss, and insomnia., (© 2022. The Author(s).)

Background: The study aims are to evaluate the associations between nasopharyngeal carcinoma (NPC) risk and cigarette smoking and to explore the effects of cigarette smoking on Epstein-Barr virus (EBV) infection for NPC risk., Methods: 1235 male NPC cases and 1262 hospital-based male controls matched to cases were recruited across six collaborative hospitals between 2010 and 2014. Using a standardized questionnaire, information on cigarette smoking and other potential risk factors for NPC was obtained. Blood was collected and used for anti-EBV VCA IgA and anti-EBV EA-EBNA1 IgA testing using standard methods. Unconditional logistic regression analysis was used to estimate odds ratio (OR) with 95% confidence interval (CI) for each risk factor after adjusting for confounders., Results: 63.6% of cases and 44.0% of controls reported ever smoking cigarettes. After full adjustment, current smokers had a significant 1.60-fold (95% CI = 1.30-1.97) and former smokers a borderline significant 1.27-fold (95% CI = 1.00-1.60) increased NPC risk compared to never smokers. NPC risk increased with increasing duration, intensity, and pack-years of cigarette smoking but not with age at smoking initiation. Among controls, anti-EBV VCA IgA seropositivity rate was higher in current smokers than never smokers (14.0% vs 8.4%; OR = 1.82; 95% CI = 1.19-2.79). Mediation analyses showed that more than 90% of the cigarette smoking effect on NPC risk is mediated through anti-EBV VCA IgA., Conclusion: This study confirms the association between long-term cigarette smoking and NPC and demonstrates that current smoking is associated with seropositivity of anti-EBV VCA IgA antibodies., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Genetic susceptibility is associated with nasopharyngeal carcinoma (NPC). We previously identified rare variants potentially involved in familial NPC and common variants significantly associated with sporadic NPC., Methods: We conducted targeted gene sequencing of 20 genes [16 identified from the study of multiplex families, three identified from a pooled analysis of NPC genome-wide association study (GWAS), and one identified from both studies] among 819 NPC cases and 938 controls from two case-control studies in Taiwan (independent from previous studies). A targeted, multiplex PCR primer panel was designed using the custom Ion AmpliSeq Designer v4.2 targeting the regions of the selected genes. Gene-based and single-variant tests were conducted., Results: We found that NPC was associated with combined common and rare variants in CDKN2A/2B ( P = 1.3 × 10 -4 ), BRD2 ( P = 1.6 × 10 -3 ), TNFRSF19 ( P = 4.0 × 10 -3 ), and CLPTM1L/TERT ( P = 5.4 × 10 -3 ). Such associations were likely driven by common variants within these genes, based on gene-based analyses evaluating common variants and rare variants separately (e.g., for common variants of CDKN2A/2B, P = 4.6 × 10 -4 ; for rare variants, P = 0.04). We also observed a suggestive association with rare variants in HNRNPU ( P = 3.8 × 10 -3 ) for NPC risk. In addition, we validated four previously reported NPC risk-associated SNPs., Conclusions: Our findings confirm previously reported associated variants and suggest that some common variants in genes previously linked to familial NPC are associated with the development of sporadic NPC., Impact: NPC-associated genes, including CLPTM1L/TERT, BRD2 , and HNRNPU , suggest a role for telomere length maintenance in NPC etiology., (©2019 American Association for Cancer Research.)

Objectives: Our study was designed to ascertain the outcomes of functional endoscopic sinus surgery (FESS) combined with submucosal resection (SMR)/septoplasty in reducing FESS revision rates., Study Design: Retrospective population-based study., Setting: Academic tertiary medical center., Subjects and Methods: By using the Taiwan Longitudinal Health Insurance Database, we obtained the patients who underwent FESS for chronic rhinosinusitis. These patients were divided into 2 groups: the control group (FESS alone) and the study group (FESS combined with SMR). The primary outcome was the revision operative rate., Results: In total, 4484 patients who had undergone FESS were recruited into this study. The number of patients who underwent revision FESS was 528 (11.78%). In our sample, 80.45% of patients received FESS alone, whereas 19.54% of the patients underwent concurrent SMR/septoplasty during FESS. There are more female patients and older patients in the control group than in the study group. The revision rates of these 2 groups were significantly different (12.36% vs 9.36%, respectively; P = .016). Moreover, logistic regression analysis came out that patients in the control group had a higher revision rates than those in the study group. Male patients and younger patients were found to have higher revision rates. In addition, patients with asthma or allergic rhinitis had higher revision rates compared with those patients without these 2 comorbidities., Conclusions: This study showed an association between FESS combined with concurrent SMR/septoplasty and less incidence of revision rate of FESS. Patients with asthma or allergic rhinitis have an increased risk of requiring more revision surgeries after FESS., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2014.)

Objective: To investigate whether adenotonsillectomy reduces upper respiratory tract infections (URIs) in the pediatric population., Methods and Subjects: We identified 415 children, aged ≤18 years who had undergone adenoidectomy and/or tonsillectomy during the period from 1999 to 2006, from the Taiwan National Health Insurance Research Database. The comparison group consisted of 1630 children without the surgery randomly selected from the same database frequency matched with sex, age and the surgery date (index date). Changes in physician visits for URIs 2-year period before and 2-year period after the index date were compared between the two groups of children., Results: The number of outpatient visits for URIs decreased with time, children with tonsillectomy and/or adenoidectomy had a greater reduction than comparison children (mean changes, -14 times and -6 times, respectively) in the 2-year period after the index date. Multivariate analyses using generalized estimated equation revealed a significant effect in reducing URIs visits from the surgery (relative ratio=0.85, p<0.0001), strongest for children undergoing both tonsillectomy and adenoidectomy (relative ratio=0.76, p<0.0001). The association between surgery and the decrease in URIs was more pronounced for children aged 12 years and less., Conclusion: This population-based study suggests that tonsillectomy and/or adenoidectomy is associated with fewer physician visits for URIs. The association is weakened in old children., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Conclusion: Our findings suggest that, in Asian patients with severe obstructive sleep apnea (OSA), obesity is a better predictor of uvulopalatopharyngoplasty (UPPP) failure than Friedman stage III., Objectives: This study evaluated UPPP success rates in obese and non-obese Asian patients treated for severe OSA., Methods: Records of patients who underwent UPPP for treatment of OSA were retrospectively reviewed. Preoperative and postoperative apnea/hypopnea index (AHI) and Epworth Sleepiness Scale (ESS) score, and Friedman stage were compared in non-obese (body mass index (BMI) <27 kg/m(2)) and obese (BMI ≥27 kg/m(2)) patients. Treatment success was defined as >50% reduction in preoperative AHI or postoperative AHI of <20 events/h., Results: Treatment success was significantly lower (p < 0.0001) in the obese group (24.6%) compared with the non-obese group (62.5%). After adjusting for gender, age, BMI, Friedman stage, and preoperative AHI and ESS score, obesity was a significant independent negative predictor of treatment success (adjusted OR = 0.297, 95% CI = 0.114-0.773, p = 0.013).

This study aimed at evaluating the association and interaction among human 8-oxoguanine DNA N-glycosylase 1 (hOGG1) genotypic polymorphism, smoking status and oral cancer risk in Taiwan. For this purpose, the well-known polymorphic variants of hOGG1, codon 326, was analyzed for its association with oral cancer susceptibility, and its joint effect with individual smoking habits on oral cancer susceptibility. In total, 620 patients with oral cancer and 620 healthy controls were recruited from the China Medical Hospital and genotyped. The results showed that the hOGG1 codon 326 genotypes were differently distributed between the oral cancer and control groups (p=0.0266), with the C allele of hOGG1 codon 326 being significantly (p=0.0046) more frequently found in cancer patients than in controls. We further analyzed the genetic-smoking joint effects on oral cancer risk and found an interaction between hOGG1 codon 326 genotypes and smoking status. The hOGG1 codon 326 CC genotype was associated with oral cancer risk only in the smoker group (p=0.0198), but not in the non-chewer group (p=0.8357). Our results provide evidence that the C allele of hOGG1 codon 326 may have a joint effect with smoking on the development of oral cancer.

Aim: The cell cycle regulator cyclin D1 (CCND1) is a critical regulator of the G1/S phase transition and plays an important part in several tumor types. This study aimed at investigating the association of CCND1 with and examining the interaction among CCND1 genotype and individual smoking habit in nasopharyngeal carcinoma susceptibility., Patients and Methods: A total of 352 native Taiwanese consisting of 176 cases and 176 controls were enrolled in this hospital-based study, and CCND1 A870G (rs9344) and C1722G (rs678653) genotyping were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and partially verified by direct sequencing., Results: The results showed that there were significant differences between nasopharyngeal carcinoma and control groups in the distribution of the genotypic (p=0.0222) and allelic (p=0.0322) frequencies in the CCND1 A870G genotype. Individuals who carried at least one G allele (GG or AG) had a 0.71-fold lower risk of developing nasopharyngeal carcinoma compared to those who had the AA genotype (95% confidence interval=0.53-0.96). In addition, there is an obvious joint effect of CCND1 A870G genotype with smoking habit on nasopharyngeal carcinoma susceptibility., Conclusion: These findings support the conclusion that the cell cycle regulation may play a role in nasopharyngeal carcinoma development and that CCND1 A870G polymorphism maybe a useful biomarker for nasopharyngeal carcinoma progression.

The adenoid is a bacterial reservoir that contributes to chronic otolaryngologic infections. Staphylococcus aureus (S. aureus) is a common pathogen in the adenoid. The increase of antibiotic resistance in S. aureus has become an important issue in public health. The aim of this study was to compare adenoid hyperplasia and biofilm formation in children with S. aureus adenoiditis in Taiwan. The patients were divided into methicillin-resistant and methicillin-sensitive S. aureus groups according to the S. aureus obtained from adenoid tissue after antibiotic susceptibility testing. Adenoid hyperplasia was assessed by lateral cephalometry, and the severity of sinusitis was evaluated by Water's view. Microbiological investigation of available S. aureus isolates was performed by in vivo morphological observation and an in vitro bacterial biofilm assay. Sixty isolates of S. aureus were identified in 283 children (21.2%) after adenoidectomy, of which 21 (35%) were methicillin-resistant S. aureus (MRSA). The severity of adenoid hyperplasia and extensive biofilm formation were more prominent in patients infected with methicillin-resistant S. aureus than in those infected with methicillin-sensitive S. aureus (MSSA). The primary outcome of this study was to provide evidence that S. aureus constituted a significant portion of the adenoidal pathogens. The secondary outcome of this study was that MRSA adenoiditis may be associated with adenoid hyperplasia and biofilm formation.

Background: Caveolin-1 (Cav-1), which has been proposed as a candidate tumor suppressor, plays a regulatory role in several signaling pathways. High expression of Cav-1 in nasopharyngeal carcinoma (NPC) may enhance tumor cell migration and correlate with poor prognosis of the patients, while the genetic alterations of Cav-1 during nasopharyngeal carcinogenesis are still largely unknown. The aim of this study was to evaluate the association between NPC susceptibility and Cav-1 genotypes., Patients and Methods: One hundred and seventy six patients with NPC and 176 age- and gender-matched healthy controls recruited in Taiwan were genotyped and analyzed by PCR-restriction fragment length polymorphism., Results: There were significant differences between the NPC and control groups in the distributions of the genotypic (p=0.0019) and allelic frequencies (p=2.5 10(-4)) in the Cav-1 T29107A (rs7804372) polymorphism., Conclusion: In this first report of Cav-1 involvement in NPC the A allele of Cav-1 T29107A is found to be protective against the development of NPC and may be a novel useful genomic marker for early screening and prediction of NPC.

The aim of this study was to evaluate the association and interaction of genotypic polymorphism in methylenetetrahydrofolate reductase (MTHFR) with smoking habits and oral cancer in Taiwan. Two well-known polymorphic variants of MTHFR, C677T (rs1801133) and A1298C (rs1801131), were analyzed in association with oral cancer risk, and their joint effects with individual smoking habits on oral cancer risk are discussed. In total, 620 oral cancer patients and 620 non-cancer controls in central Taiwan were recruited and genotyped. The MTHFR C677T genotype, but not the A1298C, was differently distributed between the oral cancer and control groups. The T allele of MTHFR C677T was significantly more frequently found in controls than in oral cancer patients. Joint effects of smoking and MTHFR C677T genotype significantly affected oral cancer susceptibility. The MTHFR C677T CT and TT genotypes in association with smoking conferred lower odds ratios of 0.66 and 0.54 (95% confidence interval=0.49-0.82 and 0.39-0.86), respectively. Those patients with MTHFR C677T CT and TT genotypes also had a lower risk of oral cancer metastasis. MTHFR C677T genotype may have joint effects with smoking on oral carcinogenesis, and may be a useful biomarker for prediction and prognosis of oral cancer.

Background: Caveolin-1, which has been proposed as a candidate tumor suppressor, plays a regulatory role in several signaling pathways. The aim of this study was to evaluate the association between oral cancer susceptibility and Cav-1 genotypes. In this hospital-based case-control study, the association of Cav-1 polymorphisms with oral cancer risk in a central Taiwanese population was investigated., Methods: Six hundred patients with oral cancer and 620 age- and sex-matched healthy control subjects were genotyped and analyzed by polymerase chain reaction-restriction fragment length polymorphism., Results: There were significant differences between oral cancer and control groups in the distributions of their genotypes (P = 1.7 × 10(-18) and 2.6 × 10(-4)) and allelic frequencies (P = 3.3 × 10(-19) and 9.5 × 10(-6)) in the Cav-1 G14713A (rs3807987) and T29107A (rs7804372) polymorphisms, respectively. As for the combined genotype analysis, those who had GG/AT or GG/AA at Cav-1 G14713A/T29107A showed a 0.72-fold (95% confidence interval = 0.52-0.99) decreased risk of oral cancer compared to those with GG/TT, while those of any other combinations were of increased risk. The presence of metastasis was also correlated to both Cav-1 G14713A AA and Cav-1 T29107A TT genotypes., Conclusions: Cav-1 is involved in oral cancer, the A allele of the Cav-1 G14713A is risky, the A allele of the Cav-1 T29107A is protective, and AA/TT on these two polymorphisms may be the most risky combined genotype for the development of oral cancer and may be novel risk markers for early detection and prediction of distant metastasis.

Problem: The role of elective neck dissection in early stage tongue and buccal squamous cell carcinoma with negative neck lymph nodes is still controversial., Methods: We retrospectively reviewed patients with T1-2N0M0 buccal and tongue cancer who underwent primary tumour excision with or without elective neck dissection between January 1997 and December 2006., Results: Elective neck dissection specifically improved disease-free survival of T2N0M0 buccal cancer and overall survival of T2N0M0 tongue cancer., Conclusion: Elective neck dissection seems to improve the disease-free survival rate of T2N0M0 buccal cancer and the overall survival rate of T2N0M0 tongue cancer but has no beneficial effect on the survival rate of T1N0M0 buccal and tongue cancer.

Unlabelled: The cell cycle regulator cyclin D1 (CCND1) is thought to play a major role in the transition of the cell cycle from G(1) to S-phase. It is known that cancer cells have unbalanced cell cycle regulation. This study aimed to investigate the association of CCND1 single nucleotide polymorphisms A870G (rs9344) and C1722G (rs678653) with oral cancer risk and examine the interaction between CCND1 and smoking habit., Materials and Methods: In this hospital-based case-control study, the CCND1 polymorphisms were investigated in 620 patients and 620 age- and gender-matched controls., Results: Significant differences were shown between the oral cancer and control groups in the distribution of the genotypes (p=0.0014) and allelic frequency (p=0.0027) in the CCND1 rs9344 genotype. Individuals who carried at least one G allele (GG or AG) had a 0.64-fold decreased risk of developing oral cancer compared to those who carried the AA wild-type genotype (95% CI: 0.50-0.81). There was an obvious joint effect of CCND1 rs9344 genotype with smoking habit on oral cancer., Conclusion: Cell cycle regulation may play a role in oral carcinogenesis and CCND1 rs9344 polymorphism maybe a useful biomarker for oral oncology.

Aim: Several epidemiological studies have investigated the association between ataxia telangiectasia mutated (ATM) gene polymorphisms and breast cancer risk. However, published data are still inconclusive and there are no such studies for Taiwan. Thus, the polymorphic variants of ATM were investigated for their association with breast cancer in Taiwan for the first time here., Patients and Methods: In this hospital-based matched case-control study, associations of seven ATM single nucleotide polymorphisms (rs600931, rs652311, rs227060, rs227292, rs624366 and rs189037) with breast cancer risk in a Taiwanese population were investigated. One thousand two hundred and thirty-two patients with breast cancer and the same number of age-matched healthy controls recruited were genotyped and analyzed., Results: There was a slight difference between breast cancer and control groups in the distributions of their genotypic (p = 0.0774) and allelic frequencies (p = 0.0217) in the rs189037 polymorphism. As for the other six polymorphisms there was no differential distribution., Conclusion: Our data indicate that ATM polymorphism is associated with breast cancer, and the A allele of ATM rs189037 is a minor risky biomarker of breast cancer in Taiwan. The gene-gene and gene-environment interactions of ATM with other factors is worthy of further investigation.

Aim: To evaluate the association and interaction among hOGG1 genotypic polymorphism, betel quid chewing status and oral cancer risk in Taiwan., Materials and Methods: The well-known polymorphic variants of hOGG1, codon 326, were analyzed in association with oral cancer susceptibility, and discussed regarding its joint effect with individual habits on oral cancer susceptibility. In total, 620 patients with oral cancer and 620 healthy controls recruited from the China Medical Hospital were analyzed by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP)., Results: The hOGG1 codon 326 genotypes were differently distributed between the oral cancer and control groups (p=0.0266) and the C allele of hOGG1 codon 326 was significantly (p=0.0046) more frequently found in cancer patients than in controls. We further analyzed the joint effects of gene variants and habits on oral cancer risk and found an interaction between hOGG1 codon 326 genotype and betel quid chewing status. The association of the C allele for hOGG1 codon 326 with oral cancer risk was found to be significant only in the betel quid chewer group (p=0.0149), not in the non-chewer group (p=0.8028)., Conclusion: Our results provide evidence that the C allele of hOGG1 codon 326 may have a joint effect with betel quid chewing on the development of oral cancer.

The DNA repair gene X-ray repair complementing defective repair in Chinese hamster cells 4 (XRCC4) is thought to play a major role in the caretaking of the whole genome via double-strand break repair. However, the association of polymorphic variants of XRCC4 with colorectal cancer susceptibility has never been reported. In this hospital-based case-control study, the association of XRCC4 polymorphisms C-1622T (rs7727691), G-1394T (rs6869366), G-652T (rs2075685), C-571T (rs2075686), intron 3 DIP (rs28360071), S247A (rs3734091) and intron 7 DIP (rs28360317) with colorectal cancer risk in a Taiwanese population was investigated. The genotypes of XRCC4 of 370 patients with colorectal cancer and 370 age- and gender-matched healthy controls were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. We found significant differences in the genetic and allelic frequencies of the XRCC4 G-1394T between the colorectal cancer and control groups (p=0.0003 and 8.32 x 10(-5), respectively). The distributions of other genetic polymorphisms between cases and the control group were not significantly different. We conclude that the G allele of XRCC4 G-1394T may contribute to colorectal carcinogenesis and may be useful for early detection of colorectal cancer.

Background: The DNA repair gene xeroderma pigmentosum group D (XPD), an important caretaker of the overall genome stability, is thought to play a major role in the development of human malignancy. Polymorphic variants of XPD, at codon 312 (rs1799793), 751 (rs13181) and promoter-114 (rs3810366), were chosen to be studied for their association with bladder cancer susceptibility in a central Taiwanese population., Patients and Methods: In this hospital-based case-control study, bladder cancer patients (308) and age- and gender-matched healthy controls (308) were recruited and their genotypes were analyzed by a polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) method., Results: A significant difference in the frequency of the XPD codon 312 genotype, but not the XPD codon 751 or promoter-114 genotypes, was found between the bladder cancer and control groups. Those who had G/A or A/A at XPD codon 312 showed a 1.85-fold (95% confidence interval=1.34-2.56) increased risk of bladder cancer compared to those with G/G. As for XPD codon 312 and promoter-114, there was no difference in distribution between the bladder cancer and control groups., Conclusion: The heterozygous and homozygous A allele of the XPD codon 312 may be responsible for bladder carcinogenesis and useful in the early detection and prediction of bladder cancer.

Exonuclease 1 (Exo1) is an important nuclease involved in the mismatch repair system that helps to maintain genomic stability, to modulate DNA recombination, and to mediate cell cycle arrest. Potential polymorphisms in Exo1 may alter cancer risks by influencing the repair activity of Exo1. Therefore, we hypothesized that single-nucleotide polymorphisms in Exo1 were associated with the risk of oral cancer. In this hospital-based study, the associations of Exo1 A-1419G (rs3754093), C-908G (rs10802996), A238G (rs1776177), C498T (rs1635517), K589E (rs1047840), G670E (rs1776148), C723R (rs1635498), L757P (rs9350) and C3114T (rs851797) polymorphisms with oral cancer risk in a central Taiwan population were investigated. In total, 680 patients with oral cancer and 680 age- and gender-matched healthy controls recruited from the China Medical University Hospital were genotyped. A significantly different distribution is found in the frequency of the Exo1 K589E genotype, but not the other genotypes, between the oral cancer and control groups. The A allele Exo1 K589E conferred a significant (P=6.18E-8) increased risk of oral cancer. Gene-environment interactions with smoking were significant for Exo1 K589E polymorphism (OR=2.509, 95% CI=1.914-3.287). Our results provide evidence that the A allele of the Exo1 K589E may be associated with the development of oral cancer.