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Summary: Objectives: Arginine is a nonessential amino acid which can regulate tumor growth. Argininosuccinate synthetase (ASS) is the rate-limiting enzyme for de novo arginine production. The expression pattern of ASS and the feasibility of arginine deprivation therapy in head and neck cancer have not been investigated. Materials and methods: The growth-inhibitory effect of arginine deprivation therapy was assessed either by proliferation assay with head and neck cancer cells cultured in arginine-free medium, or by tetrazolium/formazan dye assay with cells treated with an arginine-depleting drug (arginine deiminase, ADI). The tumor ASS status of 73 oral squamous carcinoma (OSCC) patients was then evaluated immunohistochemically and subsequently correlated with the corresponding clinicopathological parameters. Results: Head and neck cancer cells cultured in arginine-free medium either completely stopped proliferating, or proliferated minimally. In addition, ADI treatment inhibited the growth of all 8 head and neck cancer cell lines to different degrees. Although cellular ASS level did not correlate well with ADI-sensitivity among these cell lines, knockdown of endogenous ASS potentiated the growth-inhibitory effect of ADI in each individual cell line (FaDu and OEC-M1). In multivariable analysis, high tumor ASS level independently predicted an unfavorable disease-free survival in OSCC patients. Conclusion: High tumor ASS status is an independent variable predicting a poor disease-free survival in OSCC patients. Arginine deprivation therapy may potentially be used as a new approach to treat head and neck cancer. [ABSTRACT FROM AUTHOR]

The success of using glycolytic inhibitors for cancer treatment depends on studying the individual role of frequently deregulated glycolytic genes in cancer. This report aims to study the prognostic implication, and determine the cellular role and action mechanism of glycolytic ENO1 overexpression in head and neck cancer. The relationship of ENO1 mRNA expression in 44-pair clinical specimens with patient clinicopathologic characteristics was analysed by semi-quantitative RT-PCR, Kaplan–Meier survival curve and Cox model analyses. Following ectopic ENO1 expression or knockdown, we studied the proliferative, migratory, invasive, colony-forming and tumourigenic abilities of ENO1-genetically altered cells. DNA microarray analysis was used to identify downstream targets responsible for the ENO1 action in the cells. The expression of ENO1 mRNA was increased in 68% of tumour (T) specimens when compared to their normal (N) counterparts, and positively associated with clinical progression (p <0.05). High ENO1 expression (T/N⩾2) was frequently observed in the patients with large primary tumours, late clinical stages or advanced neck metastasis. Moreover, high ENO1 patients had significantly poorer clinical outcomes than low expressers (T/N<2). Ectopic ENO1 expression stimulated cell transformation, invasion and tongue tumour formation. ENO1 knockdown abrogated the stimulation. Suppression of ENO1-induced proinflammatory CCL20 chemokine expression significantly attenuated its stimulatory effects on cell transformation and invasion. A concordant expression of ENO1 and CCL20 was validated both in ENO1-expresing cells and in clinical specimens. Together, we demonstrate a prognostic role of ENO1 overexpression in head and neck cancer and ENO1-mediated promotion of cell transformation and invasion partly via induced CCL20 expression. [Copyright &y& Elsevier]

Purpose: Radiotherapy is the most effective treatment for nasopharyngeal carcinoma (NPC). The aim of this study is to evaluate the efficacy and toxicity of fractionated stereotactic body radiation therapy (SBRT) boost for NPC. Methods and Materials: Sixty-four patients with newly diagnosed, nonmetastatic NPC were treated with conventional radiotherapy 64.8–68.4 Gy followed by fractionated SBRT boost 12–15 Gy between January 2002 and July 2004. Most patients (72%) presented with Stage III-IV disease. Fifty-two patients also received cisplatin-based concurrent (38) or neoadjuvant (14) chemotherapy. The major endpoints were local control, overall survival, and complications. Results: All patients finished the planned dose of radiotherapy. After a median follow-up of 31 months (range, 22–54), 15 patients developed tumor recurrences—3 in the nasopharynx, 4 in the neck, 5 in distant sites, 1 in both nasopharynx and neck, 2 in the neck and a distant site. The 3-year actuarial rate of local control was 93.1%, regional control 91.4%, freedom from distant metastasis 90.3%, and overall survival 84.9%, respectively. There were no Grade 4 acute or chronic radiation-related complications. Conclusions: Fractionated SBRT boost for NPC is technically feasible and provides good local control without any severe complications. [Copyright &y& Elsevier]

Summary: Amphiregulin (AR), an epidermal growth factor (EGF)-like molecule, is a mitogen for keratinocytes. Squamous cell carcinoma (SCC) is a tumor derived from keratinoctyes. Expression of AR mRNA positively correlated with the clinical progression of 39 oral SCC. Oral SCC line, KB, was used as a model to study if increased expression of AR altered the biological behaviors of SCC cells. Exogenous AR dose-dependently enhanced the proliferation of KB cells expressing EGF receptor 1 (EGFR-1), a major receptor for AR, but little AR. Neutralizing anti-AR antibody significantly reversed the stimulatory effect of exogenous AR on KB cell proliferation. Ectopically expressed AR in stable clones manifested higher abilities to proliferate, migrate and invade Matrigel than vector control. Cyclooxygenase 2 (COX-2), but not metalloprotease 9 (MMP-9) mRNA, was increased in all the AR-expressing stable clones. In summary, AR behaves as a tumor promoter for oral SCC cells partly via increased expression of COX-2. [Copyright &y& Elsevier]

Summary: Early-stage oral cancer patients may have distinct clinical outcomes and respond differently to the same treatment. Up to now, there is still no individual marker to identify such patients with poor outcome. Down-regulation of a tumor suppressor gene, S100A2, in oral cancer cells was identified by mRNA profiling analysis then confirmed by RT-PCR and Southern blotting. The expression of nuclear S100A2 protein examined by immunohistochemistry was not significantly associated with any patient characteristic among the 70 early-stage oral squamous cell carcinoma (SCC) patients. Intriguingly, the loss of nuclear S100A2 positivity was significantly associated with shorter disease-free survival (p =0.019) while having no effect on the overall survival of these patients. Cox regression analysis with backward elimination identified S100A2 (p =0.006), tobacco smoking (p =0.013), and betel quid chewing (p =0.019) as independent predictors of disease-free survival. This is a first study to demonstrate that loss of nuclear S100A2 may serve as an independent prognostic marker for early-stage oral cancer patients at high risk of recurrence. A more aggressive treatment modality and intensive follow-up may be recommended for the patients with reduced expression of S100A2 in tumor cell nuclei. [Copyright &y& Elsevier]

Oral cancer is one of the most common types of human cancer in the world. Although the risk factors for oral cancer are well-recognized in different countries, the molecular mechanism responsible for this malignancy remains elusive particularly in the countries where betel quid chewing is prevalent. The cDNA microarray analysis was used to analyse the mRNA expression patterns of 1177 genes in ten oral cancer patients with betel quid chewing history. Eighty-four genes involving cell adhesion, cell shape, growth, apoptosis, angiogenesis, metastasis, and metabolism were deregulated. Although the expression profile of these genes was shared by certain clinical patients, there was no significant association of the expression profile with clinical staging. Functional implication of four validated genes including caspase-1, STAT-1, COX-2 and pleiotrophin was discussed. This study provides pilot data for understanding the pathogenesis of oral cancer in countries like Taiwan where betel quid chewing is prevalent. [Copyright &y& Elsevier]

The choice of salvage modalities of recurrent squamous cell carcinoma (SCC) of the oral cavity remains controversial. We investigated the feasibility of the surgical salvage treatment as a primary option. From 1989 to 1999, curative intended surgery was performed on 191 patients with SCC of the oral cavity at National Cheng Kung University Hospital in Taiwan. These patients were divided into fresh group and salvage group. Survival and complication rates were analyzed for both groups. Patients with early and late recurrent stage had 60 and 38% 5-year absolute survival after salvage surgery. The overall complication rate was higher in the salvage group (60.7 vs 30.4%, P<0.0001), but the major complication rate was not significantly different between these groups (P=0.121). Surgery achieves an acceptable survival in recurrent oral SCC without increasing the major complication rate. Thus surgery is concluded to be a reliable and feasible treatment of choice. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Background To investigate the association between the diagnosis-to-treatment interval (DTI) and overall survival (OS) in patients with oral cavity squamous cell carcinoma (OSCC). Methods A total of 18,677 patients with first primary OSCC identified in the Taiwanese Cancer Registry Database between 2004 and 2010 were examined. The effect of DTI on 5-year OS rates was investigated with multivariate Cox regression analysis. After the identification of the optimal cutoff for DTI based on the 5-year OS rates, DTI was classified in the following 20-day groups: ≤20 days (57% of the study patients), 21–45 days (34%), 46–90 days (6%) and ≥91 days (3%). In additional exploratory analyses, DTI was reclassified in the following 30-day interval groups: ≤30 days (81% of the study patients), 31–60 days (14%), 61–90 days (2%) and ≥91 days (3%). Results Multivariate analyses identified DTI (≤20 days versus other subgroups), sex (female versus male), age (<65 versus ≥65 years), clinical stage (p-stage I versus p-stage II, III, IV) and treatment modality (initial surgery versus initial non-surgery) as independent prognostic factors for 5-year OS. Compared with a DTI ≤20 days, the DTI categories ≥91 days (hazard ratio [HR]: 1.28, P < 0.001), 46–90 days (HR: 1.25, P < 0.001) and 21–45 days (HR: 1.07, P = 0.007) were independently associated with a higher risk of 5-year mortality. Similar results were obtained for DTI ≤30 days groups. Conclusions DTI is independently associated with 5-year OS in OSCC patients. A DTI longer than 30 days or even 20 days may potentially decrease survival. [ABSTRACT FROM AUTHOR]

Summary Objectives This analysis examined the life expectancies (LE) and expected years of life lost (EYLL) in relation to oral cancer in Taiwan. Materials and methods A semi-parametric extrapolation method was applied to estimate gender, age, histology, subsite, and stage stratified LE, EYLL of 22,024 pathologically verified oral cancer patients retrospectively recruited from the National Cancer Registry of Taiwan during 2002–2009, who were followed up to 2011. Results The patients were predominantly male 20,101, (91.3%), and over 80% were less than 65 years old. The mean age at diagnosis of males was younger than that of females (52.73 years vs. 60.76 years). The LE after diagnosis was longer among females than males (15.26 years vs. 12.73 years), with a smaller loss of the corresponding EYLL (8.88 years vs. 14.05 years), which prevails after stratification by age and stage. More than half of the oral cancer cases were diagnosed at a later stage, with 2921 cases (13.3%) of stage III and 8488 (38.5%) of stage IV. The five-year overall survival rate of oral cancer for stages I, II, III, and IV were 78.98%, 69.38%, 54.62%, and 36.17%, respectively. The earlier the diagnosis, the longer the life expectancy and the smaller the EYLL. Conclusions We concluded that early detection and early intervention of oral cancer can prolong life expectancy and reduce the years of life lost, indicating the importance of proactive screening and oral hygiene. [ABSTRACT FROM AUTHOR]

Summary: Objectives:: 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. Materials and methods:: 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. Results:: 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 teeth <2times/day (OR=1.51, 95% CI: 1.02–2.23), frequent gum bleeding (OR=3.15, 95% CI: 1.36–7.28), and loss of >20 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). Conclusions:: 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. [Copyright &y& Elsevier]

Little is known about the specificity of angiogenic properties of oral cancer cells and the possible mechanisms. Stimulatory effects on proliferation and migration of human umbilical vein endothelial cells (HUVEC) characterized the angiogenic properties of oral cancer cells but not normal oral keratinocytes (NOK). ELISA found the presence of vascular endothelial growth factors (VEGF) both in the tested oral cancer cells and NOK. Attenuation of the proangiogenic effects by neutralizing VEGF antibodies suggests VEGF play a key role in the acquisition of the angiogenic phenotype in oral cancer cells. Western blotting of p53 and murine double mutant 2 (Mdm2) together with p53 DNA sequencing analysis indicate that p53 function loss by mutation or overexpression of Mdm2 occurred in all tested oral cancer cells regardless of their etiology. In summary, the angiogenic property of oral cancer cells is mediated by many factors in addition to VEGF and the functional status of p53. [ABSTRACT FROM AUTHOR]

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 <4 mm and <5 mm predict poor CSS and OS, respectively.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. [ABSTRACT FROM AUTHOR]