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Background: To investigate the prognostic value of lymph node ratio (LNR), as well as the correlation with docetaxel, cisplatin, and 5-FU (TPF) induction chemotherapy, in patients with locally advanced oral squamous cell carcinoma (OSCC)., Methods: Two-hundred and forty-five patients from a phase 3 trial involving TPF induction chemotherapy in stage III/IVA OSCC patients (NCT01542931) were enrolled in this study between 2008 and 2010. The clinical and pathological data were collected and analyzed. The cutoff value for LNR was calculated on the receiver operating characteristic (ROC) curve. Univariate and multivariate Cox regression models, and Kaplan-Meier method were used for survival analysis., Results: According to the ROC curve, the cutoff value for LNR was 7.6%. With a median follow-up period of 80 months, the OSCC patients with high-risk LNR (> 7.6%), or positive extranodal extension (ENE) had significantly worse clinical outcomes than patients with low-risk LNR (≤7.6%) or negative ENE. Multivariate analysis on pathological covariates showed that only high-risk LNR was an independent negative predictive factor for survival (P < .05). The cutoff value of LNR of 7.6% was also verified with the similar results using an open TCGA database, high-risk LNR indicating worse overall survival (P < .001) and disease-free survival (P < .001)., Conclusion: Oral squamous cell carcinoma patients with high-risk LNR have a worse clinical outcome than patients with low-risk LNR. High-risk LNR is an independent negative predictive factor for clinical outcome in patients with locally advanced OSCC., (© 2020 The Authors. Journal of Oral Pathology & Medicine published by John Wiley & Sons Ltd.)

The oral microbiota plays an important role in the human microbiome and human health, and imbalances between microbes and their hosts can lead to oral and systemic diseases and chronic inflammation, which is usually caused by bacteria and contributes to cancer. There may be a relationship between oral bacteria and oral squamous cell carcinoma (OSCC); however, this relationship has not been thoroughly characterized. Therefore, in this study, we compared the microbiota compositions between tumor sites and opposite normal tissues in buccal mucosal of 50 patients with OSCC using the 16S rDNA sequencing. Richness and diversity of bacteria were significantly higher in tumor sites than in the control tissues. Cancer tissues were enriched in six families ( Prevotellaceae, Fusobacteriaceae, Flavobacteriaceae, Lachnospiraceae, Peptostreptococcaceae , and Campylobacteraceae ) and 13 genera, including Fusobacterium, Alloprevotella and Porphyromonas . At the species level, the abundances of Fusobacterium nucleatum, Prevotella intermedia, Aggregatibacter segnis, Capnocytophaga leadbetteri, Peptostreptococcus stomatis , and another five species were significantly increased, suggesting a potential association between these bacteria and OSCC. Furthermore, the functional prediction revealed that genes involved in bacterial chemotaxis, flagellar assembly and lipopolysaccharide (LPS) biosynthesis which are associated with various pathological processes, were significantly increased in the OSCC group. Overall, oral bacterial profiles showed significant difference between cancer sites and normal tissue of OSCC patients, which might be onsidered diagnostic markers and treatment targets. Our study has been registered in the Chinese clinical trial registry (ChiCTR1900025253, http://www.chictr.org.cn/index.aspx)., (Copyright © 2020 Zhang, Liu, Zheng and Zhang.)

Background: The clinical degradation rate and strength of biodegradable implant exposed to postoperative radiotherapy (PORT) are unknown., Methods: A prospective randomized control trial of 40 consecutive mandibulotomy patients randomly divided into titanium and biodegradable cohorts. All patients received PORT. The following parameters were compared: maximal mouth opening, occlusal force, center of force trajectory, occlusal status, radiographic evidence of bony union, mandibular function impairment questionnaire (MFIQ), overall satisfaction score, and complication rates., Results: Both the mandibular function and occlusal status parameter of the biodegradable and the titanium groups were not significantly difference. Biodegradable cohort showed better MFIQ scores (P = .08) and overall satisfaction scores (P = .64) but was not statistically significant. Of note, 40% of patients in the titanium cohort complained of plate palpability/cold intolerance and required plate removal (P = .02); 10% of patients in the titanium cohort developed osteoradionecrosis., Conclusion: Biodegradable osteosynthesis is as reliable as titanium osteosynthesis for mandibulotomy fixation. PORT did not increase the complication rate in the biodegradable group., (© 2019 Wiley Periodicals, Inc.)

Purpose: To find the potential biomarkers in the diagnostic model of oral and squamous cell carcinoma (OSCC), and to further validate the biomarker., Experimental Design: With the MALDI-TOF-MS analysis between tissues from oral cancer patients and normal oral mucosa from healthy controls, scavenger receptor class A member 5 (scara5) is found to be potentially significant after searching the protein database. In addition, Immunohistochemical staining, PCR, ELISA, and Western blot technique are used to detect scara5 expression in clinical samples and cell lines., Results: In this study, the results indicate that scara5 expression is decreased in tumor group in the MALDI-TOF-MS analysis. Furthermore, down-regulation of scara5 expression is related with cell proliferation and invasion. Serum scara5 detection can discriminate OSCC samples from normal samples with high sensitivity., Conclusions and Clinical Relevance: Scara5 has the potential to be considered as a serum biomarker in the early diagnosis of OSCC. The clinical relevance of the study lies in finding the biomarker by proteomics and subsequently validating it with clinical samples and cell lines., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Platelet-derived growth factor alpha (PDGFRA) is a gene encoding tyrosine kinase receptor and both EGFR and PDGFRA activate tyrosine kinases. The implication of PGFRA in many cancers and its prognostic significance irrespective to EGFR status in spinal chordoma, gliomas, and uterine cancers have shown a need for its investigation in oral squamous cell carcinoma (OSCC). We investigated the prognostic value of PDGFRA mRNA expression in OSCC., Patients and Methods: The study was conducted in the department of oral maxillofacial surgery-head and neck oncology, at a tertiary hospital. The data on PDGFRA mRNA expression and immunohistochemical staining status in primary OSCC patients treated for curative surgery from 2010 to 2012 were analyzed. Univariate and multivariate analyses were performed with other cofactors for survival., Results: A total of 114 consecutive patients with primary OSCC who received treatment were studied. Thirty-one patients died of the disease. Strong PDGFRA immunohistochemical staining and high expression of PDGFRA mRNA were associated with positive pN status (P < .001), disease-free survival (P < .001), and overall survival (P < .001) in multivariate cox regression when all other factors such as pN status and histological grading were analyzed. Kaplan-Meier analysis revealed that the 2-year survival and 3-year survival of patients with PDGFRA mRNA low expression were 96.83%. However, 2-year survival for PDGFRA mRNA high expression level was 59.64%, which decreased to 45.57% by 3-years., Conclusion: PDGFRA overexpression in oral SCC, in respect to strong PDGFRA immunohistochemical staining and high PDGFRA mRNA expression, was positively associated with regional metastasis and reduced patient survival., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Venous thromboembolism (VTE) is a preventable complication in which early ambulation is expected after head and neck surgery. Thus, the role of VTE prophylaxis is questionable and needs further assessment. The purpose of this study was to specify the relative contributing risk factors for patients who underwent head and neck cancer ablation with immediate reconstruction., Methods: A retrospective analysis was conducted of consecutive head and neck cancer ablations with immediate reconstructions between 2008 and 2013. Dextran and prostaglandin E2 (PGE2) were routinely given as flap thromboprophylaxis. Logistic regression was applied to analyze the potentially significant risk factors., Results: Of 1953 subjects, the incidence of symptomatic VTE was 2.2% with 0.1% mortality rate. Prolonged surgery (>592.5 minutes; P = .048), immobilization (>4 days; P = .019), and subjects without postoperative flap thromboprophylaxis (P = .002) are significant risk factors for VTE development., Conclusion: Our flap thromboprophylaxis regime might have played a crucial role in keeping the incidence of VTE low. Despite prolonged immobilization in fibula flap reconstruction, the incidence of VTE remained low when flap thromboprophylaxis was given., (© 2017 Wiley Periodicals, Inc.)

Background: Platelet-derived growth factors alpha (PDGFA) is a tyrosine kinase receptor activator which is known to be amplified in the malignancies, and their expression levels are correlated to tumor progression and reduced overall survival. The expression of PDGFRA is different among the tumors and normal tissues; furthermore, their expression level is site specific. Under a physiological condition, PDGFRA and its ligand are expressed in distinct cell populations and activated in a paracrine manner. Nevertheless, heterodimer characteristic of PDGFRA allows it to be trans-activated by non-specific ligands or via autocrine manner. The future of cancer therapy can be based on PDGFRA receptor blockade and therefore warrants further investigation to determine the differing expression of PDGFRA between controls and patients with oral squamous cell carcinoma (OSCC)., Methods: We performed a case-control study of 111 patients with newly diagnosed tongue squamous cell carcinoma and 111 control subjects without a cancer diagnosis, matched for age and gender, to evaluate the association between PDGFRA expression levels in oral mucosa. We then performed smoking stratification in each cohort. Independent t test analysis was applied for case-control comparisons., Results: Mean value of PDGFRA mRNA level (-ΔCt) for normal cohort is -30.242, whereas mean value of PDGFRA mRNA level for patients with OSCC is -11.516. PDGFRA mRNA level (-ΔCt) was significantly higher in oral cancer cohort, P<.001. Smokers have a significantly higher PDGFRA mRNA expression in comparison with non-smokers (P=.002) among the non-cancer group. Likewise, this trend is observed in cancer cohort too, P=.044., Conclusion: PDGFRA expression is significantly higher in oral cancer cohort with or without the establishment of tobacco risk factor., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

CD73 is a cell surface immunosuppressive enzyme involved in tumor progression and metastasis. While patients whose cancer cells express elevated CD73 are typically associated with an unfavorable outcome, the clinical impact of CD73 expression in patients with Head and neck squamous cell carcinoma (HNSCC) remains unclear. In the present study, we investigated the prognostic significance of CD73 in HNSCC using gene and protein expression analyses. Our results demonstrate that high levels of CD73 are significantly associated with reduced overall survival in patients with HNSCC. We also investigated the functional role of CD73 in vitro and demonstrated that CD73 promotes HNSCC migration and invasion through adenosine A3R stimulation and the activation of EGF/EGFR signaling. Moreover, in vivo xenograft studies demonstrated that CD73 promotes tumorigenesis. In conclusion, our study highlights a role for CD73 as a poor prognostic marker of patient survival and also as a candidate therapeutic target in HNSCCs., Competing Interests: The authors have declared that no conflicts of interest.

Purpose: To investigate the mutation status of growth differentiation factor 15 (GDF15) in patients with oral squamous cell carcinoma (OSCC), as well as the prognostic value of missense GDF15 mutations., Patients and Methods: Formalin-fixed paraffin-embedded biopsy samples from 46 OSCC patients were involved in this study. GDF15 and TP53 mutations were sequenced using the Ion Torrent Personal Genome Machine, GDF15 protein expression was detected using immunohistochemistry. Torrent Suite Software v.3.6, Integrative Genomics Viewer; v.2.3, statistical software SPSS18.0 for Windows were used for analysis. All hypothesis-generating tests were two-sided at a significance level of 0.05., Results: Twenty-nine GDF15 mutations were identified in 19 out of 46 patients (41.3%), including eighteen missense mutations, two nonsense mutations and nine synonymous mutations. The patients with missense GDF15 mutations had poorer prognostic outcomes than those with wild-type GDF15, including overall survival (P = 0.035), disease-free survival (P = 0.032), locoregional recurrence-free survival (P = 0.015), and distant metastasis-free survival (P = 0.070). Missense GDF15mutations was an independent increased risk factor of overall survival (HR = 5.993, 95% CI:1.856-19.346, P = 0.003), disease-free survival (HR = 3.764, 95% CI:1.295-10.945, P = 0.015), locoregional recurrence-free survival (HR = 4.555, 95% CI:1.494-13.889, P = 0.008), and distant metastasis-free survival (HR = 4.420, 95% CI:1.145-13.433, P = 0.009)., Conclusions: Patients with missense GDF15 mutations have significantly poorer outcomes than those with wild-type GDF15, missense GDF15 mutations could be used as an independent increased risk factor of poor prognosis in OSCC patients.

The aim of this study was to compare the outcomes of elective neck dissection (END) with that of a more conservative approach comprising of observation plus therapeutic neck dissection for nodal relapse (OBS), by conducting a meta-analysis of randomized controlled trials (RCTs) that compare these two surgical approaches in patients. RCTs conducted prior to May 2015 were identified from electronic databases such as MEDLINE EMBASE and Cochrane Library. Reference lists within the retrieved articles were used as secondary reference sources. Disease-free survival (DFS) and overall survival (OS) were the primary outcome measures. Five RCTs with a combined subject population of 779 patients were included. Meta-analysis of these 5 RCTs showed that DFS in END group was higher than that in the OBS group with a significant inter-group difference (Risk Ratio [RR]:1.33; 95% Confidence Interval [CI] 1.06, 1.66); P=0.01; five trials, 779 participants]. However, there was a significant statistical heterogeneity among the studies (I-squared=56%, P=0.06). Four studies had reported on OS. Meta-analysis of these 4 RCTs revealed a higher OS in the END group as compared to that that in the OBS group with a significant inter-group difference (RR: 1.18; 95% CI 1.07, 1.29); P=0.0009; four trials, 708 participants]. The statistical heterogeneity of these 4 studies is small (I-squared=14%, P=0.32). The results of this meta-analysis suggest that END at the time of resection of the primary tumor confers a DFS and OS benefit in patients with clinically node-negative oral cancer., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Previously, we conducted a randomized phase III trial of TPF (docetaxel, cisplatin, and 5-fluorouracil) induction chemotherapy in surgically managed locally advanced oral squamous cell carcinoma (OSCC) and found no improvement in overall survival. This study reports long-term follow-up results from our initial trial. All patients had clinical stage III or IVA locally advanced OSCC. In the experimental group, patients received two cycles of TPF induction chemotherapy (75mg/m2 docetaxel d1, 75mg/m2 cisplatin d1, and 750mg/m2/day 5-fluorouracil d1-5) followed by radical surgery and post-operative radiotherapy; in the control group, patients received upfront radical surgery and post-operative radiotherapy. The primary endpoint was overall survival. Among 256 enrolled patients with a median follow-up of 70 months, estimated 5-year overall survival, disease-free survival, locoregional recurrence-free survival, and distant metastasis-free survival rates were 61.1%, 52.7%, 55.2%, and 60.4%, respectively. There were no significant differences in survival rates between experimental and control groups. However, patients with favorable pathologic responses had improved outcomes compared to those with unfavorable pathologic responses and to those in the control group. Although TPF induction chemotherapy did not improve long-term survival compared to surgery upfront in patients with stage III and IVA OSCC, a favorable pathologic response after induction chemotherapy may be used as a major endpoint and prognosticator in future studies. Furthermore, the negative results observed in this trial may be represent type II error from an underpowered study. Future larger scale phase III trials are warranted to investigate whether a significant benefit exists for TPF induction chemotherapy in surgically managed OSCC.

Background: Although molecular mechanism of growth differentiation factor 15 (GDF15) in tumorigenesis of oral squamous cell carcinoma (OSCC) is not clear, the diagnostic and prognostic value of serum GDF15 detection has been noticed. However, serum GDF15 levels in patients with oral leukoplakia and GDF15 as a potential predictive biomarker for response to induction chemotherapy in patients with OSCC have not been reported., Methods: Pretreatment serum GDF15 concentration was detected using an enzyme-linked immunosorbent assay in 30 healthy persons, 24 patients with oral leukoplakia, and 60 patients with OSCC., Results: Serum GDF15 concentration was significantly higher in patients with oral leukoplakia and OSCC, compared with healthy controls (F = 13.701, df = 2, P < 0.001). From a diagnostic standpoint, a cutoff value of 346.9 ng/l of serum GDF15 concentration was calculated using receiver operating characteristic curve, with a sensitivity of 0.750, specificity of 0.867, Youden's Index of 0.617, and area under curve of 0.863. From a prognostic standpoint, patients with serum GDF15 concentration <346.9 ng/l had an improved 3-year disease-free survival rate (64.3% vs 56.5%) compared with those above 346.9 ng/l, but the difference was not statistically significant. A decreased concentration of GDF15 (<346.9 ng/l) showed a predictive trend toward an improved response to induction chemotherapy compared with elevated concentration with clinical response rates of 100% and 71.4%, respectively, but the difference was not significant., Conclusion: Elevated GDF15 level may be not only a diagnostic biomarker for oral leukoplakia, but also a prognostic/predictive biomarker associated with decreased survival and diminished response to induction chemotherapy for patients with OSCC., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The benefit of induction chemotherapy in locally advanced oral squamous cell carcinoma (OSCC) remains to be clearly defined. Induction chemotherapy is likely to be effective for biologically distinct subgroups of patients and biomarker development might lead to identification of the patients whose tumors are to respond to a particular treatment. Annexin A1 may serve as a biomarker for responsiveness to induction chemotherapy. The aim of this study was to investigate Annexin A1 expression in pre-treatment biopsies from a cohort of OSCC patients treated with surgery and post-operative radiotherapy or docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy followed by surgery and post-operative radiotherapy. Furthermore we sought to assess the utility of Annexin A1 as a prognostic or predictive biomarker., Methods: Immunohistochemical staining for Annexin A1 was performed in pre-treatment biopsies from 232 of 256 clinical stage III/IVA OSCC patients. Annexin A1 index was estimated as the proportion of tumor cells (low and high, <50% and ≥50% of stained cells, respectively) to Annexin A1 cellular membrane and cytoplasm staining., Results: There was a significant correlation between Annexin A1 expression and pathologic differentiation grade (P=0.015) in OSCC patients. The proportion of patients with low Annexin A1 expression was significantly higher amongst those with moderate/poorly differentiated tumor (78/167) compared to those with well differentiated tumor (18/65). Multivariate Cox model analysis showed clinical stage (P=0.001) and Annexin A1 expression (P=0.038) as independent prognostic risk factors. Furthermore, a low Annexin A1 expression level was predictive of longer disease-free survival (P=0.036, HR=0.620) and locoregional recurrence-free survival (P=0.031, HR=0.607) compared to high Annexin A1 expression. Patients with moderate/poorly differentiated tumor and low Annexin A1 expression benefited from TPF induction chemotherapy as measured by distant metastasis-free survival (P=0.048, HR=0.373) as well as overall survival (P=0.078, HR=0.410)., Conclusions: Annexin A1 can be used as a prognostic biomarker for OSCC. Patients with moderate/poorly differentiated OSCC and low Annexin A1 expression can benefit from the addition of TPF induction chemotherapy to surgery and post-operative radiotherapy. Annexin A1 expression can potentially be used as a predictive biomarker to select OSCC patients with moderate/poorly differentiated tumor who may benefit from TPF induction chemotherapy.

Induction chemotherapy is likely to be effective for biologically distinct subgroups of patients with cancer with biomarker detection. To investigate the prognostic and predictive values of cyclin D1 expression in patients with oral squamous cell carcinoma (OSCC) who were treated in a prospective, randomized, phase III trial evaluating standard treatment with surgery and postoperative radiotherapy preceded or not by induction docetaxel, cisplatin, and 5-fluorouracil (TPF), immunohistochemical staining for cyclin D1 was conducted in pretreatment biopsy specimens of 232 out of 256 clinical stage III/IVA OSCC patients randomized to the clinical trial. Cyclin D1 index was estimated as the proportion of tumor cells with cyclin D1 nuclear staining. A low cyclin D1 expression predicted significantly better overall survival (OS; P = 0.001), disease-free survival (P = 0.005), locoregional recurrence-free survival (P = 0.003), and distant metastasis-free survival (DMFS; P = 0.002) compared with high cyclin D1 expression. Cyclin D1 expression levels were not predictive of benefit from induction TPF in the population overall. However, patients with nodal stage cN2 whose tumors had high cyclin D1 expression treated with TPF had significantly greater OS (P = 0.025) and DMFS (P = 0.025) when compared with high cyclin D1 cN2 patients treated with surgery upfront. Patients with low cyclin D1 level or patients with cN0 or cN1 disease did not benefit from induction chemotherapy. This study indicates that cN2 OSCC patients with high cyclin D1 expression can benefit from the addition of TPF induction chemotherapy to standard treatment. Cyclin D1 expression could be used as a biomarker in further validation studies to select cN2 patients that could benefit from induction therapy., Competing Interests: of potential conflicts of interest: The authors declare that they have no potential conflicts of interests, (©2013 AACR)

Objectives: Functional role of Annexin A1 in tumorigenesis is poorly understood. The aim of this study was to investigate the relationship between Annexin A1 protein expression and pathological differentiation grade in biopsy samples from a large cohort of patients with oral squamous cell carcinoma (OSCC); and to evaluate the potential role of Annexin A1 on cell proliferation and tumorigenesis of OSCC., Materials and Methods: We investigated the relationship between Annexin A1 expression by immunohistochemical staining and pathological differentiation grade of biopsy samples from 232 OSCC patients, and the relationship between Annexin A1 expression and cell proliferation as well as tumor formation using both in vitro and in vivo OSCC models., Results: Annexin A1 expression correlated significantly with pathological differentiation grade in OSCC patients, a lower Annexin A1 expression correlating with a poorer differentiation grade. Forced Annexin A1 overexpression in OSCC cell lines, CAL27 and Tca8113, significantly reduced the cell proliferation whereas down-regulation of Annexin A1 expression in OSCC cell line, HB96, significantly increased proliferation of HB96 cells. Tumors formed from CAL27 cells overexpressing Annexin A1 grown significantly slower compared to the parental CAL27 cells in nude mice and showed a significantly reduced nuclear Ki-67 labeling index. Interestingly, these tumors also showed a well differentiated histology pattern whereas the tumors formed from the parental cells were consistently moderately differentiated., Conclusions: These data support a significant correlation between Annexin A1 expression and pathological differentiation grade, and a functional role of Annexin A1 in inhibiting cell proliferation and cell differentiation in OSCC., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Induction chemotherapy has been investigated as a possible strategy to shrink or downstage locally advanced head and neck cancers, providing opportunity to remove the lesions completely after induction chemotherapy, especially in the patients with resectable advanced disease. The aim of this study was to investigate the definitive effect of induction chemotherapy in patients with resectable head and neck squamous cell carcinoma., Methods: A meta-analysis of randomized trials (1965-2011) was performed on the impact of induction chemotherapy on survival, disease control, and toxicity in this population of patients. Kaplan-Meier curves were read by Engauge-Digitizer. Data combining was performed using RevMan., Results: Fourteen trials (2099 patients) were involved in this analysis. There was no significant difference on overall survival, disease free survival, or locoregional recurrence between the patients treated with and without induction chemotherapy (P >0.05). However, the patients treated with induction chemotherapy had a lower rate of distant metastasis by 8% (95% confidence interval 1%-16%, P = 0.02) than those treated without induction chemotherapy. In patients with laryngeal cancer, comparing to radical surgery, the larynx could be preserved in responders to induction chemotherapy without survival decease (P >0.05). Induction chemotherapy-associated death was 0%-5%., Conclusions: Based on the results above, there is a significant benefit of induction chemotherapy on decreasing distant metastasis in patients with resectable head and neck squamous cell carcinoma. In patients with laryngeal cancer, induction chemotherapy provides larynx preservation in responders to induction chemotherapy.

Purpose: To evaluate induction chemotherapy with docetaxel, cisplatin, and fluorouracil (TPF) followed by surgery and postoperative radiotherapy versus up-front surgery and postoperative radiotherapy in patients with locally advanced resectable oral squamous cell carcinoma (OSCC)., Patients and Methods: A prospective open-label phase III trial was conducted. Eligibility criteria included untreated stage III or IVA locally advanced resectable OSCC. Patients received two cycles of TPF induction chemotherapy (docetaxel 75 mg/m(2) on day 1, cisplatin 75 mg/m(2) on day 1, and fluorouracil 750 mg/m(2) on days 1 to 5) followed by radical surgery and postoperative radiotherapy (54 to 66 Gy) versus up-front radical surgery and postoperative radiotherapy. The primary end point was overall survival (OS). Secondary end points included local control and safety., Results: Of the 256 patients enrolled onto this trial, 222 completed the full treatment protocol. There were no unexpected toxicities, and induction chemotherapy did not increase perioperative morbidity. The clinical response rate to induction chemotherapy was 80.6%. After a median follow-up of 30 months, there was no significant difference in OS (hazard ratio [HR], 0.977; 95% CI, 0.634 to 1.507; P = .918) or disease-free survival (HR, 0.974; 95% CI, 0.654 to 1.45; P = .897) between patients treated with and without TPF induction. Patients in the induction chemotherapy arm with a clinical response or favorable pathologic response (≤ 10% viable tumor cells) had superior OS and locoregional and distant control., Conclusion: Our study failed to demonstrate that TPF induction chemotherapy improves survival compared with up-front surgery in patients with resectable stage III or IVA OSCC.

Purpose: This study was performed to gain some knowledge on the possible relation between surgical site infection (SSI) and geriatric patients who undergo surgical treatment of oral squamous cell carcinoma and to identify the risk factors in this specific population., Patients and Methods: A retrospective study from 2004 through 2010 at the Department of Oral and Maxillofacial Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine was conducted. The primary outcome variable was the presence of SSIs. Twenty-seven variables of the patients concerning general characteristics, comorbidities, disease information, and treatment options were investigated. A multivariate analysis using logistic regression was implemented to find SSI risk factors., Results: The data of 376 patients (183 men, 48.7%; 193 women, 51.3%) older than 65 years with the diagnosis of oral squamous cell carcinoma were included in the present analysis. In multivariate logistic regression analysis, 6 parameters were identified for a significant and independent association with the development of SSI: body mass index (P = .0086); diabetes (P < .0001); American Society of Anesthesiologists score (P = .0127); Adult Comorbidity Evaluation-27 score (P = .0392); operation time (P = .0003); and reconstruction with pectoralis major myocutaneous flaps or free flaps (P < .0001)., Conclusions: Special attention to SSIs should be given to elderly patients with oral squamous cell carcinoma. The authors advocate a preoperative evaluation of comorbidities and the selection of high-risk elderly patients for a more effective prevention of SSIs., (Copyright © 2012 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives/hypothesis: Is the severity of acute oral mucositis in patients who receive postoperative intensity-modulated radiotherapy (PO-IMRT) for oral tongue squamous cell carcinoma (SCC) reduced by sparing the oral mucosa outside of the planning target volume (PTV)?, Study Design: Prospective, randomized trial., Methods: Forty-eight patients with oral tongue SCC who received PO-IMRT at our institution were randomized to two groups: the oral-sparing (OR-SP) group and oral-unsparing (OR-USP) group. For the OR-SP group (n = 24), the oral mucosa outside of the PTV was spared. Furthermore, the mucosa including the bilateral cheeks, upper lip, and lower lip was defined as the united site and given <32 Gy. For the OR-USP group (n = 24), none of the oral mucosa was protected. The severity of clinical acute mucositis in each patient was assessed weekly during PO-IMRT until completely healed. Oral mucositis was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Dosimetry and therapeutic measures related to acute mucositis between the two groups were compared., Results: During PO-IMRT, no patient experienced grade 4+ acute mucositis in any oral site. Compared to the OR-USP group, there was less grade 2 and 3 mucositis in the united site of the OR-SP group (0% and 25% vs. 45.8% and 54.2%, respectively; P = .000). Also, the mean dose to the united site was significantly lower with OR-SP compared to OR-USP (41.8 ± 7.4 Gy vs. 58.8 ± 2.2 Gy; P = .000). The OR-SP group was associated with significant reductions in the use of analgesics (P = .043) and intravenous antibiotics (P = .039). No recurrences were detected in the vicinity of the spared oral mucosa (the united site) during a median follow-up time of 30 months., Conclusions: OR-SP PO-IMRT for patients with oral tongue SCC resulted in a significant decrease in the severity of acute mucositis and improved quality of life. The sparing of the oral mucosa outside of the PTV is safe and does not compromise oncologic outcomes., (Copyright © 2012 The American Laryngological, Rhinological, and Otological Society, Inc.)

Objective: This retrospective study is to analyze the outcomes of cN0 stage tongue squamous cell carcinoma and to discuss a reasonable neck management for these cases., Methods: Totally 132 cases of cN0 stage tongue squamous cell carcinomas were included. Seventy-one cases were performed neck dissection(group ND), 61 cases were under wait-and-see (group WS). The clinical, pathological and follow up data of two groups were analyzed., Results: The cumulative three-year-survival between group ND and group WS were 87.3% and 83.4% respectively. In group ND, the survival of T1 and T2 cases were 89.3% and 83.3% respectively, while 89.6% and 58.3% in WS. For T2b cases which the size was larger than 3.0 cm, the survival of group WS was greatly lower than that of group ND. Both in ND and WS groups. The pathologically poor differentiation cases got poor survival than middle and well cases., Conclusion: The wait-and-see policy is recommanded for T1 stage cN0 tongue squamous cell carcinoma. For T2 cases that the tumor size is smaller than 3.0 cm, the wait-and-see is also reasonable, while the neck dissection should be considered in cases of poor differentiation. For large T2 cases, the selective neck dissection should be performed.

Objective: To investigate the mRNA expression of collagen genes in oral squamous cell carcinoma (OSCC) and paired normal oral mucosal tissue., Methods: The differential mRNA expressions of collagen genes between 30 OSCC tissues and the paired normal oral mucosal tissues were detected by RT-PCR., Result: The relative expression level of COL1A1 mRNA in the 30 cancerous tissues was up-regulated by 2.78 folds as compared with its expression in the paired normal samples, suggesting its significant overexpression in OSCC (P<0.001). The expression levels of COL1A2, COL4A1, COL4A2, and COL5A2 mRNA in the cancerous tissues were up-regulated by 1.07, 1.15, 1.27, and 1.16 folds compared to those in paired normal samples (P>0.05)., Conclusion: COL1A1 mRNA overexpression may play an important role in the carcinogenesis of OSCC and can be a potential molecular marker of OSCC.

MicroRNAs (miRNAs) are small non-coding RNAs that function as negative regulators of gene expression. They are strongly implicated in human cancers, including oral squamous cell carcinoma (OSCC). Evidence for the involvement of miRNAs as important regulators of chemosensitivity and chemoresistance in OSCC is not well understood. In this study, miRNA microarray was firstly used to compare the differential miRNAs levels between the cisplatin-sensitive tongue squamous cell carcinoma line (Tca8113) and its cisplatin-resistant subline (Tca/cisplatin). Three miRNAs of miR-21, -214, and -23a were validated by miRNAs real-time PCR, and intervened by anti-miRNA oligonucleotides (miR-214 and -23a) and pre-miRNA plasmid transfection (miR-21). Further relationship between miR-23a and DNA topoisomerase II beta (TOP2B) on the chemoresistance against cisplatin was studied. There were 19 out of 480 differential miRNAs between the Tca8113 and Tca/cisplatin cells. miR-214 and -23a were found increased as with chemoresistance against cisplatin in the Tca/cisplatin cells while miR-21 was found decreased as with chemosensitivity for cisplatin in the Tca/cisplatin cells. Intervention of these three miRNAs could decrease the chemoresistance against cisplatin in Tca/cisplatin cells. Transfection of anti-miR-23a into the Tca/cisplatin cells could increase the TOP2B protein expression. Our results suggest the existence of differential miRNAs with chemosensitivity and chemoresistance between the cisplatin-sensitive and resistant tongue squamous cell carcinoma lines. miR-21 serves as a chemosensitive miRNA, while miR-214 and -23a serve as chemoresistant miRNAs in the tongue squamous cell carcinoma lines. miR-23a is an up-stream regulator of TOP2B to realize the chemoresistance of cisplatin., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Purpose: To investigate the role of NF-kappaB signal transduction pathway in apoptosis induced by shikonin in human tongue squamous cell carcinoma Tca-8113 cell line., Methods: Expression of IkappaBa, phosphatase-IkappaBa, bcl-2 and Bax proteins were detected by Western blot, NF-kappaB DNA-binding activity was detected by electrophoretic mobility shift analysis (EMSA), and activities of caspase 3, caspase 8 and caspase 9 were analyzed by enzyme linked immunosorbent assay(ELISA). The data was analyzed by one-way ANOVA test and t test using SPSS12.0 software package., Results: The expression of phosphatase-IkappaBa protein and the nuclear NF-kappaB DNA-binding activity was significantly decreased in shikonin treated cells by Western and EMSA. Bcl-2 protein expression was also decreased in the process. The activity of all the three proteases was elevated and pancaspase inhibitor Z-Asp-CH2-DCB could protect Tca8113 cells from shikonin-induced apoptosis(P=0.02)., Conclusions: Anti-tumor effects of shikonin in Tca-8113 cells act at least partially through the inactivation of NF-kappaB pathway and subsequent activation of protease caspase family. Pharmacologic inhibition of the NF-kappaB activity by shikonin might be a powerful treatment option for OSCC.

Purpose: To investigate the clinical application value of serum tumor markers detection combined with support vector machine (SVM) model in the diagnosis of oral squamous cell carcinoma., Methods: Serum levels of neuron-specific enolase (NSE), cancer antigen 242 (CA242), cancer antigen 19-9 (CA199), carcinoembryonic antigen (CEA), tissue polypeptide antigen (TPA), cancer antigen 72-4 (CA724), cancer antigen 21-1 (CA211) and alpha fetoprotein (AFP) were detected with enzyme-linked immunosorbent assay (ELISA) and time-resolved fluoroimmunoassay (TRFIA) in 163 oral squamous cell carcinoma patients and 160 healthy persons. All the data was analyzed with SVM; the SVM models for diagnosis of oral squamous cell carcinoma were created, trained and validated by cross validation., Results: Among the 163 oral squamous cell carcinoma patients, there were 128 males and 35 females with the male-to-female ratio of 3.66:1; the age ranged from 30 to 85 years old with a mean age of 59.3 years old; according to the primary site of tumor, 72 cases in tongue, 34 in gingiva, 22 in buccal mucosa, 15 in palatal mucosa, 13 in floor of mouth, 4 in lip and 3 in retromolar region; according to the TNM-UICC classification, there were 33 patients at stage T1, 72 at T2, 44 at T3, 14 at T4, 119 at N0, 42 at N1, 2 at N2, 159 at M0, 4 at M1, 27 at clinical stage I, 51 at stage II, 52 at III, and 33 at IV; according to the pathological differentiation grade, 109 tumors were well differentiated, 42 were moderately differentiated and 12 were poorly differentiated. Five serum tumor markers of CA211, CA199, TPA, CA724 and NSE were selected optimally to create the optimal SVM model for diagnosis of oral squamous cell carcinoma. The accuracy, specificity, sensitivity and positive predictive value of the optimal SVM model were 88.54%, 93.13%, 84.05% and 92.57%, respectively., Conclusion: From the results, SVM model combined with 5 optimal serum tumor markers is suggested to be used in the diagnosis of oral squamous cell carcinoma. Supported by Shanghai Leading Academic Discipline Project (Grant No.Y0203).

Objective: To investigate the mRNA expression of matrix metalloproteinase 1 (MMP1) gene in oral squamous cell carcinoma (OSCC) and the paired normal tissues., Methods: The differential expression of MMP1 mRNA between 30 OSCC and paired normal tissues were detected with reverse transcription-PCR (RT-PCR)., Results: The relative expression level of MMP1 mRNA in the OSCC tissues showed a 3.26-fold increase in comparison with that in the paired normal tissues (4.06-/+0.52 vs 1.24-/+0.17, P<0.0001). In the 30 OSCC tissues, the relative expression level of MMP1 mRNA was higher in histological grade II/III tissues (4.31-/+0.68) than in grade I (3.87-/+0.57) tissues, higher in OSCC in advanced stages (III/IV) than in tumors in early stages (I/II) (4.18-/+0.67 vs 3.65-/+0.53), and also higher in OSCC with cervical lymph node invasion than in those without cervical lymph node invasion (4.32-/+0.71 vs 3.91-/+0.51), but these differences were not statistically significant (P>0.05)., Conclusion: MMP1 gene may play a role in local invasion of OSCC, and can serve as a potential biomarker molecule for diagnosis, treatment and prognostic evaluation of OSCC, with also clinical value for OSCC classification.

Objective: To investigate osteopontin (OPN) mRNA expression in oral squamous cell carcinoma (OSCC) and normal oral mucosa tissues., Methods: Differential OPN gene expression were detected in 30 cancerous tissues and their paired normal tissues using real-time reverse transcription-PCR (real-time RT-PCR), and the data were analyzed statistically., Results: Real-time RT-PCR results demonstrated that the relative expression level of OPN mRNA in the cancerous tissues were significantly higher than that in paired normal samples (4.17-/+0.51 vs 0.97-/+0.12, P<0.001), showing a 4.3-fold up-regulation. In the 30 OSCC specimens, OPN mRNA expression in the OSCC of histological grades I showed a 3.1-fold down-regulation, significantly lower than the expression in grade II/III tumors (2.16-/+0.17 vs 6.80-/+0.72, P<0.05); its expression was significantly lower in early stage than in advanced stage OSCCs (2.34-/+0.17 vs 4.73-/+0.35, P<0.05). In cases of cervical lymph node metastasis, the expression was significantly higher than that in cases without lymphatic metastasis (6.38-/+0.56 vs 2.89-/+0.32, P<0.05)., Conclusion: OPN mRNA overexpression may play an important role in OSCC carcinogenesis and can be a potential target for OSCC therapy.

Background: Saliva is the body fluid in the oral cavity and contacts directly with oral mucosa. As a detective media, it is acceptable and non-traumatic. Cyfra 21-1, being the soluble fragment of cytokeratin 19(CK19), correlates well with oral squamous cell carcinoma (OSCC)., Objective: To investigate the saliva Cyfra 21-1 concentrations in OSCC patients and healthy persons, and the correlation between the Cyfra 21-1 concentration in saliva and the CK19 expression in tissue from OSCC patients., Design: Saliva Cyfra 21-1 concentration was detected by ELISA in 30 OSCC patients and 30 healthy persons; CK19 protein expression and CK19 mRNA level were, respectively, detected by immunohistochemistry and fluorescent real-time RT-PCR in cancerous and paracancerous tissues from 33 OSCC patients., Results: Saliva Cyfra 21-1 concentration in OSCC patients (85.95+/-78.00 microg/L) was significantly higher than that in healthy persons (42.27+/-40.84 microg/L) (P=0.009); it was also significantly higher in the patients suffering later tumour recurrence (130.95+/-66.38 microg/L) than that in the patients without tumour recurrence (74.84+/-63.45 microg/L) (P=0.023). CK19 protein expression increased significantly in OSCC tissues (P<0.001) with positive rate of 90.9%, CK19 mRNA level in cancerous tissues was 2.21 folds higher than that in paracancerous tissues (P=0.020); significant correlation was found between tissue CK19 protein expression and tissue CK19 mRNA level (P=0.003), and great correlation was found between tissue CK19 protein expression and saliva Cyfra 21-1 concentration (P=0.051)., Conclusions: The increased CK19 expression in OSCC tissues plays an important role in the increase of saliva Cyfra 21-1 concentration. Potential clinical value of saliva Cyfra 21-1 detection is suggested for OSCC. Further studies are encouraged to reveal the real diagnostic and prognostic value of detecting saliva Cyfra 21-1 concentration for OSCC.

Objective: To investigate cytokeratin 19 (CK19) expression in oral squamous cell carcinoma (OSCC) tissue as well as its correlation with pathologic differentiation grade and prognosis., Study Design: Cancerous and distant tissues from 33 primary OSCC patients were collected during surgery. Each sample was divided into 2 parts, one for CK19 protein detection using immunohistochemistry, and the other for CK19 mRNA-level detection of relative quantification using fluorescent real-time reverse transcriptase polymerase chain reaction (RT-PCR)., Results: The CK19 positive rate in cancerous tissue was 90.9% (30 out of 33) detected using immunohistochemistry, which was significantly higher than that in distant tissue (15.2%, 5 out of 33) by chi-square test (P < .001). The CK19 positive score in cancerous tissue was also significantly higher than that in the corresponding distant tissue by paired samples t test (P < .001). Patients with positive CK19 expression in distant tissue had higher tumor recurrence rate (P = .008) and lower survival rate (P = .015) than those with negative CK19 expression in distant tissue. Using fluorescent real-time RT-PCR, CK19 mRNA level in cancerous tissue was 2.21-fold higher than that in distant tissue (P = .020). The CK19 expression correlated significantly with pathologic differentiation grade, which was detected not only using immunohistochemistry (P = .002) but also using fluorescent real-time RT-PCR (P = .025), poorer differentiated indicating higher CK19 positive score and CK19 mRNA level., Conclusions: Increased CK19 protein expression and gene transcription in OSCC tissue correlate significantly with pathologic differentiation grade. Positive CK19 expression in distant tissue suggests a higher tumor recurrence rate and a lower survival rate.

Background: Oral squamous cell carcinoma (OSCC) is the most common malignant tumor in oral and maxillofacial region with poor prognosis. E-cadherin plays a key role in cell-to-cell adhesion. E-cadherin expression in the metastatic cervical lymph node, especially in the micrometastatic cervical lymph node has seldom been reported in OSCC patients., Objective: To investigate the E-cadherin expression in cervical lymph nodes from OSCC patients as well as its clinical significance., Design: Thirty-three OSCC patients were involved in this study; among them, there were 28 males and 5 females, the age ranged from 34 to 78 years (mean 58.8 years). The most suspicious metastatic cervical lymph node (total 99 lymph nodes) from three cervical regions of each OSCC patient was selected for detection of E-cadherin using routine pathological examination and immunohistochemistry., Results: Increased E-cadherin expression in the metastatic cervical lymph nodes was detected, which was diagnosed by routine pathological examination using HE staining. However, in the micrometastatic cervical lymph node, E-cadherin expression was negative. The survival rate of OSCC patients correlated with decreased E-cadherin expression (P=0.001), N stage (P=0.024) and tumor recurrence (P<0.001). Tumor recurrence is the only independent factor on the prognosis (RR=20.83 and P=0.014)., Conclusions: Decreased E-cadherin expression in cancerous tissue correlates with the poor prognosis of OSCC patients. Detection of E-cadherin expression is useful to confirm the cervical lymph node metastasis and maybe useless to detect the cervical lymph node micrometastasis; further studies are encouraged to reveal the detail mechanism of E-cadherin expression in formation of lymph node metastatic focus.

Objective: To investigate the appropriate nanomanipulation of slides of human tongue squamous cell carcinoma tissue and cultured cells by atomic force microscopy (AFM), and develop methods to improve the resolution and contrast of AFM images., Methods: Human tongue squamous carcinoma cells of the line Tca8113 were cultured. Cell masses were isolated and collected, and sectioned. Then the white lead and silvery white sections were transferred on mica slides, dried. Eighty slides were used and divided into 2 groups to be immersed into hydrogen dioxide of the concentrations 20% and 30% for 0, 5, 10, 15, 20, 25, 30, and 40 min respectively. Samples of human tongue squamous carcinoma were collected from 15 cases. Every sample was divided into 2 halves. Half of every sample underwent routine paraffin preparation of slide and adhered onto glass, dissolving of paraffin with dimethylbenzene for 0, 10, 15, 30, 45, or 60 min; and half of the sample underwent routine preparation of slides for electron microscopy, the white lead and silvery white sections were transferred on mica slides, dried. The slides were observed by contact mode AFM in air., Results: In the ultrathin sections the metastructure of the cell such as the cell membrane, nuclear membrane and nucleolus could be distinct from each other clearly. The profile of the cell and the nucleus inside could be revealed by AFM after the paraffin sections were treated in dimethylbenzene for 15-30 min. AFM manipulation could be achieved within nanometer range by precise modulation of scanning force, area, angle and so on. The appropriate needle point should contain elastic coefficient > 5.0 N/m. The force exerted on the needle point should be within the range 50-300 nN. After location the scanning direction should be within the range of 20 nm-1 microm., Conclusion: A series of modified techniques of preparing and treating AFM samples, such as adhering the sections onto mica slide, dissolving of epoxy resin by hydrogen dioxide and removal of paraffin by dimethylbenzene, were developed, thus realizing high resolving power AFM imaging, especially for nuclear membrane, and nucleolus, and providing a base of AFM location, dissection, isolation and obtainment at nanometer scale.

Purpose: To investigate the expression and its significance of cytokeratin 13 gene in oral squamous cell carcinoma (OSCC)., Methods: Differential CK13 gene expression between 30 cases of paired normal and cancerous tissues were detected by reverse transcription-PCR (RT-PCR), and immunohistochemistry was conducted using monoclonal antibody against CK13 in them. The data were analyzed with SAS6.12 software for Fisher's exact test., Results: RT-PCR results demonstrated that CK13 gene mRNA was upregulated in 27 cases of normal tissues than in paired cancerous samples, by 4.2-fold in total; and immunostain results revealed that expression of CK13 protein between normal oral squamous cell and OSCC, high differentiated OSCC and poor differentiated ones were significantly decreased (P<0.05)., Conclusions: CK13 gene might play an important role in OSCC carcinogenesis and be regulated at post-transcriptional levels. Further research will contribute to confirm its role and mechanism.

Objective: To discuss the treatment of cN(0) tongue carcinoma patients., Methods: 185 cases of the mobile tongue carcinoma patients (male 102, female 83, aged 28 to 88) treated with surgery from 1988.5 to 1995.6 had been followed up and retrospectively analyzed. Extensive resection of the primary tumors and neck dissections were performed, and all the samples were pathological positive., Results: The cervical lymphatic node metastasis rates for stage I-II, III-IV disease, grade I, II disease were 16.66%, 38.05%, 17.42% and 37.50% respectively. And the rates were 9.00%, 31.37% and 55.55% for submucous infiltration, muscle infiltration and perineural infiltration, respectively. The overall 5 year survival was 72.43%, and the 5 year specific survival rate was 44.44% and 83.96% for those having or not having cervical node metastasis. The levels of 29 patients with positive node metastasis for 148 cN(0) patients were submandibular and submental lymphatic nodes (22.64%), superior deep cervical lymphatic nodes (35.84%), middle deep cervical lymphatic nodes (26.41%), inferior deep cervical lymphatic nodes (15.09%), posterior neck lymphatic nodes (0.00%). The over all 5 year survival rates for selective neck dissection were 85.13% and 21.62% in therapeutic dissection (chi(2) = 29.73, P < 0.01). Patients performed selective neck dissection the rates were 68.96% and 89.07% respectively with or without lymphatic node metastasis. Comparably the 5-year rate was only 20.00% for the patients performed the therapeutic dissection with lymphatic node metastasis., Conclusions: (1) cN(0) patients should be observed carefully in stage I, and the selective dissection must be performed in stage II-IV. (2) Supraomohyoid ND is essential for T(2) patients, and functional ND is essential for T(3 - 4) patients. (3) There is correlation between cervical metastasis and the stage, grade or infiltration of tongue cancer (P < 0.05). The prognosis could be expected from these factors.