Search

Evidence on the association between dietary component, dietary pattern and nasopharyngeal carcinoma (NPC) is scarce. A major challenge is the high degree of correlation among dietary constituents. We aimed to identify dietary pattern associated with NPC and to illustrate the dose-response relationship between the identified dietary pattern scores and the risk of NPC. Taking advantage of a matched NPC case-control study, data from a total of 319 incident cases and 319 matched controls were analyzed. Dietary pattern was derived employing partial least square discriminant analysis (PLS-DA) performed on energy-adjusted food frequencies derived from a 66-item food-frequency questionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated with multiple conditional logistic regression models, linking pattern scores and NPC risk. A high score of the PLS-DA derived pattern was characterized by high intakes of fruits, milk, fresh fish, vegetables, tea, and eggs ordered by loading values. We observed that one unit increase in the scores was associated with a significantly lower risk of NPC (ORadj = 0.73, 95% CI = 0.60-0.88) after controlling for potential confounders. Similar results were observed among Epstein-Barr virus seropositive subjects. An NPC protective diet is indicated with more phytonutrient-rich plant foods (fruits, vegetables), milk, other protein-rich foods (in particular fresh fish and eggs), and tea. This information may be used to design potential dietary regimen for NPC prevention.

An improved prognostic stratification of patients with oral cavity squamous cell carcinoma (OSCC) and pathologically positive (pN+) nodes is urgently needed. Here, we sought to examine whether an ultra-deep targeted sequencing (UDT-Seq) gene panel may improve the prognostic stratification in this patient group.A mutation-based signature affecting 10 genes (including genetic mutations in 6 oncogenes and 4 tumor suppressor genes) was devised to predict disease-free survival (DFS) in 345 primary tumor specimens obtained from pN+ OSCC patients. Of the 345 patients, 144 were extracapsular spread (ECS)-negative and 201 were ECS-positive. The 5-year locoregional control, distant metastases, disease-free, disease-specific, and overall survival (OS) rates served as outcome measures.The UDT-Seq panel was an independent risk factor (RF) for 5-year locoregional control (P = 0.0067), distant metastases (P = 0.0001), DFS (P < 0.0001), disease-specific survival (DSS, P < 0.0001), and OS (P = 0.0003) in pN+ OSCC patients. The presence of ECS and pT3-4 disease were also independent RFs for DFS, DSS, and OS. A prognostic scoring system was formulated by summing up the significant covariates (UDT-Seq, ECS, pT3-4) separately for each survival endpoint. The presence of a positive UDT-Seq panel (n = 77) significantly improved risk stratification for all the survival endpoints as compared with traditional AJCC staging (P < 0.0001). Among ECS-negative patients, those with a UDT-Seq-positive panel (n = 31) had significantly worse DFS (P = 0.0005) and DSS (P = 0.0002). Among ECS-positive patients, those with a UDT-Seq-positive panel (n = 46) also had significantly worse DFS (P = 0.0032) and DSS (P = 0.0098).Our UDT-Seq gene panel consisting of clinically actionable genes was significantly associated with patient outcomes and provided better prognostic stratification than traditional AJCC staging. It was also able to predict prognosis in OSCC patients regardless of ECS presence.

Human papillomavirus (HPV) infections are deemed to play a role in the pathogenesis of oral cavity cancer (OCC). However, their exact prevalence and clinical significance remain unclear. Herein, we investigated the prevalence and prognostic value of HPV infections in a large sample of Taiwanese OCC patients.This study was designed as a retrospective cohort study. Between 2004 and 2011, we identified 1002 consecutive patients with newly diagnosed OCC who were scheduled for standard treatment. HPV genotyping was performed in tumor specimens using polymerase chain reaction-based HPV blots. To investigate the temporal trends of HPV infections and their impact on 5-year overall survival (OS), patients were divided into 2 cohorts according to calendar periods: "2004 cohort" (2004-2007; n = 466) and "2008 cohort" (2008-2011; n = 536). Univariate and multivariate Cox regression models were also used to identify the independent predictors of OS in the 2 cohorts. A weighted risk score was assigned to each factor based on the range of their corresponding hazard ratios and validated in both cohorts using the c-statistic.The overall prevalence of HPV infections was 19%, with a trend toward decreasing rates from 2004 to 2011. In patients without risky oral habits, the 5-year OS rate of HPV-positive patients was significantly lower than that of HPV-negative cases (49% vs 80%; P = 0.021). In the 2004 cohort, multivariate analysis identified HPV16, pathological T3/T4, pathological N1/N2, and extracapsular spread as independent adverse prognostic factors for OS. In the 2008 cohort, pathological N1/N2, pathological stage III/IV, and histological tumor depth >8 mm were identified as independent adverse prognostic factors. Using a weighted grading system incorporating HPV16 infection, we devised a prognostic index that identified 4 distinct risk categories with 5-year OS rates ranging from 25% to 89% (c-statistic = 0.76) in the 2004 cohort. The validity of the index was internally confirmed in the 2008 cohort (c-statistic = 0.71).We conclude that HPV infections are common in Taiwanese OCC patients and predict 5-year OS. If independently validated, our composite prognostic score comprising HPV16 infection may be useful for allocating OCC patients to risk-adapted therapies., Competing Interests: The authors declare no conflicts of interest.

Background: Head and neck cancer (HNC) is a prevalent cancer worldwide; however, clinically useful tumor markers for HNC have not been identified. Here, we aimed to identify secretory proteins from the tumor microenvironment as candidate circulating tumor markers., Methods: Samples derived from seven pairs of tumor interstitial fluid (TIF) and normal interstitial fluid (NIF) samples from patients with HNC were analyzed. The proteomes were determined by gel-based-mass-spectrometry proteomic methods. The most up-regulated protein, fascin was confirmed in the cancer tissues and cell culture supernatant by immunoblotting and immunohistochemistry assays. Serum fascin was determined in 40 HNC and 40 normal individuals by ELISA., Results: After proteomics analysis, 189 peptides were identified, corresponding to 75 proteins. Of the 21 proteins which were identified more than twice, five up-regulated proteins identified most frequently including fascin. The most elevated fascin was over-expressed in cancer tissues and cell culture supernatant. Serum fascin was significantly up-regulated in the cancer patients (p<0.001) and correlated with pathological lymph node metastasis (p=0.022). To assess the diagnostic efficacy, serum levels of fascin and another potential biomarker SCCA were determined. Fascin showed a high predictable value with an area under the curve (AUC) of 0.808 (95% CI 0.723-0.901) in the receiver operator curve (ROC), compared to 0.501 (95% CI 0.378-0.634) for SCCA., Conclusions: We have identified 75 potential circulating tumor markers associated with HNC, including fascin. Serum fascin could discriminate cancer patients from healthy individuals; thus, it may serve as a circulating biomarker for HNC.

Background/purpose: Narrow band imaging (NBI)-guided flexible laryngoscopy tissue sampling for laryngopharyngeal lesions is a novel technique. Patients underwent the procedure in an office-based setting without being sedated, which is different from the conventional technique performed using direct laryngoscopy. Although the feasibility and effects of this procedure were established, its financial impact on the institution and Taiwanese National Health Insurance program was not determined., Methods: This is a retrospective case-control study. From May 2010 to April 2011, 20 consecutive patients who underwent NBI flexible laryngoscopy tissue sampling were recruited. During the same period, another 20 age-, sex-, and lesion-matched cases were enrolled in the control group. The courses for procedures and financial status were analyzed and compared between groups., Results: Office-based NBI flexible laryngoscopy tissue sampling procedure took 27 minutes to be completed, while 191 minutes were required for the conventional technique. Average reimbursement for each case was New Taiwan Dollar (NT$)1264 for patients undergoing office-based NBI flexible laryngoscopy tissue sampling, while NT$10,913 for those undergoing conventional direct laryngoscopy in the operation room (p < 0.001). The institution suffered a loss of at least NT$690 when performing NBI flexible laryngoscopy tissue sampling., Conclusion: Office-based NBI flexible laryngoscopy tissue sampling is a cost-saving procedure for patients and the Taiwanese National Health Insurance program. It also saves the procedure time. However, the net financial loss for the institution and physician would limit its popularization unless reimbursement patterns are changed., (Copyright © 2013. Published by Elsevier B.V.)

Objectives/hypothesis: Vocal cord leukoplakia is a clinical diagnosis that comprises a spectrum of benignities, premalignancies, and malignancies. Accurate recordings of the visual characteristics of the affected area are important for communication between physicians and are helpful in further management. The objective of this study was to determine the laryngoscopic characteristics among patients with vocal cord leukoplakia and the reliability of examinations between different raters., Study Design: Retrospective chart review conducted in a tertiary referral center in Taiwan., Methods: From January 2010 to April 2013, 107 consecutive patients with vocal leukoplakia who had accepted excisional biopsy were recruited and classified into two groups according to histologic findings. The patients without clear preoperative flexible laryngoscope images stored in the picture archiving and communication system were excluded. There were 68 patients who met the inclusion criteria, and the preoperative laryngoscope images were reviewed by two laryngologists. The inter-rater reliabilities of the recordings were assessed. Correlation between the variables and histologic classification was also performed., Results: The inter-rater reliability of the assessment was significant in the recordings of color, texture, size, hyperemia, thickness, and symmetry (κ = 0.267 to 0.573, P < .05) but not in vocal cord edema. The laryngoscopic findings including color, texture, size, and hyperemia were associated with the grade of dysplasia (P < .05)., Conclusions: The specific proposed laryngoscopic characteristics are consistent in the recordings between raters and can be potentially used for stratifying patients' risk., Level of Evidence: 4., (© 2014 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives/hypothesis: The benefits of elective neck dissection (END) in early-stage tongue cancer have been widely discussed but are still controversial regarding early-stage buccal cancer. In this study, we evaluate the role of END and the treatment outcome in early-stage buccal cancer in an areca-quid endemic area., Study Design: Retrospective case-control study., Methods: One hundred seventy-three cT1-2N0M0 buccal cancer patients all staged by computed tomography or magnetic resonance imaging were recruited. A total of 151 patients received radical surgery with END, whereas 22 received observation (OBS). Adjuvant radiotherapy with or without chemotherapy was given in selected high-risk patients., Results: The 5-year overall survival (OS) rates for cT1 lesions and cT2 lesions were 86.14% and 75.45%, respectively (P = .105). In the END group, the occult metastasis rate was 1.8% for cT1 lesions and 10.6% for cT2 lesions (P = .053). The 5-year neck control rate rates (P = .001) and disease-free survival rates (P = .0101) were significantly better in the END group compared to the OBS group but were not significant in OS (P = .689). Eighteen (10.41%) patients developed a second primary tumor (SPT), and five (2.89%) patients developed a third primary tumor. Ninety-four percent of SPTs were located within the oral cavity., Conclusions: END was suggested in T1-T2N0 buccal cancer to improve the neck control rate. In patients for whom END is not performed at the time of tumor excision, regular follow-up of neck status is necessary because the metastatic lesions are mostly salvageable and do not influence the OS., (© 2014 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Human papillomaviruses (HPV) seem to be related to distant metastasis (DM) in advanced oral cavity squamous cell carcinoma (OSCC) patients., Objectives: This study aimed to investigate whether high-risk HPV viral load may predict DM among OSCC patients and stratify patients for risk-adapted treatment., Study Design: Viral loads of E7 oncogenes for HPV 16/18 were measured by quantitative PCR tests in paraffin-embedded lesional specimens from 312 OSCC of which the HPV genotypes had been determined previously. Multivariable Cox regression analysis was used to identify the independent prognostic factors for 5-year DM and C statistics were further computed., Results: By multivariable analysis, high HPV 16 E7 viral load (≥15.0 copies/genome); high HPV 18 E7 viral load (≥15.0 copies/genome); pathological N2 status (pN2); tumor depth ≥11 mm; extracapsular spread (ECS); and level IV/V metastases were independent risk factors for DM. We further identified three prognostic groups. In the high-risk group (level IV/V metastases or high HPV 16/18 E7 viral load plus pN2, tumor depth ≥11 mm, or ECS), the 5-year distant metastasis rate was 74%. In the intermediate-risk group (high HPV 16/18 E7 viral load, pN2, tumor depth ≥11 mm, or ECS), the 5-year DM rate was 17%. Finally, the 5-year DM rate was 1% in the low-risk group (no risk factors). The value of the C statistics was 0.78., Conclusions: Among OSCC patients, high HPV 16/18 E7 viral load identifies a small subgroup of patients at high-risk of 5-year DM and suggest the need for more intensive treatments and follow-up strategies., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: MicroRNA-196 (miR-196), which is highly up-regulated in oral cancer cells, has been reported to be aberrantly expressed in several cancers; however, the significance of miR-196 in oral cancer has not yet been addressed., Methods: Cellular functions in response to miR-196 modulation were examined, including cell growth, migration, invasion and radio/chemosensitivity. Algorithm-based studies were used to identify the regulatory target of miR-196. The miR-196 target gene and downstream molecular mechanisms were confirmed by RT-qPCR, western blot, luciferase reporter and confocal microscopy analyses. miR-196 expression was determined in paired cancer and adjacent normal tissues from oral cancer patients., Results: Both miR-196a and miR-196b were highly over-expressed in the cancer tissue and correlated with lymph node metastasis (P = 0.001 and P = 0.006, respectively). Functionally, miR-196 actively promoted cell migration and invasion without affecting cell growth. Mechanistically, miR-196 performed it's their function by inhibiting NME4 expression and further activating p-JNK, suppressing TIMP1, and augmenting MMP1/9., Conclusion: miR-196 contributes to oral cancer by promoting cell migration and invasion. Clinically, miR-196a/b was significantly over-expressed in the cancer tissues and correlated with lymph node metastasis. Thus, our findings provide new knowledge of the underlying mechanism of cancer metastasis. miR-196 may serve as a promising marker for better oral cancer management.

Objectives: We sought to investigate whether there is evidence of field cancerization in patients with oral cavity squamous cell carcinoma (OSCC) enrolled in a betel quid chewing area. We also assessed whether betel quid chewing is an independent risk factor for field cancerization in OSCC patients., Methods: We retrospectively examined the records of 1570 OSCC patients who underwent radical tumor resection between 1996 and 2011. A total of 1243 study participants (79%) had a positive history of betel quid chewing before surgery. Of the 767 patients treated with surgery alone, 599 (78%) were preoperative chewers, whereas a history of preoperative betel quid chewing was identified in 644 (80%) of the 803 patients who received adjuvant therapy. The 5-year control, survival, and second primary tumors (SPTs) rates served as the main outcome measures., Results: Regardless of the treatment modality, more than 70% of the SPTs were located in the oral cavity or soft palate. Despite a similar risk profile in terms of tumor depth, lymph node metastasis, and pathological margin status, preoperative chewers showed a significantly higher incidence of 5-year SPTs and local recurrences compared with non-chewers. Moreover, multivariate analysis demonstrated that preoperative betel quid chewing was an independent prognostic factor for 5-year local control and SPTs occurrence rates., Conclusions: Our results demonstrate that preoperative betel quid chewers had a higher incidence of local recurrence and SPTs than non-chewers, suggesting that field cancerization may occur in OSCC patients with a history of betel quid chewing., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Squamous cell carcinoma antigen (SCC-Ag) and C-reactive protein (CRP) levels have been successfully used to stratify risk groups in primary oral squamous cell carcinoma (OSCC) patients; however, related biomarkers have rarely been investigated in recurrent OSCC. The purpose of the present study was to analyze the relationships of SCC-Ag and CRP levels at the time of recurrence with clinical factors and prognosis. We retrospectively recruited patients with recurrence in a cohort of 534 OSCC patients between March 2001 and July 2013. One hundred patients had recurrence. The serum SCC-Ag and CRP levels were measured at the time of cancer diagnosis, 3 to 6 months after treatment with clinical disease-free, and at the time of recurrence. The SCC-Ag levels were significantly lowered after treatment (paired t-test: p = 0.001) and re-elevated at the time of recurrence (paired t-test: p = 0.027). An SCC-Ag level ≥2.0 ng/ml and a CRP level ≥5.0 mg/L at the time of recurrence were significantly associated with recurrent tumor status (P<0.001), recurrent nodal metastasis (χ2 trend test: P = 0.020), distant metastasis (P<0.001), and overall survival (P<0.001). Moreover, the influence of both elevated SCC-Ag and CRP levels on overall survival (P<0.001, H.R. [95% CI]: 5.406 [2.210-13.222]) still existed after adjusting for the recurrent tumor stage and patient age. The present study demonstrates that concurrent high levels of both SCC-Ag and CRP at the diagnosis of recurrence acts as a predictor of recurrent tumor status, recurrent advanced tumor stage, distant metastasis, and survival after the diagnosis of recurrence. This study expands the applicability of these two markers in the risk stratification in recurrent OSCC.

Background: To evaluate the efficacy and adverse events of cisplatin, tegafur, and leucovorin concomitantly with radiotherapy for patients with advanced, non-metastatic squamous cell carcinoma (SCC) of the oropharynx and hypopharynx., Methods: The PTL regimen consisted of cisplatin (P) 50 mg/m 2 on day 1, oral tegafur (T) 800 mg/day plus leucovorin (LV) 60 mg/day on days 1 through 14. It was repeated every 2 weeks through the radiotherapy course. Conventional radiotherapy with 1.8-2.0 Gy/day, 5 days per week, was delivered in a total dose of between 70 and 72 Gy., Results: Sixty-five patients with stage III or IV of SCC of the head and neck were consecutively treated between May 2002 and November 2005. Forty-six (70.7%) patients had complete response after concomitant chemoradiotherapy (CCRT). With a median follow-up of 54.0 months (range 1-103 months), the 5-year locoregional control, progression-free survival, and overall survival rates were 50.6%, 40.7%, and 59.7%, respectively. Three (4.6%) patients had toxic death during treatment. Fifty-one (80.0%) patients experienced grade 3-4 mucositis which occurred in about 35% of the CCRT duration. The functional preservation rate among post-CCRT complete responders was 93.5% (43/46). The median cisplatin accumulated dosage was 150 mg, and the rate of hearing impairment among the survivors was 7.8%., Conclusion: CCRT with outpatient-based PTL for advanced SCC of oropharynx and hypopharynx is feasible and has comparative efficacy and acceptable adverse events.

Objectives/hypothesis: The role of tumor volume in T4a laryngeal cancer remains unclear among different treatment modalities. Using tumor volumetry, we investigated the impact of primary tumor volume on this subset of patients., Study Design: Retrospective cohort study of 62 T4a laryngeal cancer patients., Methods: From October 2002 to September 2010, 48 patients were treated with definitive chemoradiation therapy (CRT), and 14 patients had undergone total laryngectomy. Tumor volume was calculated and was correlated with the overall survival (OS), progression-free survival (PFS), and local control rate (LCR) data of each treatment group., Results: The 5-year OS, PFS, and LCR were significantly lower in the CRT group with tumor volume ≥ 15 cm(3) (22.5% vs. 48.7%, P = 0.009; 32.2% vs. 64.3%, P = 0.003; 45.2% vs. 67.3%, P = 0.039). Multivariate analysis showed that tumor volume was an independent poor prognosticator for OS, PFS, and LCR in the CRT group. For tumor volume ≥ 15 cm(3) , total laryngectomy provided a significantly higher 5-year OS and PFS (54.5% vs. 22.5%, P = 0.039; 80.0% vs. 32.2%, P = 0.017) than for those tumors treated with definitive CRT., Conclusions: Patients with T4a laryngeal cancer with primary tumor volume ≥ 15 cm(3) had poorer survival outcomes after definitive CRT compared with total laryngectomy. It was also an independent poor prognosticator on LCR, PFS, and OS for those receiving definitive CRT. For patients with tumor volume ≥ 15 cm(3), total laryngectomy provided a better survival outcome than definitive CRT., (© 2013 The American Laryngological, Rhinological and Otological Society, Inc.)

Purpose: To investigate the results of postoperative radiotherapy (PORT) for the treatment of pathologic N2b/c squamous cell carcinoma of the oral cavity (OSCC)., Materials and Methods: This study reviewed cancer registry data collected in our hospital from 1998 to 2009 with the following inclusion criteria: primary OSCC, treatment with radical surgery, and multiple nodal metastases. Patients who had extracapsular spreading of the lymph node metastases or positive resection margins or who refused to undergo PORT were excluded. The prescribed dose of PORT was 60-66 Gy. Concurrent chemotherapy was optional. Patient characteristics, treatment parameters and clinical outcome were recorded. The primary end point was overall survival, and the secondary endpoint was disease status., Results: There were 138 eligible cases, and the median follow-up period was 35 months. The 3-year overall survival rate was 56%. Univariate analysis revealed that pathologic T4 status (pT4), bone marrow invasion, and lymphatic invasion were significantly correlated with poor outcome (p<0.05). Multivariate analysis showed that pT4, lymphatic invasion, and the no concurrent chemotherapy were independent poor prognostic factors (p<0.05). Fifty-four patients had tumor recurrence. The 3-year recurrence-free survival rate was 59%. Skin invasion, pT4, and bone marrow invasion were correlated with poor prognosis in the univariate analysis (p<0.05). Only pT4 (p<0.01) and no concurrent chemotherapy (p = 0.03) were independently correlated with poor recurrence-free survival., Conclusion: For OSCC patients with multiple-node metastases without extracapsular spreading or positive resection margins, PORT without concurrent chemotherapy correlated to inferior outcome. Multiple lymph node metastases might be considered an indication for concurrent chemotherapy.

Objectives: The aim of this cohort study was to examine the role of the chemokine (C-X-C motif) ligand 9 (CXCL9) on nasopharyngeal carcinoma (NPC)., Materials & Methods: Sera from 205 NPC patients and 231 healthy individuals, and 86 NPC tumor samples were enrolled. CXCL9 expression in tissue samples was analyzed by quantitative real-time PCR and immunohistochemistry. CXCL9 serum concentrations were measured by enzyme-linked immunosorbent assay., Results: CXCL9 expression was significantly higher in tumors than in normal epithelium. CXCL9 serum concentrations were also significantly higher in NPC patients compared to those in healthy individuals (516.8±617.6 vs. 170.7±375.0 pg/mL, P<0.0001). Serum CXCL9 levels were significantly higher in NPC patients with higher tumor stages, nodal stages, and overall stages (P<0.001, P = 0.001, and P<0.001, respectively). We found a statistically significant correlation between the concentrations of CXCL9 and EBV DNA load in the NPC patients (Spearman's correlation analysis; r = 0.473, P<0.001; 95% confidence interval, 0.346-0.582). Moreover, NPC patients with higher CXCL9 levels (>290 pg/mL, median) before treatment had worse prognoses for overall survival and disease-free survival (P = 0.045 and P = 0.008, respectively). Multivariate logistic regression analyses also indicated that higher CXCL9 serum levels were an independent prognostic factor for disease-free survival (P = 0.015)., Conclusion: Our study demonstrated that CXCL9 is associated with tumor burden and aggressiveness of NPC tumors and the serum level of this ligand may be useful as a prognostic indicator.

Objectives/hypothesis: Elevated inflammatory biomarkers such as C-reactive protein (CRP) and the recently identified neutrophil/lymphocyte ratio (NLR) were demonstrated to be associated with prognosis in human cancers. The aim of our present study is to analyze the relationship of preoperative levels of CRP and NLR with clinicopathological factors and prognosis in oral squamous cell carcinoma (OSCC) patients., Study Design: Retrospective study., Methods: This study was performed on 226 OSCC patients between July 2007 and April 2012. Their serum CRP levels and NLR were measured preoperatively., Results: CRP level ≥ 5.0 mg/L was significantly associated with NLR ≥ 2.44 (linear regression, P < .001). Elevated CRP and NLR were significantly associated with pathological tumor status (P < .001), pathologic nodal metastasis (P < .001), tumor depth (≥10 mm vs. <10 mm, P < .001), disease-free survival (P < .001), and overall survival (P = .001). The influence of CRP level and NLR on disease-free survival (hazard ratio [HR] = 2.259, 95% confidence interval [CI] = 1.170-4.361) and overall survival (HR = 2.176, 95% CI = 1.116-4.245]) still existed after adjusting for tumor status, lymph node metastasis, and tumor cell differentiation., Conclusions: The present study demonstrates that elevated CRP is an independent prognostic factor in OSCC. Elevated NLR in the high CRP group identifies patients at high risks of recurrence and shorter survival. Incorporating NLR into CRP level therefore has significant potential as a biomarker for risk stratification in OSCC., (Copyright © 2013 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Although human papillomavirus (HPV) infections have been causally linked to oral cavity squamous cell carcinoma (OSCC), the potential role of low-risk HPV (LR-HPV) types in the pathogenesis of this malignancy remains unclear., Objectives: We sought to investigate the distribution of HPV genotypes and their prognostic significance in OSCC patients treated by radical surgery, either with or without adjuvant therapy., Study Design: We studied two non-overlapping OSCC cohorts for the periods 2005-2006 (2005 cohort, n = 204) and 2010-2011 (2010 cohort, n = 206). Paraffin-embedded tissue blocks were collected, and the HPV genotype was determined using PCR plus HPV blot tests. The primary study endpoint was the prevalence of HPV genotypes. The secondary endpoints were the 2-year therapeutic outcomes., Results: The overall prevalence of HPV infections did not differ significantly in the two study cohorts. However, the prevalence of LR-HPV was significantly higher in the 2010 cohort than in the 2005 cohort (p = 0.002). The overall prevalence of HPV infections was not significantly associated with the 2-year outcomes. However, multivariate analysis demonstrated that LR-HPV infection was a predictor of poor 2-year disease-free survival (p = 0.036, hazard ratio [HR] = 3.1), disease-specific survival (p = 0.014, HR = 3.8), and overall survival (p = 0.016, HR = 3.2) in the subgroups of OSCC patients with poor differentiation, pN2 lymph node metastases, or extracapsular spread (n = 150)., Conclusions: LR-HPV infections may have an important role in determining the clinical outcomes of certain OSCC patients bearing specific risk factors., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Somatic mutations affecting the mitochondrial DNA (mtDNA) have been frequently observed in human cancers and proposed as important oncological biomarkers. However, the clinical significance of mtDNA mutations in cancer remains unclear. This study was therefore performed to explore the possible clinical use in assessing oral squamous cell carcinoma (OSCC) of pathogenic mtDNA mutations. The entire mitochondrial genome of 300 OSCC with their matched control DNAs was screened by direct sequencing and criteria were set to define a pathogenic somatic mutation. The patients' TP53 R72P genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. The relationships between pathogenic somatic mutations, clinicopathogical features, TP53 R72P genotype and clinical prognosis were analyzed. Overall, 645 somatic mtDNA mutations were identified and 91 of these mutations were defined as pathogenic. About one quarter (74/300) of the OSCC tumor samples contained pathogenic mutations. Individuals with the TP53 R allele had a higher frequency of pathogenic somatic mutation than those with the PP genotype. Kaplan-Meier analysis indicated that TP53 R allele patients with pathogenic somatic mutations demonstrated a significant association with a poorer disease-free survival than other individuals (HR = 1.71; 95% CI, 1.15-2.57; p = 0.009) and this phenomenon still existed after adjusting for mtDNA haplogroup, tumor stage with treatment regimens, differentiation and age at diagnosis (HR = 1.59; 95% CI, 1.06-2.40; p = 0.03). Subgroup analyses showed that this phenomenon was limited to patients who received adjuvant radiotherapy/chemo-radiotherapy after surgery. The results strongly indicated that pathogenic mtDNA mutations are a potential prognostic marker for OSCCs. Furthermore, functional mitochondria may play an active role in cancer development and the patient's response to radiotherapy/chemo-radiotherapy.

Objectives: We have previously shown that the resection outcomes of cT4a and cT4b oral cavity squamous cell carcinoma (OSCC) are comparable, but whether similar conclusions can be applied for the pathological stage of this disease needs investigation. In this study, we sought to compare the outcomes and to identify the risk factors for both pT4a and pT4b tumors., Methods: We retrospectively examined 181 pT4 OSCC patients who had radical resections between 2003 and 2010. The 5-year control and survival rates were the main outcome measures., Results: Of the 181 resected pT4 OSCC patients, 133 (73%) had pT4a disease, and 48 (27%) had pT4b disease. All of the resected T4b tumors were below the mandibular notch (infra-notch pT4b). The 5-year outcomes of the patients with infra-notch pT4b and pT4a were comparable: local control, 80% vs. 78%, p=0.7275; neck control, 87% vs. 82%, p=0.4798; distant metastases, 22% vs. 23%, p=0.8871; disease-free survival, 63% vs. 55%, p=0.2813; disease-specific survival, 68% vs. 60%, p=0.3526; and overall survival, 62% vs. 44%, p=0.2643, respectively. Extracapsular spread was the only independent prognostic factor for 5-year survival rates in pT4a patients. Poor tumor differentiation and pN2 status were the independent 5-year survival prognostic factors for the infra-notch pT4b tumor patients., Conclusions: Infra-notch pT4b had outcomes comparable with those of pT4a tumors, although they displayed different risk factors. We therefore recommend that resectable infra-notch pT4b tumors should be classified as pT4a disease in the AJCC tumor staging., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objectives: To evaluate the prognostic value of maximum standardized uptake value (SUVmax) measured in [(18)F]-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) for patients with non-disseminated nasopharyngeal carcinoma (NPC)., Materials and Methods: From January 2002 to July 2008, 371 NPC patients who underwent (18)F-FDG-PET before radical intensity-modulated radiotherapy (IMRT) were recruited. The SUVmax was recorded for the primary tumor (SUVmax-T) and neck lymph nodes (SUVmax-N)., Results: The median follow-up was 64months. The optimal cutoff value was 9.3 for SUVmax-T and 7.4 for SUVmax-N. Patients with a lower SUVmax-T or SUVmax-N had a significantly better 5-year distant metastasis-free survival (DMFS), but showed no significant difference in local control or regional control. Patients were divided into four groups by SUVmax, as follows: (a) both lower SUVmax-T and SUVmax-N, (b) higher SUVmax-T only, (c) higher SUVmax-N only, and d) both higher SUVmax-T and SUVmax-N. There were significant differences between these four groups in 5-year DMFS: (a) 95.5%, (b) 90.0%, (c) 83.3%, and (d) 79.9%, respectively (p=0.004). When looking at the stage of disease, the 5-year DMFSs in group a, b, c, d were 96.9%, 94.6%, 97.4%, and 84.3%, respectively in stage I-III patients (p=0.037) and were 91.6%, 82.9%, 68.5%, and 76.7% in stage IVA-B patients (p=0.145). Using multivariate analysis, the SUVmax grouping, gender, and stage were independent factors for DMFS., Conclusion: The SUVmax of the primary tumor and neck lymph nodes were independent prognostic factors for DMFS in NPC patients treated with IMRT., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The levels of squamous cell carcinoma antigen (SCC-Ag) and C-reactive protein (CRP) can be used to predict tumor invasion, lymph node metastasis, staging and survival in patients with oral cavity cancer. The present study analyzed the relationship between pre-treatment levels of SCC-Ag and CRP in relation to clinicopathological factors in patients with pharyngolaryngeal cancer (PLC) and determined whether elevated levels of CRP and SCC-Ag were associated with tumor metabolic activity via [18F] fluorodeoxyglucose positron emission tomography (FDG-PET). We retrospectively recruited one hundred and six PLC patients between June 2008 and December 2011. All patients received computed tomography (CT)/magnetic resonance imaging (MRI) and FDG-PET staging analyses, and the serum levels of SCC-Ag and CRP in these patients were measured prior to treatment. A SCC-Ag level ≥2.0 ng/ml and a CRP level ≥5.0 mg/L were significantly associated with clinical stage (P<0.001), clinical tumor status (P<0.001), and clinical nodal status (P<0.001). The elevation of both SCC-Ag and CRP levels was correlated with the standardized uptake value (SUV) max of the tumor (≥8.6 mg/L) and lymph nodes (≥5.7 ng/ml) (P = 0.019). The present study demonstrated that the presence of high levels of both pre-treatment SCC-Ag and CRP acts as a predictor of clinical stage, clinical tumor status, and clinical nodal status in patients with PLC. Moreover, elevated levels of SCC-Ag and CRP were associated with a high metabolic rate as well as the proliferative activity measured according to the SUVmax of the tumor and lymph nodes. Therefore, elevated levels of these two factors have the potential to serve as biomarkers for the prediction of tumor aggressiveness in cases of PLC.

Aim: To understand the frequency, clinical significance, and benefits of salvage therapy in oral cavity squamous cell carcinoma (OSCC) patients with regional nodal recurrence at unusual sites (prelaryngeal area, parotid area, and retropharyngeal area)., Methods: We examined 178 patients with neck recurrence at levels I-V (usual group) and 26 patients outside levels I-V (unusual group). The 5-year survival rates served as the main outcome measure., Results: Of the 26 unusual group patients, the neck recurrence sites were as follows: 5 at the prelaryngeal area, 13 at the parotid area, and 8 at the retropharyngeal area. Multivariate analyses demonstrated that poor differentiation, pN2, extracapsular spread (ECS), tumor depth≥10 mm, relapse time≤10 months, local recurrence, neck recurrence at unusual sites, and distant metastases were independent prognostic factors for 5-year disease-specific survival (DSS), whereas pN2, ECS, tumor depth≥10 mm, relapse time≤10 months, neck recurrence at unusual sites, and distant metastases were independent prognostic factors for 5-year overall survival (OS). The 6-month and 18-month survival rates after the N-relapse date for the salvaged-usual group, the salvaged-unusual group, and the nonsalvaged patients were 73%/46%, 40%/0%, and 10%/0% (P<0.0001), respectively [DSS: salvaged-unusual group (hazard ratio/95 % confidence interval), 2.060/1.058-4.008, P=0.033; salvaged-usual group, 6.420/4.340-9.496, P<0.001; OS: salvaged-unusual group, 2.100/1.080-4.081, P=0.029; salvaged-usual group, 6.514/4.418-9.606, P<0.001]., Conclusions: Our findings demonstrate that OSCC patients with regional nodal recurrence at unusual sites had poor outcomes.

Direct suspension laryngoscopic biopsy of neoplasms in larynx, oropharynx, and hypopharynx was an arduous procedure in patients with a history of head and neck cancer and difficult airways. This preliminary study was aimed to report the efficacy and safety of a narrow band imaging-guided biopsy of this category by flexible laryngoscopy. This is a retrospective chart review study conducted in setting of tertiary referral centre. Nineteen consecutive head and neck cancer patients with difficulty in general anesthesia and rigid endoscopic approach due to trismus, craniofacial deformities, and/or limited neck extension after cancer therapy were referred for endoscopic biopsy of their suspicious lesions in larynx, hypopharynx, or parts of oropharynx. Following topical anesthesia, a flexible laryngoscope was introduced through the nose into the pharynx. Under narrow band imaging magnified view, the specified tumor foci were biopsied in an office-based setting. All of the lesions were reached and biopsied to obtain sufficient tissue samples. The procedure took <20 min in every case. Twelve of the 19 pathologic examinations disclosed the malignancies at the first biopsy, and another underwent a second biopsy to prove cancer recurrence. The other six patients with benign lesions received further follow-up for at least 6 months and showed no recurrence. There were no complications associated with the technique. This study introduced that flexible laryngoscopy with narrow band imaging has the advantages of nimbleness, precision, and minimal morbidity. This combined technique may be a safe and promising method for tissue sampling of suspicious recurrence in head and neck cancer patients with difficult airways.

Background: The aim of this study was to compare the outcomes of postoperative adjuvant concomitant chemoradiotherapy using two different schedules of cisplatin for patients with high-risk oral squamous cell carcinoma (OSCC)., Methods: From Feb. 2008 to Aug. 2010, 55 patients with high-risk OSCC were included in this study. Patients were randomized into treatment groups that either received 100 mg/m2 cisplatin once every 3 weeks (arm A) or 40 mg/m2 cisplatin once per week (arm B). All patients were irradiated with 66 Gy in 33 fractions., Results: Of the 50 eligible patients, 26 were assigned to arm A, and 24 were assigned to arm B. Both groups of patients received the same mean doses of radiotherapy and cisplatin. However, 88.5% of patients in arm A and 62.5% of those in arm B (p=0.047) received ≥ 200 mg/m2 of cisplatin in total. The overall toxicity was significantly greater in arm B (p=0.020), and all of the grade 4 toxicities occurred in patients in arm B., Conclusions: Three-weekly high-dose cisplatin treatment showed higher compliance, and lower acute toxicity compared to weekly low-dose cisplatin treatment.

Background: Squamous cell carcinoma antigen (SCC-Ag) level and C-reactive protein (CRP) have been shown to be associated with tumor invasion, lymph node metastasis, staging and survival in patients with oral squamous cell carcinoma (OSCC). The purpose of the present study was to analyze the relationship between preoperative levels of both SCC-Ag and CRP, with clinicopathologic factors and prognosis in OSCC patients., Methods: A retrospective study was performed on 142 OSCC patients between March 2008 and March 2011. Their serum SCC-Ag and CRP levels were measured preoperatively., Results: SCC-Ag level of ≥2.0 ng/ml and CRP level ≥5.0 mg/L were significantly associated with pathologic tumor status (P < 0.001), pathologic nodal metastasis (P = 0.001), tumor depth (≥10 mm vs. <10 mm, P < 0.001), disease-free survival (P ≤ 0.001) and overall survival (P ≤ 0.001). The influence of SCC-Ag and CRP level on disease-free survival (hazard ratio 4.046, 95 % confidence interval 1.698-9.692) and overall survival (hazard ratio 3.655, 95 % confidence interval 1.464-9.130) still existed after adjusting for tumor status, lymph node metastasis and tumor cell differentiation., Conclusions: Concurrent high levels of both preoperative SCC-Ag and CRP levels act as a predictor for lymph node metastasis, advanced tumor stage and tumor recurrence. It therefore has significant potential as a biomarker for risk stratification in OSCC.

Objective: To evaluate the long-term voice characteristics and quality of life of early glottic cancer patients after definitive treatment., Study Design: Case series with chart review in a tertiary care medical center in Taiwan., Methods: Forty-two consecutive patients who received radiation therapy (RT) or transoral laser microsurgery (TLM) for early glottic cancer over 12 months were evaluated for voice laboratory data and quality-of-life measurements., Results: Twenty-four patients received RT, and 18 underwent TLM. There was no difference between the two groups on acoustic and aerodynamic voice measures except for modal fundamental frequency in males. In the Functional Assessment of Cancer Therapy-Head and Neck survey, the TLM group had better communication than the RT group, but there were no differences in voice quality and strength. There was also no significant difference in the Voice Handicap Index 10 evaluation., Conclusions: Male patients who received TLM have higher modal fundamental frequency than male patients who received RT and norms. Voice-related life quality is similar in patients regardless of RT or TLM treatment for early glottic cancer, but those who receive TLM have better communication abilities than those who receive RT., (Copyright © 2012 The Voice Foundation. Published by Mosby, Inc. All rights reserved.)

Purpose: Extracapsular spread (ECS) to the cervical lymph nodes is a major adverse prognostic factor in oral cavity squamous cell carcinoma (OSCC). We prospectively examined the value of FDG PET immediately before postoperative radiotherapy/concurrent chemoradiotherapy (pre-RT/CCRT PET) to detect residual/relapsing disease in the early postsurgical follow-up period in high-risk OSCC patients with ECS., Methods: We examined 183 high-risk OSCC patients with ECS who underwent preoperative FDG PET/CT for staging purposes. Of these patients, 29 underwent a second pre-RT/CCRT FDG PET/CT scan. The clinical utility of the second FDG PET/CT was examined using Kaplan-Meier curve analysis., Results: Patients who underwent the second FDG PET/CT scan had baseline clinicopathological characteristics similar to those who did not undergo a second scan. Of the patients who underwent the second scan, seven (24 %) had unexpected, newly discovered lesions. Five eventually died of the disease, and two had no evidence of recurrence after a change in RT field and dose. In an event-based analysis at 2 months, rates of neck control (6/29 vs. 6/154, p = 0.001), distant metastases (3/29 vs. 4/154, p = 0.046), and disease-free survival (7/29 vs. 10/154, p = 0.003) were significantly higher in patients who received a second PET scan than in those who did not. The second pre-RT/CCRT PET scan was of particular benefit for detecting new lesions in OSCC patients with both ECS and lymph node standardized uptake value (SUV) of ≥ 5.2 in the first PET scan., Conclusion: The present findings support the clinical value of pre-RT/CCRT FDG PET for defining treatment strategy in OSCC patients with both ECS and high nodal SUV, even when FDG PET had already been performed during the initial staging work-up.

Pathological lymph node metastases (pN+) are an established prognostic factor in oral cavity squamous cell carcinoma (OSCC). We retrospectively examined the prognostic significance of lymph node (LN) density in pN+ OSCC patients who underwent neck dissection (ND) and postoperative adjuvant therapy. We examined 309 pN+ patients who underwent levels I-III ND and 148 pN+ patients treated with levels I-V ND. The 5-year control and survival rates served as the main outcome measures. The 5-year rates for patients treated with levels I-III and I-V NDs were as follows: local control, 79%, 74% (p=0.0630); neck control, 81%, 68% (p=0.0014); distant metastasis, 21%, 36% (p=0.0003); disease-free survival (DFS), 59%, 43% (p=0.0001); disease-specific survival (DSS), 66%, 46% (p<0.0001); and overall survival (OS), 49%, 37% (p=0.0048), respectively. Multivariate analysis demonstrated that an LN density ≥0.16 was an independent prognostic factor for 5-year neck control (all data presented as p, hazard ratio [95% confidence interval]) (0.003, 2.691 [1.412-5.128]), distant metastases (0.001, 2.831 [1.520-5.270]), DFS (<0.001, 2.464 [1.571-3.866]), and DSS (0.036, 1.781 [1.040-3.052]) in levels I-III ND patients. An LN density ≥0.048 was an independent predictor of 5-year local control (0.004, 4.871 [1.654-14.344]), neck control (0.002, 24.738 [3.367-181.771]), DFS (<0.001, 4.151 [2.264-7.610]), DSS (<0.001, 3.791 [2.017-7.125]), and OS (<0.001, 2.806 [1.706-4.613]) in levels I-V ND patients. Our findings demonstrate the prognostic value of LN density for guiding treatment strategies in OSCC patients who are to receive adjuvant therapy., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Cyclin D1 gene regulates cell cycle and plays an important role in the tumorigenesis of human cancers. The association between cyclin D1, clinicopathologic parameters and prognosis in oral cavity squamous cell carcinoma (OSCC) is inconclusive., Methods: A total of 264 male OSCCs were examined for cyclin D1 protein expression using immunohistochemistry (IHC). The expression levels of cyclin D1 were defined as overexpression when more than 10% of tumor cells displayed nuclear staining with moderate to strong intensity., Results: Overexpression of cyclin D1 was found in 97 (36.7%) OSCCs. Cyclin D1 protein overexpression was significantly associated with lymph node metastasis (P = 0.002), tumor cell differentiation (P = 0.031) and tumor stage (P = 0.051), but not associated with age onset, cigarette smoking, alcohol drinking, or areca quid chewing. Overexpression of cyclin D1 was also significantly associated with poor clinical outcomes in terms of disease-free survival (DFS, P = 0.002) and overall survival (OS, P < 0.001). The effects of cyclin D1 protein overexpression on DFS (hazard ratio (HR) = 1.540; 95% confidence interval (CI), 1.068 - 2.222) and OS (HR = 1.702; 95% CI, 1.168 - 2.480) were still existed after adjusting for clinicopathological parameters (such as age, primary tumor status, tumor cell differentiation, and lymph node metastasis) using logistic multivariate analysis., Conclusion: Cyclin D1 protein worked as an independent prognostic factor and can be as a biomarker for the aggressiveness of OSCC.

Background: The association between human leukocyte antigen (HLA) genes (located in the Major Histocompatibility Complex [MHC] region of chromosome 6p21) and NPC has been known for some time. Recently, two genome-wide association studies (GWAS) conducted in Taiwan and China confirmed that the strongest evidence for NPC association was mapped to the MHC region. It is still unclear, however, whether these findings reflect direct associations with Human Leukocyte Antigen (HLA) genes and/or to other genes in this gene-rich region., Methods: To better understand genetic associations for NPC within the MHC region of chromosome 6, we conducted an evaluation that pooled two previously conducted NPC case-control studies in Taiwan (N = 591 cases and N = 521 controls). PCR-based genotyping was performed for 12 significant SNPs identified within 6p21 in the Taiwan NPC GWAS and for the HLA-A gene (exons 2 and 3)., Findings: After confirming homogeneity between the two studies, pooled odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression. We found that HLA-A (p-trend = 0.0006) and rs29232 (within the GABBR1 gene; p-trend = 0.005) were independent risk factors for NPC after adjustment for age, gender, study and each other. NPC risk was highest among individuals who were homozygous for the HLA-A*0207 risk allele and carriers of the rs29232 risk allele (A)., Conclusion: Our study suggests that most of the SNPs significantly associated with NPC from GWAS reflect previously identified HLA-A associations. An independent effect of rs29232 (GABBR1), however, remained, suggesting that additional genes within this region might be associated with NPC risk.

Reprogramming of energy metabolism in cancer cells has been directly/indirectly linked to mitochondria and mitochondrial functional defects and these changes seem to contribute to the development and progression of cancer. Studies have indicated that mitochondrial DNA haplogroups are associated with risk in relation to various diseases including cancer. However, few studies have examined the effect of haplogroups on cancer prognosis outcome. In order to explore the role of haplogroups on oral squamous cell carcinoma (OSCC) prognosis, the mitochondrial genomes of 300 male OSCC patients were comprehensively analyzed by direct sequencing. They were then haplotyped and grouped into four major geographic haplogroups, namely the East Asia AN, Southeast Asia RBF, East Asia MGE and Northeast Asia CZD groups. The Kaplan-Meier plot analysis indicated that individuals who were members of the CZD haplogroup showed a significant association with better disease-free survival (DFS) than the other three haplogroups and this phenomenon still existed after adjusting for tumor stage, differentiation and age at diagnosis (hazard ratio=0.55; 95% CI=0.36-0.84). In addition, an interaction between membership of the RBF haplogroup and radiotherapy/chemo-radiotherapy in DFS was also identified. The results strongly support the hypothesis that an individual's haplogroup, by defining their genomic background, plays an important role in tumor behavior and mitochondrially-targeted anticancer drugs are promising future therapeutic approaches.

Background: Human papillomavirus (HPV) is an oncogenic virus causing oropharyngeal cancers and resulting in a favorable outcome after the treatment. The role of HPV in oral cavity squamous cell carcinoma (OSCC) remains ambiguous., Objective: This study aimed to examine the effect of HPV infection on disease control among patients with OSCC following radical surgery with radiation-based adjuvant therapy., Patients and Method: We prospectively followed 173 patients with advanced OSCC (96% were stage III/IV) who had undergone radical surgery and adjuvant therapy between 2004 and 2006. They were followed between surgery and death or up to 60 months. Surgical specimens were examined using a PCR-based HPV blot test. The primary endpoints were the risk of relapse and the time to relapse; the secondary endpoints were disease-free survival, disease-specific survival, and overall survival., Results: The prevalence of HPV-positive OSCC was 22%; HPV-16 (9%) and HPV-18 (7%) were the genotypes most commonly encountered. Solitary HPV-16 infection was a poor predictor of 5-year distant metastases (hazard ratio, 3.4; 95% confidence interval, 1.4-8.0; P = 0.005), disease-free survival (P = 0.037), disease-specific survival (P = 0.006), and overall survival (P = 0.010), whereas HPV-18 infection had no impact on 5-year outcomes. The rate of 5-year distant metastases was significantly higher in the HPV-16 or level IV/V metastasis group compared with both the extracapsular spread or tumor depth ≥ 11-mm group and patients without risk factors (P<0.001)., Conclusions: HPV infections in advanced OSCC patients are not uncommon and clinically relevant. Compared with HPV-16-negative advanced OSCC patients, those with a single HPV-16 infection are at higher risk of distant metastases and poor survival despite undergoing radiation-based adjuvant therapy and require a more aggressive adjuvant treatment and a more thorough follow-up.

This study was designed to explore the relationship between epidermal growth factor receptor (EGFR) copy number and EGFR protein expression in oral cavity squamous cell carcinoma (OSCCs) in Taiwan. A total of 160 oral cavity squamous cell carcinomas were examined for EGFR protein overexpression using immunohistochemistry and for copy number using a fluorescence in situ hybridization (FISH) assay. Overexpression and increased gene copy numbers of EGFR were found in 75 (46.88%) and 50 (31.25%) cases, respectively. The concordance rate for EGFR gene amplification and protein overexpression was 100%. EGFR overexpression was associated with a poor prognosis both in terms of disease-free survival (DFS) and overall survival (OS). On the other hand, the association between an increase in EGFR gene copies and DFS or OS was insignificant. This was despite the observed significant associations between gene copy number and tumor stage, depth of tumor invasion, lymph node metastasis, bone invasion and perineural invasion. EGFR protein overexpression is closely related to EGFR copy number. Standard methodological and interpretation criteria need to be established that allows EGFR copy number combined with EGFR protein expression to be determined in a manner that allows individualized EGFR targeted therapy in OSCC patients., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Purpose: In the American Joint Committee on Cancer 2010 classification system, pT1-2N0 oral cavity squamous cell carcinoma (OSCC) is considered an early-stage cancer treatable with surgery alone (National Comprehensive Cancer Network 2010 guidelines). Our aim was to evaluate the feasibility of surgery alone for pT1-2N0 OSCC patients., Methods and Materials: Among 1279 previously untreated OSCC patients referred to our hospital between January 1996 and May 2008, we identified 457 consecutive patients with pT1-2N0 disease. All had radical tumor excision with neck dissection. A total of 387 patients showing pathologic margins greater than 4 mm and treated by surgery alone were included in the final analysis. All were followed up for at least 24 months after surgery or until death. The 5-year rates of control, distant metastasis, and survival were the main outcome measures., Results: The 5-year rates in the entire group of pT1-2N0 patients were as follows: local control, 91%; neck control, 92%; distant metastases, 1%; disease-free survival, 85%; disease-specific survival, 93%; and overall survival, 84%. Multivariate analysis identified poor differentiation and pathologic tumor depth of 4 mm or greater as independent risk factors for neck control, disease-free survival, and disease-specific survival. A scoring system using poor differentiation and tumor depth was formulated to define distinct prognostic groups. The presence of both poorly differentiated tumors and a tumor depth of 4 mm or greater resulted in significantly poorer 5-year neck control (p < 0.0001), disease-free (p < 0.0001), disease-specific (p < 0.0001), and overall survival (p = 0.0046) rates., Conclusion: The combination of poor differentiation and pathologic tumor depth of 4 mm or greater identified a subset of pT1-2N0 OSCC patients with poor outcome, who may have clinical benefit from postoperative adjuvant radiotherapy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: A case-control study was conducted to evaluate the role of adult diet on nasopharyngeal carcinoma (NPC) in Taiwan., Methods: A total of 375 incident NPC cases and 327 controls matched to the cases on sex, age, and residence were recruited between July 1991 and December 1994. A structured questionnaire inquiring complete dietary history, socio-demographic characteristics, and other potential confounding factors was used in the personal interview. Unconditional logistic regression analysis was used to estimate multivariate-adjusted odds ratio (OR(adj)) with 95% confidence interval (CI) after accounting for known risk factors., Results: Fresh fish (OR(adj), 0.56; 95% CI, 0.38-0.83 for the highest vs. lowest tertile of intake), green tea (OR(adj), 0.61; 95% CI, 0.40-0.91 for drinking ≥1 times/week vs. never) and coffee (OR(adj), 0.56; 95% CI, 0.37-0.85 for drinking ≥0.5 times/week vs. never) were inversely associated with the NPC risk. No association with NPC risk was observed for the intake of meats, salted fish, fresh vegetables, fruits and milk. Intake of vitamin A from plant sources was associated with a decreased NPC risk (OR(adj), 0.62; 95% CI, 0.41-0.94 for the highest vs. lowest tertile)., Conclusion: The study findings suggest that certain adult dietary patterns might protect against the development of NPC.

Purpose: Extracapsular spread (ECS) in neck lymph nodes is a major adverse prognostic factor in patients with oral cavity squamous cell carcinoma (OSCC). We conducted a retrospective analysis of prognostic factors in this patient group and tried to identify a subset of patients with a worse prognosis suitable for more aggressive therapeutic interventions., Methods and Materials: Enrolled in the study were 255 OSCC patients with ECS in neck nodes and without evidence of distant metastasis. All participants were followed-up for at least 2 years or censored at last follow-up. The 5-year rates of control, distant metastasis, and survival were the main outcome measures., Results: Level IV/V lymph node metastases and tumor depth ≥12 mm were independent predictors of 5-year survival and identified three prognostic groups. In the low-risk group (no level IV/V metastases and tumor depth <12 mm), the 5-year disease-free, disease-specific, and overall survival rates were 60%, 66%, and 50%, respectively. In the intermediate-risk group (no level IV/V metastases and tumor depth ≥12 mm), the 5-year disease-free, disease-specific, and overall survival rates were 39%, 41%, and 28%, respectively. In the high-risk group (evidence of level IV/V metastases), the 5-year disease-free, disease-specific, and overall survival rates were 14%, 12%, and 10%, respectively., Conclusions: Among OSCC patients with ECS, those with level IV/V metastases appear to have the worst prognosis followed by without level IV/V metastases and tumor depth ≥12 mm. An aggressive therapeutic approach may be suitable for intermediate- and high-risk patients., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: The objective of this retrospective study was twofold: (1) to investigate prognostic factors for clinical outcomes in patients with poorly differentiated oral cavity squamous cell carcinoma and (2) to identify specific prognostic subgroups that may help to guide treatment decisions., Methods and Materials: We examined 102 patients with poorly differentiated oral cavity squamous cell carcinoma. All patients were followed for at least 24 months after surgery or until death. The 5-year rates of local control, neck control, distant metastasis, disease-free, disease-specific, and overall survival served as main outcome measures., Results: The 5-year rates were as follows: local control (79%), neck control (64%), distant metastases (27%), disease-free survival (48%), disease-specific survival (52%), and overall survival (42%). Multivariable analysis showed that the number of pathologically positive nodes (≥4 vs. ≤3) was a significant predictor of neck control, distant metastasis, and disease-free, disease-specific, and overall survival rates. In addition, the presence of tumor depth of ≥11 mm (vs. <11 mm) was a significant predictor of distant metastasis, disease-specific survival, and overall survival rates. The combination of the two predictors (26.5%, 27/102) was independently associated with poorer neck control (p = 0.0319), distant metastasis (p < 0.0001), and disease-free (p < 0.0001), disease-specific (p < 0.0001), and overall survival (p < 0.0001) rates., Conclusions: In patients with poorly differentiated oral cavity squamous cell carcinoma, the presence of at least 4 pathologically positive lymph nodes and of a pathological tumor depth ≥11 mm identifies a subset of subjects with poor clinical outcomes. Patients carrying both risk factors are suitable candidates for the development of novel therapeutic approaches., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The prognosis of well-differentiated oral cavity squamous cell carcinoma (OSCC) is better than less-well-differentiated neoplasms. The aim of this retrospective study was to identify prognostic factors in patients with well-differentiated OSCC. The 5-year outcomes of 467 patients with well-differentiated OSCC who underwent radical surgery and neck dissection were analyzed. In the entire cohort, the presence of pathological node metastases (pN+ vs. pN0) was an independent predictor of 5-year outcomes. In pN0 patients, tumor depth (≥8 mm) was the only independently prognostic factor for 5-year survival rates on multivariable analysis (disease-free survival [DFS], P=0.001, hazard ratio [HR]=2.634, 95% confidence interval [95% CI]=1.496-4.636; disease-specific survival [DSS], P<0.001, HR=6.794, 95% CI=2.364-19.525). In pN+ patients, level IV/V neck nodal metastases (DFS, P<0.001, HR=47.483, 95% CI=8.942-252.122; DSS, P<0.001, HR=14.301, 95% CI=5.337-38.323), and ≥3 positive nodes (DFS, P=0.037, HR=2.107, 95% CI=1.047-4.242; DSS, P=0.044, HR=2.093, 95% CI=1.020-4.295) were independently associated with 5-year outcomes. Our results suggest that a tailored treatment approach in well-differentiated OSCC patients should take into account the presence of either pN0 or pN+ disease., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Oral cavity cancers (ORC) are the most common cancers, and standard treatment is radical surgery with postoperative radiotherapy. However, locoregional failure remains a major problem, indicating radioresistance an important issue. Our previous work has shown that GP96 contributed to radioresistance in nasopharyngeal and oral cancer cell lines. In this study, we determined clinical significance of GP96 in ORC by evaluation of GP96 expression and its association with disease prognosis in patients receiving radiotherapy, Methods: Total of 79 ORC patients (77 males, median age: 48 years old) receiving radical surgery and postoperative radiotherapy between Oct 1999 and Dec 2004 were enrolled. Patients in pathological stages II, III and IV were 16.5%, 16.5% and 67%, respectively. For each patient, a pair of carcinoma tissue and grossly adjacent normal mucosa was obtained. GP96-expression was examined by western blot analysis, and the association with clinicopathological status was determined., Results: Three-year locoregional control (LRC), distant metastasis-free survival (DMFS), disease-specific survival (DSS) and overall survival (OS) rates were 69%, 79%, 63% and 57%, respectively. We found that 55 patients (70%) displayed GP96-overexpression in the tumor tissue, which correlated with a higher pN stage (p = 0.020) and tumor depth (> 10 mm) (p = 0.045). Nodal extracapsular spreading (ECS) and GP96-overexpression predicted adverse LRC (p = 0.049 and p = 0.008). When stratified by nodal ECS, the adverse impact of GP96 remained significant in three-year LRC (p = 0.004). In multivariate analysis, GP96-overexpression was also an independent predictor of LRC, DSS and OS (p = 0.018, p = 0.011 and p = 0.012)., Conclusion: GP96 may play roles in radioresistance which attributes to tumor invasiveness in oral cancer patients receiving radiotherapy. GP96 may serve as a novel prognostic marker of radiotherapy. However, further independent studies are required to validate our findings in a larger series.

Background: The NCCN 2010 guidelines recommend the use of postoperative adjuvant radiotherapy (RT) for patients with pT3 oral cavity squamous cell carcinoma (OSCC). We sought to determine whether postoperative adjuvant RT improves outcomes in pT3N0 OSCC patients., Methods: A total of 119 consecutive patients with pT3N0 disease were involved. A total of 42 patients received postoperative adjuvant RT, while the remaining 77 did not. The 5-year rates of control, distant metastasis, and survival were the main outcome measures., Results: We found no differences in the risk profile of patients with and without postoperative adjuvant RT, the only exceptions being a higher frequency of tumor depth ≥10 mm (78.6% vs. 48.0%, P = .001) and close margins ≤4 mm (11.9 % vs. 2.7%, P = .043) in those treated by adjuvant RT. Tumor depth ≥10 mm was the only independent prognostic factor for 5-year local control, disease-free survival, and disease-specific survival in multivariable analysis. Tumor depth ≥13 mm was the only independent prognostic factor for the 5-year rate of distant metastases (16% [7 of 50] vs. 2% [1 of 67]). After stratification for tumor depth and adjuvant RT, patients with pT3N0 disease who received adjuvant RT did not show a survival advantage., Conclusions: Tumor depth ≥10 mm was the only prognostic factor identified in patients with pT3N0 disease. Adjuvant RT did not improve outcomes in pT3N0 patients, regardless of tumor depth. Patients with pT3N0 and tumor depth ≥13 mm (43% of pT3N0) were at the highest risk for distant metastases.

Background: Oral cavity squamous cell carcinoma (OSCC) is one of the most common cancers worldwide and has been considered to be highly associated with altered biological processes, including immunocyte chemotaxis, inflammatory response, angiogenesis, and/or immune regulation, suggesting that the levels of the tumor-related cytokines and chemokines will be dysregulated in the tumor microenvironment as well as in the systemic circulation and might be associated with some OSCC phenotypes., Methods: To profile cytokines in OSCC patients, the plasma levels of 48 proteins (26 cytokines, 10 chemokines, and 12 growth factors) were measured in 111 untreated OSCC patients, 112 healthy individuals, and 107 individuals with oral premalignant lesion (OPL)., Result: Compared to the plasma levels in the healthy individuals and OPL group, the levels of 12 proteins were significantly dysregulated in the OSCC patients. Further analysis demonstrated that the levels of IFN-α2, IL-2RA, and SCF were significantly lower in patients with higher pT status. IFN-α2 levels also decreased in patients with higher tumor depths. Moreover, OSCC patients with greater levels of VEGF (>4.87 pg/ml) before treatment had worse prognoses for overall survival after treatment (P=0.035)., Conclusions: This is the first report showing that the plasma VEGF levels may be a useful prognostic indicator of OSCC., (Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.)

Objectives/hypothesis: Previous studies have demonstrated a relationship between elevated serum squamous cell carcinoma (SCC) antigen (SCC-Ag) levels and shorter survival in cancer patients. Few studies, however, have investigated the role of serum SCC-Ag levels in oral SCC (OSCC). This study was conducted to analyze the relationship between preoperative SCC-Ag levels, clinicopathologic factors, and prognosis in OSCC patients., Study Design: Retrospective case-control study., Methods: Seventy-nine OSCC patients from Chang Gung Memorial Hospital were retrospectively recruited between April 2008 and March 2010. Serum SCC-Ag levels were measured preoperatively., Results: An SCC-Ag level of ≥2.0 ng/mL was significantly associated with the pathologic tumor status (P < .001), pathologic nodal status (P = .037), lymph node extracapsular spread (P = .016), and tumor depth (>10 mm vs. ≤10 mm, P < .001). It was not significantly associated with histologic differentiation (P = 1.000). A univariate analysis revealed that positivity for SCC-Ag was associated with disease-free survival (DFS) (P = .034) and overall survival (OS) (P < .001). In SCC-Ag-positive patients, the distant metastatic rate was higher than in the SCC-Ag-negative patients (P = .053)., Conclusions: This study demonstrated that preoperative SCC-Ag is a good marker of pathologic lymph node metastasis, an advanced tumor stage, and a higher rate of distant metastasis. The preoperative SCC-Ag level is a potential prognostic indicator in DFS and OS, but studies with a longer follow-up period are needed to confirm these results., (Copyright © 2011 The American Laryngological, Rhinological, and Otological Society, Inc.)

Oral squamous cell carcinoma (OSCC) has the highest rate of increase among male cancers in Taiwan. An understanding of the molecular pathogenesis of this disease as well as the development of prognostic markers for the clinical management of this disease is very important. Thus, a systematic loss of heterozygosity (LOH) analysis was performed to define minimally deleted regions (MDRs) in 63 male OSCCs using 400 polymorphic microsatellite markers. For increasing reliability, genomic DNA was extracted from >90% tumor cells that had been purified by LCM, and only when a microsatellite marker provided LOH information in >30% of the OSCCs was there considered to be successful allelotyping. A correlation of the various MDRs with clinicopathological parameters and prognosis was carried out. In total, 32 MDRs were identified and ten were noted as novel. In addition, six MDRs were found to be associated with cigarette smoking. Among these markers, a loss of MDR c7r2 (7q32.2-q35) was significantly associated with poor disease-free survival (DFS) and ten MDRs were associated with allelic imbalance (AI) in tumors. Among the latter, a loss of MDR c14r1 (14q24.2-q32.12) and c11r1 (11q13.4-q25) had a synergistic effect on poor DFS and were able to reduce further the DFS rate in patients with MDR c7r2 loss. Taken together, the results generated in this study provide new insights that help with exploring the molecular mechanisms associated with OSCC tumorigenesis and cigarette smoking. They also should aid the development of potential prognostic markers for the clinical management of OSCC., (2011 Wiley-Liss, Inc.)

Background: The purpose of this study was to evaluate the Model for Endstage Liver Disease (MELD) scoring system for predicting the morbidity and mortality of patients with head and neck cancer with liver cirrhosis undergoing tumor resection with microsurgical free-tissue transfer., Methods: Between January 2000 and December 2008, 3108 cases were retrospectively reviewed., Results: There were 59 men and 2 women enrolled in this study. Preoperatively, 31 and 30 patients were classified as having lower (<9.73) and higher (>9.73) MELD scores, respectively. Patients with higher MELD scores had significantly more postoperative medical morbidities including pulmonary complications and gastrointestinal bleeding. The mortality rate was also significantly higher for higher MELD scorers (23.3% vs 3.2%; p = 0.026). By logistic regression model, preoperative MELD score was a significant predictive factor for morbidity and mortality in multivariate analysis., Conclusion: MELD score could be used to predict morbidity and mortality for patients with head and neck cancer with liver cirrhosis undergoing tumor resection with microsurgical free tissue transfer., (Copyright © 2010 Wiley Periodicals, Inc.)

Our aim was to retrospectively assess the diagnostic performance from combined positron emission tomography/computed tomography (PET/CT) and magnetic resonance imaging (MRI) for the detection of bone marrow invasion of the mandible or maxilla in patients with oral cavity squamous cell carcinoma (OCSCC). A total of 114 patients with OCSCC, arising from or abutting the upper or lower alveolar ridge, underwent staging PET/CT and MRI studies before surgery. The possibility of bone marrow invasion on PET/CT and MRI was graded retrospectively on a 5-point score. Histopathology was taken as the reference standard. Sensitivity, specificity, predictive values and likelihood ratios were calculated. Clinical factors affecting the performance, like tumor origin and dentate status were also explored. PET/CT was found to be more specific than MRI (83% vs. 61%, respectively, p=0.0015) but less sensitive (78% vs. 97%, respectively, p=0.0391). Dentate status and tumor origin affected the diagnostic performance of PET/CT. In patients with positive MRI, sensitivity and specificity of PET/CT were 78% and 100% in dentate patients with alveolar ridge tumors, 75% and 80% in dentate patient with buccal tumors, 90% and 33% in edentulous patients with alveolar ridge tumors and 0% and 63% for edentulous patients with buccal tumors, respectively. PET/CT is more specific than MRI and can be used to complement the role of MRI. A negative MRI result can confidently exclude the presence of bone marrow invasion, while in patients with positive MRI findings, a negative PET/CT may be useful to rule out bone marrow invasion in dentate patients., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Unlabelled: We prospectively evaluated the sensitivity and specificity of (18)F-FDG PET in the detection of neck lymph node metastases in patients with oral cavity squamous cell carcinoma (OSCC). We also sought to evaluate whether pretreatment PET visual scores in the neck lymph nodes may improve risk stratification., Methods: We enrolled 473 OSCC patients (445 men and 28 women; mean age ± SD, 50.9 ± 11.7 y) without distant metastases. All participants underwent (18)F-FDG PET within 2 wk before surgery and neck dissection. Histopathology was taken as the reference standard for neck lymph node status. The duration of follow-up was at least 24 mo in all surviving patients., Results: (18)F-FDG PET correctly diagnosed 164 of 211 patients with neck metastases and 152 of 262 subjects without pathologic neck metastases, resulting in a patient-based sensitivity and specificity of 77.7% and 58.0%, respectively. In Cox models adjusting for age, sex, traditional risk factors, and treatment modality, PET results at the neck lymph nodes were significantly and independently associated with rates of neck control, distant metastasis, disease-free survival, disease-specific survival, and overall survival. Notably, the results of the c-statistics demonstrated that PET score improved the accuracy of risk prediction in terms of overall and disease-free survival rates., Conclusion: PET findings at the neck lymph nodes have limited sensitivity and specificity for primary staging of OSCC but improve risk stratification beyond that of traditional risk factors.

We examined the role of macrophage inflammatory protein (MIP)-3α on oral cavity squamous cell carcinoma (OSCC) and whether it was involved in modulating OSCC cell functions. The study population was comprised of 102 patients with OSCC. MIP-3α levels in tissues were examined by immunohistochemistry and quantitative real-time RT-PCR. Effects of MIP-3α on OSCC cell function were investigated by cell proliferation assays, trans-well migration/invasion assays, and RNA interference. We found that MIP-3α was overexpressed in OSCC tumor cells. MIP-3α expression was significantly higher in tumor cells vs. normal epithelial cells, as determined by both quantitative real-time RT-PCR and immunohistochemistry. Overexpression of MIP-3α was significantly correlated with positive pN status (P=0.036). Nevertheless, there were no correlations related to patient age, pT status, overall pathological stage, cell differentiation, or perineural invasion. The long-term disease-specific survival for patient subgroups stratified by the absence or presence of MIP-3α overexpression was 70.9% vs. 54.7% (P=0.041). Multivariate analysis indicated that MIP-3α overexpression had a significantly lower disease-specific survival (hazard ratio: 2.158; P=0.037). Additionally, in vitro suppression of MIP-3α expression in OECM-1 cells using specific interfering RNAs attenuated cell migration and invasiveness. These findings suggest that MIP-3α overexpression in OSCC is associated with a poorer prognosis for patient survival and contributes to tumor metastasis., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: This study was undertaken to identify the genes in response to areca nut extract, a potential carcinogen of oral cancer., Methods: Two oral cancer sublines chronically treated with areca nut extract were established. Methods such as microarray and immunohistochemistry were used to screen and validate the genes' altered expressions in areca nut extract-sublines or in cancer tissues., Results: A total of 35 genes were differentially expressed in both sublines. Several functional pathways were significantly altered. Six genes were confirmed over 2-fold of changes, including Ches1. Functional analyses showed that overexpression of Ches1 suppressed cell growth and arrested cells in the G2/M phase. Consistently, this gene has reduced expression in 52% of oral cancer tissues, which was significantly correlated with the areca nut chewing habit of patients (p = .04)., Conclusion: We identified 35 candidates and validated 6 genes that may be associated with areca nut-induced oral cancer. Loss of Ches1 may be attributed to areca nut extract-induced oral carcinogenesis., (Copyright © 2010 Wiley Periodicals, Inc.)

Conclusion: In our experience, the prognosis for parotid gland acinic cell carcinoma (AciCC) is good. Surgery alone would be sufficient in early-stage tumor. Postoperative adjuvant treatment in advanced-stage patients or those with positive resection margins usually gives satisfactory control of the disease., Objectives: AciCC is a rare tumor in parotid gland malignancy. The aim of this study was to retrospectively analyze the experience in our hospital in treating this malignancy., Methods: Twenty-five patients with AciCC diagnosed from 1983 to 2007 at the Chang Gung Memorial Hospital were retrospectively reviewed., Results: Thirteen male and 12 female patients ranged in age from 16 to 84 years (mean 37.5 years) at the time of diagnosis. Most patients (92%) presented with symptoms of infra-auricular mass. The tumor stage distributions of the patients were 24%, 44%, 28%, and 4% for stages I, II, III, and IV, respectively. Thirteen patients underwent superficial parotidectomy and 12 patients underwent total parotidectomy. Four patients had positive resection margins. Ten patients had surgery and postoperative radiotherapy; one received surgery and postoperative chemo/radiotherapy. The 10-year disease-free and overall actuarial survivals were both 84% in a mean follow-up of 75.8 months.

Purpose: To evaluate the outcome of definitive radiotherapy (RT) for oral cavity cancers and to assess prognostic factors., Methods and Materials: Definitive RT was performed on 115 patients with oral cavity cancers at Stages III, IVA, and IVB, with a distribution of 6%, 47%, and 47%, respectively. The median dose of RT was 72 Gy (range, 62-76 Gy). Cisplatin-based chemotherapy was administered to 95% of the patients. Eleven patients underwent salvage surgery after RT failure., Results: Eight-eight (76.5%) patients responded partially and 23 (20%) completely; of the patients who responded, 18% and 57%, respectively, experienced a durable effect of treatment. The 3-year overall survival, disease-specific survival, and progression-free survival were 22%, 27%, and 25%, respectively. The 3-year PFS rates based on the primary tumor sites were as follows: Group I (buccal, mouth floor, and gum) 51%, Group II (retromolar and hard palate) 18%, and Group III (tongue and lip) 6% (p < 0.0001). The 3-year progression-free survival was 41% for N0 patients and 19% for patients with N+ disease (p = 0.012). The T stage and RT technique did not affect survival. The patients who underwent salvage surgery demonstrated better 3-year overall survival and disease-specific survival (53% vs. 19%, p = 0.015 and 53% vs. 24%, p = 0.029, respectively). Subsite group, N+, and salvage surgery were the only significant prognostic factors for survival after multivariate analysis., Conclusion: The primary tumor site and neck stage are prognostic predictors in advanced-stage oral cancer patients who received radical RT. The primary tumor extension and RT technique did not influence survival., (Copyright © 2010 Elsevier Inc. All rights reserved.)