Hui-Ching Chuang

Prognostic Impact of p16, p53, Epidermal Growth Factor Receptor, and Human Papillomavirus in Oropharyngeal Cancer in a Betel Nut–Chewing Area

OBJECTIVE To evaluate the prevalence of human papillomavirus (HPV) and the prognostic significance of epidermal growth factor receptor (EGFR), p53, and p16 among patients with oropharyngeal carcinoma. DESIGN Retrospective study. SETTING Academic Institute of Otolaryngology, Kaohsiung, Taiwan. PATIENTS Two hundred seventy-four patients who were diagnosed as having oropharyngeal carcinoma underwent testing for the presence of the HPV genome in the nuclei of their tumor cells from January 1, 1992, through March 31, 2008. INTERVENTIONS The HPV genome was detected by performing polymerase chain reaction-based assays and in situ hybridization on tumor tissue from paraffin blocks. Immunohistochemistry staining for p16, p53, and EGFR was also performed. MAIN OUTCOME MEASURES We used the Fisher exact test to evaluate the correlation between the clinicopathological variables and the presence of HPV in tumor cells. Survival analysis was based on the Kaplan-Meier method. RESULTS We detected HPV in 45 of the 274 patients (16.4%); of these, HPV-16 and -18 were identified in 42 (93.3%) of the HPV-positive tumors. The HPV-positive oropharyngeal cancers were more likely to occur in females, nonsmoking individuals, and those who did not chew betel quid. The HPV-positive tumors significantly expressed p16 and were inversely associated with EGFR and p53 expression (all, P < .001). In addition, patients with tumor tissue that was positive for HPV (P = .008) and had negative expression of EGFR (P = .01), low expression of p53 (P = .01), and high expression of p16 (P = .04) had a better prognosis. CONCLUSION Our results suggest that HPV, EGFR, p53, and p16 are useful biomarkers in predicting the clinical outcomes of oropharyngeal cancer.

Clinical, pathological and molecular determinants in squamous cell carcinoma of the oral cavity

Squamous cell carcinoma of the oral cavity (OCSCC) is the most frequently observed form of head-and-neck cancer in Southeast Asia and is the sixth most common cancer worldwide. Most cases of this preventable disease are caused by alcohol consumption, smoking and betel nut chewing. The survival rates of patients with advanced OCSCC have not increased significantly in recent years. While treatments for OCSCC are similar worldwide, survival rates differ by geographical area. The various genetic profiles and individual genetic susceptibility for carcinogens may account for this discrepancy. In some respects, molecular alteration or accumulation affects tumor progression and the clinical outcomes among patients with OCSCC. Clarifying the tumor behavior of oral cancer, with regard to pathological features or molecular aspects, could help clinicians to judge, tailor and adopt more effective therapeutic strategies to treat oral cancer.

Toll-like receptor 3-mediated tumor invasion in head and neck cancer

OBJECTIVES Chronic inflammation associated with some infectious agents can lead to cancer. The Toll-like receptor (TLR) family is one of the largest and best-studied families of pathogen-associated molecular patterns. TLR3 recognizes double-stranded RNA and is a major effector of the immune response against viral pathogens. MATERIALS AND METHODS We investigated TLR3 protein expression in 153 oral squamous cell carcinoma (OSCC) specimens using tissue microarray. Furthermore, we used polyinosinic-polycytidylic acid (poly I:C) to stimulate head and neck cancer cells and an inhibitor of endosomal acidification bafilomycin A1 to block the TLR 3 signaling pathway to clarify the role of TLR 3 in OSCC. RESULTS Cytoplasmic TLR3 staining was observed in the vast majority of OSCC tissues (73.2%). Strong TLR3 expression was significantly correlated with patients whose tumors were poorly differentiated (P=0.028) and with perineural invasion (P=0.023). Three of the four head and neck cell lines tested (Fadu, OC2, and SCC4) expressed TLR3 mRNA, although at various levels. The stimulation of TLR3-expressing OC2 cells with poly I:C caused the phosphorylation of IFN regulatory factor 3 and IκB and sequentially induced the secretion of interleukin-6 and chemokine (C-C motif) ligand 5 (CCL5) in a dose- and time-dependent manner. Moreover, poly I:C stimulation promoted CCL5-mediated migration in OC2 cells. CONCLUSIONS In this report, we provide a novel mechanism for tumor invasion and the TLR3-dependent inflammatory response that could have therapeutic implications for OSCC.

Effect of Routine Esophageal Screening in Patients With Head and Neck Cancer

IMPORTANCE Transnasal esophagoscopy or pandoscopy to conduct a tumor survey is routinely recommended for patients with head and neck squamous cell carcinoma (HNSCC). Despite this recommendation, the effect of routine esophageal screening remains unclear. OBJECTIVE To investigate the effect of routine esophageal screening on the detection of second primary esophageal squamous cell carcinoma (ESCC) among patients with HNSCC. DESIGN AND SETTING Retrospective study at the Academic Institute of Otolaryngology, Kaohsiung, Taiwan. PARTICIPANTS Medical records between January 1, 2004, and December 30, 2010, from 3053 patients with HNSCC were retrospectively reviewed. INTERVENTION Patients were divided into 2 groups based on whether or not they had received routine esophageal screening, and the 2 groups were compared. MAIN OUTCOME MEASURES Univariate logistic regression analysis was performed to investigate the odds ratios (ORs) for developing second primary ESCC at different sites. The prevalence and cancer stage of second primary ESCC among these 2 groups were compared using the χ2 test. RESULTS The prevalences and ORs of second primary ESCC at different tumor sites were 0.8% (reference) for the oral cavity, 6.2% (OR, 8.35) for the oropharynx, 6.6% (OR, 8.89) for the supraglottis, 8.3% (OR, 11.43) for the transglottis, and 14.2% (OR, 20.83) for the hypopharynx. The prevalence of second primary ESCC among the routine screening group (71 of 1592 [4.5%]) was significantly higher than that among the non-routine screening group (44 of 1461 [3.0%]) (P = .04). Among 115 second primary ESCC cases, patients in the routine screening group were diagnosed at an earlier cancer stage than patients in the non-routine screening group. CONCLUSIONS AND RELEVANCE Routine esophageal screening is recommended for patients with HNSCC, especially those with oropharyngeal, supraglottic, transglottic, and hypopharyngeal cancers. Routine esophageal screening can increase the early detection of second primary ESCC.

Clinical and pathological determinants in tonsillar cancer

The purpose of this study was to present the impact of clinicopathological factors on patient survival in tonsillar squamous cell carcinoma (SCC) that needs to be evaluated.

Metformin disrupts malignant behavior of oral squamous cell carcinoma via a novel signaling involving Late SV40 factor/Aurora-A

Conventional therapeutic processes in patient with OSCC are associated with several unfavorable effects leading to patients with poor survival rate. Metformin has been shown to protect against a variety of specific diseases, including cancer. However, the precise roles and mechanisms underlying the therapeutic effects of metformin on OSCC remain elusive. In the current study, in vitro and xenograft model experiments revealed that metformin inhibited growth and metastasis of oral cancer cells. Importantly, metformin-restrained tumorigenesis of oral cancer was accompanied with strong decrease of both Aurora-A and Late SV40 Factor (LSF) expressions. Furthermore, LSF contributed to Aurora-A-elicited malignancy behaviors of oral cancer via binding to the promoter region of Aurora-A. A significant correlation was observed between LSF and Aurora-A levels in a cohort of specimens of oral cancer. These findings showed that a novel LSF/Aurora-A-signaling inhibition supports the rationale of using metformin as potential OSCC therapeutics.

A pilot study of segmental mandibulectomy with surgical navigation using fluorine-18 fluorodeoxyglucose positron-emission tomography/computed tomography†‡

To evaluate the efficacy of treating lower gum cancer using fluorine‐18 fluorodeoxyglucose positron‐emission tomography/computed tomography ([18] F‐FDG PET/CT) surgical navigation to control bony margins during segmental mandibulectomy.

Topical sucralfate for pain after oral CO2 laser surgery: a prospective, randomized, controlled trial

PURPOSE The aim of this study was to assess the effect of topical sucralfate on postoperative pain scores and other secondary outcomes including the frequency and duration of analgesic use and postoperative bleeding episodes after CO(2) laser treatment of oral leukoplakia. PATIENTS AND METHODS In this prospective trial, a total of 80 patients were randomized into the sucralfate group (n = 40) or the control group (n = 40). Postoperative pain scores, the frequency and duration of analgesic requirements, and postoperative wound bleeding episodes were compared between the 2 groups from the operative day to postoperative day 6. RESULTS Patients in the sucralfate group experienced significantly less postoperative pain on postoperative days 1 and 2. Although there was no significant difference in frequency and duration of analgesic use between the 2 groups, a trend toward lower frequency and fewer days of analgesic use in the sucralfate group was observed. CONCLUSIONS This study demonstrated the efficacy of topical sucralfate application in diminishing postoperative pain after CO(2) laser therapy for oral leukoplakia. Topical sucralfate can be considered a feasible adjuvant medication for the control of pain after CO(2) laser treatment of oral leukoplakia.

Prognosis of neutrophil-to-lymphocyte ratio in clinical early-stage tongue (cT1/T2N0) cancer

Background Inflammation plays a role in the development of cancer. This study aims to analyze the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) and other clinicopathological determinants in early-stage (cT1/T2N0) tongue cancer. Materials and methods A total of 262 patients were selected from our institute’s cancer database between 2004 and 2011. Optimal cutoff value of NLR and lymph node density (LND) were determined statistically using receiver operating characteristic curve analysis for survival prediction. The 5-year overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) rates were estimated using the Kaplan–Meier method. Results The results showed that, in this cohort, the optimal cutoff value of NLR was 2.95 and for LND, it was 0.031. Patients with NLR ≥2.95 correlated significantly with positive N classification (P=0.011), T2 classification (P=0.007), positive perineural invasion (P<0.001), and a tumor thickness of >5 mm (P=0.005). The 5-year OS among patients with NLR <2.95 was much higher than that in patients with NLR ≥2.95 (P<0.001). Similarly, the 5-year DSS among patients with NLR <2.95 was much higher than that in patients with NLR ≥2.95 (P=0.002). The 5-year DFS among patients with NLR <2.95 was much higher than that in patients with NLR ≥2.95 (P=0.004). The 5-year OS, DSS, and DFS were significantly reduced among patients with LND >0.031 compared to those with LND <0.031, respectively. In multivariate analysis, NLR, LND, and tumor thickness were independent prognostic factors for OS. Conclusion Pretreatment NLR ≥2.95 is significantly correlated with a larger tumor, positive neck lymph node metastasis, and positive perineural invasion. Importantly, it indicates reduced survival rate. Therefore, if the NLR ≥2.95 in early-stage (cT1/T2N0) tongue cancer is noted preoperatively, it reveals more invasive tumor behavior clinically. Then, aggressive treatments, including elective neck dissection, become necessary.

The side population of cancer stem-like cells in human oral cancer.

Cancer initiation and development involves a multistep process speculated to be advanced by genetic instability and/or environmental factors that drive the transformation of normal human cells into highly malignant derivates. Over the last decade, studies have suggested that tumors originate in either stem cells or progenitor cells through misregulation of the normally regulated process of self-renewal, resulting in cancer stem cells (CSCs). In the 1990s, using a combination of fluorescence-activated cell sorting and large sets of well-validated cell surface markers, stem cells were first observed in acute myeloid leukemia from aberrant hematopoietic tissues. Over the years, the same concepts and experimental approaches have been applied, and stem cells have also been observed in solid tumors in tissues including brain, lung, breast, liver, pancreas, and colon. Previous studies have shown that drug-resistant CSCs can be identified by a side population (SP) phenotype. The SP described by Goodell et al. is a small subset of enriched progenitor cells with a distinct low Hoechst 33342 dye staining pattern. The SP identification technique is the most widely used strategy to isolate cancer stem cells from cancer cell culture and primary tumors. SP cells have been detected in many normal tissues, including skeletal muscle, lung, liver, forebrain, testis, heart, kidney, prostate, and epidermis. Recently, SP has been found in solid tumors, such as neuroblastoma, glioblastoma, head and neck squamous cell carcinoma, and ovarian cancer. Moreover, Yanamoto and his colleagues also isolated and characterized cancer stem-like SP cells from oral cancer. In vitro experiments demonstrated that SP cells could grow faster and had higher colony formation ability, supporting the idea that tumorigenic cells were probably enriched in the SP fraction. In long-term culture, SP cells may undergo asymmetrical cell division and differentiate into non-SP cells. The population of SP cells in human cancer cell lines has been shown to be highly variable, from as high as 10% to merely 0.2%. The SP phenotype is determined by the expression of a protein known as the ATPbinding cassette (ABC) transporter activity, such as ABCG2. Little is known about the cellular pathways of SP, but several investigations have implicated the involvement of Wnt, Hedgehog, and Notch. Further studies are necessary to elucidate SP-specific pathways that may be pharmacological targets and prohibit some important signaling pathways that could initiate stem cell transformation. The findings to date suggest that SP represents only a small proportion of the entire tumor. However, SP possesses many stem cell properties, including unlimited proliferation potential and resis-