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Papillary thyroid cancer (PTC) is commonly associated with neck lymph node metastasis (LNM), and recurrence does occur after radioactive iodine (RAI) ablation therapy. This study aimed to analyze the effectiveness of RAI ablation with regard to disease recurrence in intermediate-risk PTC patients with neck LNM. In addition, the study identified possible predisposing risk factors that might benefit from RAI ablation and analyzed common RAI therapy complications among these patients. A retrospective analysis of 349 intermediate-risk PTC patients with neck LNM who underwent thyroidectomy with neck dissection was performed. The oncologic results and clinicopathologic characteristics of these patients together with the incidence of postoperative RAI therapy complications were evaluated. Of the 349 patients, disease recurrence after treatment occurred for 27 patients (8%) during a mean follow-up period of 58.7 months (range 7–133 months). The recurrence-free survival curve of the patients who received postoperative RAI therapy (n = 208) did not differ significantly from that of the patients who did not receive it (n = 141) (P = 0.567). Nine patients without adjuvant RAI therapy (6%, 9/141) had recurrence. The recurrence rate for the central LNM patients without RAI therapy was only 2% (2/106). Both of these patients with recurrence had pathologic extranodal spread (ENS) and a high number (> 5) of metastatic central LNs. Postoperative RAI-related complications were observed in 24 patients (12%). Postoperative RAI is not necessary for intermediate-risk papillary thyroid cancer patients with central LNM, especially for patients with negative ENS and low number (< 5) of metastatic lymph nodes.

PURPOSE Little is known about the incidence of thyroid cancer in patients with obstructive sleep apnea (OSA). This study aimed to evaluate whether OSA is associated with the incidence of thyroid cancer based on the Korea National Health Insurance Service (KNHIS) database. METHODS This study was designed as a retrospective cohort data analysis of the KNHIS dataset. A total of 198,574 patients who were over 20 years of age and had been newly diagnosed with OSA between 2007 and 2014 were enrolled. A control group of 992,870 individuals was selected based on propensity score matching by age and sex. The mean follow-up duration was 4.5 ± 2.3 years. The primary endpoint was the incidence of newly diagnosed thyroid cancer. RESULTS The hazard ratio (HR) for thyroid cancer incidence among OSA patients compared to the control was 1.72 (95% confidence interval [CI] 1.60-1.84) based on Model 1 (not adjusted by any covariate) and 1.64 (95% CI 1.53-1.76) based on Model 2 (adjusted by income level, diabetes, hypertension, and dyslipidemia). Thyroid cancer incidence was significantly higher in male patients (HR = 1.93, 95% CI 1.74-2.12) than female ones (HR = 1.39, 95% CI 1.26-1.54). When compared by age, the HR of thyroid cancer was higher in middle-aged (40 ≤ age

Although aggressive invasion and sequential lymph node metastasis (LNM) significantly affect the prognosis of patients with head and neck squamous cell carcinoma (HNSCC), studies on identifying the factors that regulate this process remain scarce. This study found an inhibitor of DNA binding 2 (ID2) as a novel molecule involved in the regulation of invasion and LNM of HNSCC and further verified its functional role. The study examined the translational significance between ID2 expression levels and the presence of LNM as well as the prognosis for 119 patients with HNSCC after treatment. In addition, in vitro and in vivo experiments were performed using ID2 gene-modulated HNSCC cell lines to determine the functional role of ID2 in the invasion and LNM of HNSCC. Elevated levels of ID2 expression were closely associated with the presence of LNM in 119 patients with HNSCC, resulting in a poor prognosis. Overexpression of ID2-induced invasion and LNM of HNSCC cells was observed in vitro and in vivo. By contrast, knockdown of the ID2 gene diminished invasion and LNM of HNSCC cells. In addition, the ID2 expression level increased the expression level of matrix metalloproteinase 1 (MMP1), a molecule downstream to ID2. Furthermore, silencing of MMP1 in ID2-overexpressed HNSCC cells rescued the elevated invasion and LNM capabilities of these cells, suggesting that ID2 enhances invasion and LNM partly via MMP1 activation. In the invasion and LNM of HNSCC, ID2 plays an important role by modulating MMP1 expression, suggesting ID2-MMP1 axis to be a novel alternative therapeutic target for invasion and LNM of HNSCC.

Nasopharyngeal carcinoma (NPC) is a rare form of the head and neck cancer of the epithelial lining of the nasopharynx and exhibits the highest metastatic rate among head and neck cancers. Underlying mechanisms of metastasis remain largely unknown. Here, we explored whether Notch1 affects the invasion and metastasis of NPC cells. In vitro migration and invasion capacities were evaluated after the knockdown of Notch1 expression in NPC cells. To investigate the role of Notch1 in in vivo metastasis, we examined the metastatic ability to the lungs following administration of cancer cells via mouse tail vein. The expression of epithelial-mesenchymal transition (EMT) markers associated with Notch1-mediated metastasis was investigated, and their roles in metastasis and relationship with Notch1 expression were investigated. Suppression of Notch1 expression increased the ability of NPC cells to invade Matrigel in vitro. Knockdown of Notch1 expression in NPC cells resulted in extensive lung metastasis in a mouse model and increased the mRNA expression of Slug in NPC cells. Slug-specific RNA interference resulted in the loss of the metastatic and invasion capacities in Notch1-suppressed NPC cells. These findings show that Notch1 has a significant suppressive role in the regulation of metastasis in NPCs, suggestive of its prudent use in clinical trials.

Objectives Signaling between cancer stem cells (CSC) and their extracellular matrix has a crucial role in CSC progression and maintenance. However, mediators of this signaling pathway in head and neck squamous cell carcinoma (HNSCC) are largely unknown. Here, we explored whether integrin β1, which is one of the key regulators of the communication between cells and their microenvironment, affected the stemness of HNSCC cells. Materials and methods We examined self-renewal capacity, chemoresistance, and xenograft tumorigenicity after knockdown of integrin β1 in primary HNSCC cells. In addition, we studied the role of focal adhesion kinase (FAK), an intracellular downstream molecule of integrin signaling, in influencing stemness of HNSCC. The relevance of Notch1 and integrin β1 interactions in HNSCC cells was also examined. Finally, immunohistochemical analysis was carried out to test whether the coexpression of integrin β1 and Notch1 in the samples from HNSCC patients correlated with their survival. Results Targeting integrin β1 in HNSCC cells inhibited self-renewal, chemoresistance, and in vivo tumor-forming capacity. Treatment with an inhibitor of FAK decreased self-renewal capacities and expression of various putative stem cell markers (Oct4, Sox2, and Nanog) in a dose-dependent manner. Moreover, knockdown of integrin β1 decreased the expression of Notch1 and its target genes (Hey1 and Hes1). Notably, HNSCC patients demonstrating simultaneous expression of integrin β1 and Notch1 in their tissue samples had significantly worse survival rate. Conclusion Integrin β1/Notch1 axis has a significant role in the regulation of stemness in HNSCC.

Objective According to American Thyroid Association (ATA) guideline, thyroid lobectomy is recommended for the management of papillary thyroid microcarcinomas (PTMC) with a diameter lesser than 1 cm. However, this procedure is associated with a risk of potential complications such as vocal cord palsy. Thus, we considered the applicability of conservative thyroidectomy, involving partial removal of the thyroid cancer lesion, not the entire ipsilateral thyroid lobe. Methods A retrospective analysis of all PTMC patients who underwent conservative thyroidectomy at Konkuk University Hospital between August 2008 and February 2014 was performed. Oncologic results of these patients along with the incidence of postoperative complications were evaluated. Seventy-nine patients who underwent conservative thyroidectomy for the treatment of PTMC were enrolled in the present study. Results Four of the 79 patients (5.0%) showed recurrence, 2 local (2.5%) and 2 regional (2.5%), respectively. All of these patients consequently underwent surgery alone and were salvaged. Temporary postoperative complications such as vocal cord palsy and hypocalcemia developed in 1 and 1 case, respectively, but completely recovered over time. Conclusions Conservative thyroidectomy is an oncologically and functionally safe procedure for surgical treatment of PTMC and can be considered as an alternative to thyroid lobectomy for the surgical management of PTMC.

The palatine tonsils (hereinafter referred to as "tonsils") serve as a reservoir for viral infections and play roles in the immune system's first line of defense. The aims of this study were to establish tonsil epithelial cell-derived organoids and examine their feasibility as an ex vivo model for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The tonsil organoids successfully recapitulated the key characteristics of the tonsil epithelium, including cellular composition, histologic properties, and biomarker distribution. Notably, the basal layer cells of the organoids express molecules essential for SARS-CoV-2 entry, such as angiotensin-converting enzyme 2 (ACE2), transmembrane serine protease 2 (TMPRSS2) and furin, being susceptible to the viral infection. Changes in the gene expression profile in tonsil organoids revealed that 395 genes associated with oncostatin M signaling and lipid metabolism were highly upregulated within 72 h after SARS-CoV-2 infection. Notably, remdesivir suppressed the viral RNA copy number in organoid culture supernatants and intracellular viral protein levels in a dose-dependent manner. Here, we suggest that tonsil epithelial organoids could provide a preclinical and translational research platform for investigating SARS-CoV-2 infectivity and transmissibility or for evaluating antiviral candidates.

SUMMARYPalatine tonsil (hereinafter referred to as “tonsil”) plays role in the immune system’s first line of defense against foreign pathogens. Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a worldwide pandemic since the infection was first reported in China in December 2019. The aim of this study was to establish tonsil epithelial cell-derived organoids and to examine their feasibility as anex vivomodel for SARS-CoV-2 infection. Using an optimized protocol, we achieved 3D tonsil organoid culture from human tonsil tissue that reflects the distinctive characteristics of the tonsil epithelium, such as its cellular composition, histologic properties, and molecular biological features. Notably, we verified that SARS-CoV-2 can infect tonsil organoids with a robust replication efficiency. Furthermore, treatment with remdesivir, an antiviral agent, effectively protected them from viral infection. Therefore, tonsil organoids could be available for investigation of SARS-CoV-2 infection-mediated pathology and for preclinical screening of novel antiviral drug candidates.One-sentence SummaryThis study established tonsil epithelial cell-derived organoids and demonstrated their feasibility as anex vivomodel for SARS-CoV-2 infection.

The canonical Wnt/β-catenin pathway is involved in diverse cancer development mechanisms, such as proliferation, migration, and invasion. However, its role in head and neck squamous cell carcinoma (HNSCC) remains largely unknown. We investigated whether the canonical Wnt/β-catenin signaling pathway acts as a controller of invasion and lymph node metastasis (LNM) in HNSCC. Loss of function experiments against the canonical Wnt/β-catenin pathway were conducted to evaluate its invasive and metastatic role in HNSCC cells. Slug was evaluated as a downstream protein in canonical Wnt/β-catenin-mediated invasion. In addition, canonical Wnt/β-catenin and Slug expression levels were examined in 119 HNSCC tissue samples to study the relevance of these proteins in LNM and prognosis of patients post-treatment. In vitro suppression of β-catenin expression led to decreased migration and invasion of HNSCC cells. Using an in vivo mouse orthotopic LNM model, a decrease in LNM was observed with mitigated β-catenin expression. Slug expression upregulation mediates invasion and LNM by the canonical Wnt/β-catenin pathway. Simultaneous expression of β-catenin and Slug is the major predictive factor of LNM and survival rate in patients with HNSCC. In conclusion, the canonical Wnt/β-catenin/Slug signaling axis significantly contributes to cancer cell invasion and LNM. Its blockade may be a treatment strategy for LNM and tumor recurrence in HNSCC.

Objectives The impact of regulatory T (Treg) cells as a prognostic factor of survival in head and neck squamous cell carcinoma (HNSCC) remains controversial. We aimed to evaluate the prognostic value of Treg cells in patients with HNSCC through a meta-analysis. Materials and Methods Through a literature search in PubMed, Embase, and Cochrane, we included 11 articles in this meta-analysis and investigated the effect of Treg cell level on the survival of patients with HNSCC. Also, we performed a subgroup analysis according to the study sample (blood vs. tumor tissue), primary tumor site, HPV infectivity, or Treg cell marker. Results High levels of circulating Treg cells in the peripheral blood of patients with HNSCC can significantly increase the disease specific survival rate of patients. Moreover, subgroup analysis showed that high levels of Treg in peripheral blood were significantly associated with better disease specific survival in patients with oral cancer, a subsite of HNSCC, but not in those with other head and neck subsite. Positivity of HPV infection did not influence the prognosis of patients with HNSCC. Conclusion Increase in the levels of circulating Treg cells in peripheral blood can be a prognostic factor of survival in patients with oral cancer.

Some studies have argued that obstructive sleep apnoea (OSA) increases the risk of breast cancer. However, the results are often conflicting. This study aimed to investigate associations between OSA and breast cancer incidence using the Korea National Health Insurance Service (KNHIS) database. This retrospective cohort study analyzed data from the KNHIS database. A total of 45,699 women (≥20 years of age) newly diagnosed with OSA between 2007 and 2014 were included. The control groups were a 5-fold, age-matched women who had not been diagnosed with OSA. Mean follow-up duration was 3.7 ± 2.3 years. The primary endpoint was newly diagnosed breast cancer. The breast cancer hazard ratio (95% confidence interval) was calculated for patients with OSA and compared with that of the control group. The incidence of breast cancer among patients with OSA was significantly higher than that among the controls (1.20 [1.04–1.39]). In particular, the incidence of breast cancer was higher among patients aged ≥65 years (1.72 [1.10–2.71]). The result suggests that OSA may be a risk factor for breast cancer in women.

Objective Untreated obstructive sleep apnea (OSA) is a risk factor for cardiovascular disease including myocardial infarction (MI), congestive heart failure (CHF), and atrial fibrillation (AF). Continuous positive airway pressure (CPAP) is an effective treatment for OSA; however, compliance with CPAP can be challenging for some patients. The objective of this study was to investigate whether uvulopalatopharyngoplasty (UPPP) reduced the risk of cardiovascular complications for patients with OSA. Methods Data from Korea National Health Insurance Corporation, a national health care database in South Korea, were analyzed. All patients with a new diagnosis of OSA from 2007 to 2014 were identified. Propensity score matching by age and sex was used to identify a control group five times larger than the OSA group for comparison. Patient demographics and comorbidities were collected. The OSA group was further divided into patients who had an UPPP and patients who did not undergo surgery. The primary endpoints were newly diagnosed MI, CHF, and AF. Results Of 192,316 patients with a new diagnosis of OSA, 22,213 had undergone UPPP. For the control group, 961,590 individuals were selected. Patients with OSA had an increased risk of CHF and AF, compared to control patients. UPPP reduced the incidence of CHF and AF significantly. Age, gender, and hypertension were also found to be risk factors for cardiac complications for patients with OSA. Conclusion OSA increases the risk of CHF and AF. UPPP in this population can significantly reduce the risk of cardiac complications in patients with OSA.

Although the incidence rates of head and neck squamous cell carcinoma (HNSCC) associated with human papilloma virus (HPV) infection have recently been on the rise, the underlying mechanism of its tumorigenesis remains largely unknown. Here, we investigated whether HNSCC cells with high expression of integrin alpha 6 (ITGα6), one of the HPV receptors, have a preference during HPV infection. In addition, we examined the gain or loss of function of the ITGα6 gene in HPV + ve HNSCC cells, as well as its prognostic value in patients with HNSCC. HPV pseudovirus was found to be more infective, with HNSCC cells featuring an overexpressed ITGα6 gene compared to the control cells. Overexpression and suppression of ITGα6 respectively increases and decreases stemness phenotypes of HPV + ve HNSCC cells. Furthermore, ITGα6 can regulate stemness by partially mediating AKT pathway in HPV + ve HNSCC cells. Finally, patients with HPV + ve HNSCC had a poor prognosis in cases of elevated ITGα6 expression; however, the expression levels of ITGα6 did not influence the survival rates of HPV-negative HNSCC patients. In conclusion, ITGα6 can serve as a potential therapeutic target for HPV + ve HNSCC cancer-like stem cells (CSCs).

Background: Head and neck squamous cell carcinomas (HNSCCs) are highly lethal epithelial tumours containing self-renewal cancer stem cells (CSCs). CSCs in HNSCCs are strongly associated with tumour initiation, invasion, and chemoradiation resistance. However, the important factors regulating stemness in HNSCCs remain unclear. Here, we investigated the molecular roles and clinical significance of inhibitor of DNA binding 2 (Id2) protein to determine if it constitutes a novel therapeutic target for ablating HNSCC cells with stemness. Methods: We performed in vitro and in vivo studies of Id2 function and its effects on stemness using HNSCC cells. We also examined whether Id2 expression could be used as a prognostic indicator through immunohistochemical staining of 119 human HNSCC tumours. Results: Expression of Id2 was higher in HNSCC cells with stemness compared with differentiated HNSCC cells. Overexpression of Id2 increased proliferation, self-renewal, and expression of the putative stemness marker CD44 in HNSCC cells in vitro and in vivo. In contrast, silencing of Id2 using short hairpin RNA attenuated the stemness phenotype of HNSCC cells by reducing self-renewal, CD44 expression, cisplatin chemoresistance, and xenograft tumourigenicity. Most importantly, increased expression of Id2 was closely associated with poorer post-treatment survival rates in HNSCC patients. Conclusions: Inhibitor of DNA binding2 represents a novel and promising therapeutic target for treating and improving the clinical outcomes for patients with HNSCC.

Objectives To investigate the association between menopausal hormone therapy (MHT) and chronic rhinitis. Methods The data used in this study were derived from the Korea National Health and Nutrition Examination Survey. The analysis included 2967 postmenopausal women under 70 years of age, and there were no missing data. Questionnaire responses regarding MHT, current life habits, reproductive history, and rhinitis were reviewed. The levels of total immunoglobulin E (IgE) and specific IgE for Dermatophagoides farinae , cockroaches, and dogs were measured, using approximately 10% of all samples. We compared women who were users of MHT and non-users of MHT. We also compared women with and without chronic rhinitis. Results Of 2967 women matching the study criteria, 567 were MHT users. The proportion of general rhinitis symptoms was greater among MHT users (24.5%) than among MHT non-users (18.9%, p = 0.003). The proportion of cases of rhinorrhea or posterior nasal drip was also greater among MHT users (6.3% vs. 4.3%, p = 0.042), while there were no differences between the two groups in the proportion of cases of nasal obstruction. There were no differences in total IgE and specific IgE levels between the two groups. MHT was used by 23.4% of women with chronic rhinitis and 18.0% of women without chronic rhinitis. Age, waist circumference, and body mass index were also greater among women without chronic rhinitis than among those with chronic rhinitis. Conclusions MHT may cause non-allergic rhinitis in postmenopausal women. Age and obesity may also affect the occurrence of non-allergic rhinitis in postmenopausal women.

Background The acquisition of stem-like phenotype is partly attributed to the induction of epithelial-mesenchymal transition (EMT). Thus, the activation of factors involved in EMT can be linked to cancer stem cell genesis. However, the underlying mechanisms in head and neck squamous cell carcinoma (HNSCC) remain largely unknown. Herein, we investigate whether slug, one of the major effectors of EMT, affects the stemness of HNSCC cells. Methods We performed in vitro experiments to determine whether slug gene manipulation can influence the stemness phenotypes, including the capacity for self-renewal, expression of putative stemness markers, chemoresistance, and invasion in HNSCC cells. Further, we identified whether Slug knockout attenuates tumorigenicity of HNSCC cells in vivo. Finally, we examined whether prognosis of HNSCC patients after curative treatment may be affected by the level of slug expression. Results Overexpression of slug promoted self-renewal of HNSCC cells via activation of sphere formation, the expression of stem cell markers, and induction of chemoresistance to cisplatin. Also, slug overexpression increased the migration and invasion of HNSCC cells in vitro and was mainly observed during the invasion in HNSCC xenograft mouse model. By contrast, slug expression knockdown abrogated their self-renewal capacity, stemness-associated gene expression, and cisplatin chemoresistance. Furthermore, high levels of slug expression correlated with poor prognosis of patients with HNSCC. Conclusion Inhibition of slug expression may represent a novel therapeutic strategy targeting HNSCC stem-like cells.

Background This study analyzed the incidence, pattern, and predictive factors for lateral lymph node (LN) recurrence in patients with papillary thyroid cancer (PTC) without clinical evidence of lateral LN metastasis. Methods A retrospective analysis was performed on 246 patients with PTC who underwent total thyroidectomy and central neck dissection from 2004 to 2010. None of the patients had clinical evidence of lateral LN metastasis at the time of diagnosis. Predictive factors for lateral LN recurrence were evaluated using the chi-square test. Binary logistic regression was used for the multivariate analysis. Recurrence-free survival rates were estimated by the Kaplan–Meier and Cox regression methods. Results Of the 246 patients, 11 (4.5%) developed lateral LN recurrence with a median follow-up of 49 months. In the multivariate analysis, tumor size >1 cm (odds ratio [OR], 8.14; 95% confidence interval [CI], 1.01–65.68; p = 0.049) and central LN metastasis (OR, 10.59; 95% CI, 1.32–85.17; p = 0.026) were independent predictive factors of lateral LN recurrence. Especially, extranodal extension of a metastatic central LN (OR, 38.82; 95% CI, 5.71–264.10; p Conclusions Tumor size and central LN metastasis were independent predictors of lateral LN recurrence in patients with PTC without initial clinical lateral neck metastasis who underwent total thyroidectomy and central neck dissection. Close surveillance may be necessary for early detection of lateral LN recurrence in PTC patients with tumor size ⩾1 cm, and central LN metastasis with extranodal extension.

Notch1 is associated with the initiation and progression of various solid tumors. However, the exact role of Notch1 expression in head and neck squamous cell carcinoma (HNSCC) remain unclear. We created cells ectopically expressing notch intracellular domain (NICD) from previously established HNSCC cells and examined self-renewal capacity and stem cell markers' expression compared with control cells. In addition, we knocked Notch1 down in primary spheres obtained from HNSCC tumor tissue and assessed the attenuation of stemness-associated traits in these cells in vitro and in vivo. Furthermore, we examined clinical relevance of Notch1 expression in HNSCC patients. Constitutive activation of NICD promoted the self-renewal capacity of HNSCC cells by activating sphere formation and increased the expression of stem cell markers such as Oct4, Sox2, and CD44. In contrast, Notch1 knockdown in primary HNSCC cancer stem cells (CSCs) attenuated CSC traits and augmented the chemosensitizing effects of cisplatin along with the decreased expression of almost all of ABC transporter genes. In addition, Notch1 knockdown in HNSCC CSCs inhibited tumor formation and increased survival of mice in a xenograft model. Also, Notch1 acted upstream of canonical Wnt signaling in HNSCC cells. Finally, elevated Notch1 expression is associated with poor prognosis in patients with HNSCC. In conclusion, Notch1 may be a critical regulator of stemness in HNSCC cells, and inactivation of this pathway could be a potential targeted approach for the treatment of HNSCC.

Summary Objectives Increasing evidence suggests that epigenetic regulation is responsible for tumor initiation and progression in head and neck squamous cell carcinoma (HNSCC). Although the polycomb group protein enhancer zeste homolog 2 (EZH2) is upregulated and a key epigenetic modifier implicated in various cancers, its molecular mechanism in HNSCC remains unknown. Herein, we investigated the role of EZH2 in HNSCC progression and its clinical implication as an HNSCC risk predictor. Materials and method A retrospective analysis was performed on 90 HNSCC patients who had curative surgery between 1999 and 2011. Patients with high and low EZH2 expression were compared by the various clinicopathological factors. Survival rates were estimated by the Kaplan–Meier method and log-rank test was used to determine significance. For functional in vitro analysis, migration/invasion assay and Western blotting were performed after EZH2 knockdown using siRNA. In addition, cell proliferation was measured to clarify the role of EZH2 on cisplatin chemotherapy. Results In patients with HNSCC, high EZH2 expression was correlated with advanced T stage and poor survival outcome. RNAi analysis revealed that EZH2 silencing increased E-cadherin expression while decreasing that of N-cadherin and Vimentin without altering Snail/Slug signaling, which led to decreased cell migration/invasion. EZH2 is also associated with tumor aggressiveness via regulating the epithelial-to-mesenchymal transition. Furthermore, we show that high EZH2 expression decreases sensitivity to cisplatin-based chemotherapy. Conclusion Our results indicate that EZH2 may not be only a predictive and prognostic biomarker but also a potential personalized therapeutic target for the treatment of HNSCC.

Laminin subunit beta-3 (LAMB3) encodes one of the three subunits of LM-332, a protein of the extracellular matrix secreted by cultured human keratinocytes. While LAMB3 is involved in the invasive and metastatic abilities of several tumor types, including those found in the colon, pancreas, lung, cervix, stomach, and prostate, its mechanism of action in thyroid cancer has not been investigated previously. Our results show that LAMB3 is up-regulated in papillary thyroid cancer, and that its suppression reduces cell migration/invasion via down-regulation of epithelial‒mesenchymal transition-associated proteins (N-cadherin, vimentin, slug) and inhibition of matrix metalloproteinase 9. LAMB3 suppression also significantly decreases Akt phosphorylation and inhibits the transcription of c-MET, reducing its activation. These results suggest that LAMB3 leads to tumor invasion via Akt activation induced by the HGF/c-MET axis in papillary thyroid cancer cells. Our findings reveal a novel mechanism of action for LAMB3 in papillary thyroid cancer cells.

Emerging evidence suggests that cancer cells present profound epigenetic alterations in addition to featuring classic genetic mutations. Valproic acid (VPA), a histone deacetylase inhibitor, can potently inhibit tumor growth and induce differentiation. However, the effect and underlying mechanism of VPA on head and neck squamous cell carcinoma (HNSCC) cancer stem cells (CSCs) remain unclear. In the present study we investigated the effects of VPA on the characteristics of HNSCC CSCs in vitro and in vivo. As a result, VPA inhibited the self-renewal abilities of HNSCC CSCs during two serial passages and decreased the expression of stem cell markers, such as Oct4, Sox2 and CD44. VPA also potentiated the cytotoxic effect of cisplatin by suppressing the ABCC2 and ABCC6 transporters as well as by inducing caspase-mediated apoptosis. In addition, the combination of VPA and cisplatin attenuated tumor growth and induced apoptosis in a xenograft model. Our results suggest that VPA might be a potential therapeutic strategy in combination with conventional cisplatin for HNSCC patients by elimination of CSC traits.

Summary Background We investigated the risk factors of the regional lymph node (LN) recurrence in papillary thyroid cancer (PTC) patients underwent thyroidectomy and neck dissection according to the clinicopathologic features, preoperative clinical nodal status and the recurrence in previously dissected or undissected compartment of the neck. Methods A retrospective analysis was performed on 297 patients who underwent total thyroidectomy and LN dissection between 2004 and 2010. Patients with and without regional recurrence were compared by the various clinicopathological factors. Recurrence-free survival rates were estimated by the Kaplan–Meier and Cox regression method. Results With a median follow-up of 53 months, 22 (7.4%) patients developed regional LN recurrence. Initial LN metastasis and tumor size ⩾1 cm were independent predictive factors for regional recurrence. In patients without preoperative clinical LN, Tumor size ⩾1 cm and extrathyroidal extension were significant risk factors for regional recurrence. In cases with preoperative clinical LN, there was no specific significant factor for recurrence. Tumor size ⩾1 cm, capsular invasion, extrathyroidal extension, and lymphovascular invasion were significant risk factors of regional recurrence in previously dissected compartments. Tumor size ⩾1 cm and extrathyroidal extension were significant predictive factors of regional recurrence in previously undissected compartments. Conclusions Tumor size and LN metastasis were independent predictors of regional LN recurrence in PTC patients after total thyroidectomy and central neck dissection. Patients with tumor size >1 cm or extrathyroidal extension were more likely to have tumor recur both within the previously dissected field as well as the un-dissected compartments.

Background: Head and neck squamous cell carcinomas (HNSCCs) display cellular heterogeneity and contain cancer stem cells (CSCs). Sex-determining region Y [SRY]-box (SOX)2 is an important regulator of embryonic stem cell fate and is aberrantly expressed in several types of human tumours. Nonetheless, the role of SOX2 in HNSCC remains unclear. Methods: We created cells ectopically expressing SOX2 from previously established HNSCC cells and examined the cell proliferation, self-renewal capacity, and chemoresistance of these cells compared with control cells. In addition, we knocked down SOX2 in primary spheres obtained from HNSCC tumour tissue and assessed the attenuation of stemness-associated traits in these cells in vitro and in vivo. Furthermore, we examined the clinical relevance of SOX2 expression in HNSCC patients. Results: SOX2 is aberrantly expressed in primary tissue of HNSCC patients but not in healthy tissue. SOX2 expression correlated with tumour recurrence and poor prognosis of HNSCC patients. Ectopic expression of SOX2 induced cell proliferation via cyclin B1 expression and stemness-associated features, such as self-renewal and chemoresistance. In addition, a knockdown of SOX2 in HNSCC CSCs attenuated their self-renewal capacity, chemoresistance (through ABCG2 suppression), invasion capacity (via snail downregulation), and in vivo tumorigenicity. Conclusions: These results suggest that SOX2 may have important roles in the ‘stemness' and progression of HNSCC. Targeting SOX2-positive tumour cells (CSCs) could be a new therapeutic strategy in HNSCCs.

Accumulating evidence suggests that a distinct subpopulation of cancer stem cells (CSCs) is responsible for tumour initiation and progression in head and neck squamous cell carcinoma (HNSCC). Wnt/β-catenin signalling is essential for stem cell regulation and tumourigenesis, but its molecular mechanism in HNSCC CSCs remains unknown. We investigated whether Wnt/β-catenin signalling regulates self-renewal and tumourigenicity of HNSCC stem-like cells in vitro and in vivo. Cytoplasmic/nuclear β-catenin, a major effector of Wnt/β-catenin signalling, was expressed in a subpopulation of tumour cells in primary HNSCC tissue but in none of normal head and neck tissues. Overexpression of β-catenin increased proliferation of HNSCC cells and induced dedifferentiation of these cells to cells with stem-like features. Knockdown of β-catenin in HNSCC stem-like cells blocked their self-renewal capacity, stemness-associated gene expression, chemoresistance, and in vivo tumourigenicity. Furthermore, β-catenin directly regulates Oct4 transcription in HNSCC stem-like cells. In addition, the effect of shRNA-mediated repression of β-catenin on CSC traits in HNSCC stem-like cells was reversed by overexpression of Oct4. In patients with HNSCC, higher levels of both cytoplasmic/nuclear β-catenin and Oct4 correlated with the worst prognosis. These results suggest inhibition of Wnt/β-catenin signalling as a novel therapeutic strategy for targeting HNSCC stem-like cells.

Summary Objectives Increasing evidence indicates that a rare subpopulation of cancer cells, namely, cancer stem cells (CSCs), is the primary cause of tumorigenesis in some tumor types, including head and neck squamous cell carcinoma (HNSCC). Hepatocyte growth factor (HGF) and its receptor, c-Met, are involved in tongue development and carcinogenesis of HNSCC. Here, we investigated whether activation of HGF/c-Met signaling influences the stem cell traits of HNSCC CSC. Materials and methods After HGF treatment, we assessed the sphere-forming capacity and stem cell marker expression in HNSCC stem-like cells compared with the respective control cells in vitro . In addition, we evaluated the effect of c-Met knockdown on the sphere-forming capacity, stem cell marker expression, and cisplatin chemosensitivity of HNSCC stem-like cells in vitro . Furthermore, we evaluated the inhibitory effect of c-Met knockdown on the capacity of HNSCC stem-like cells to initiate tumor growth in the orthotopic mouse model. Results HGF treatment promoted the sphere-forming capacity of HNSCC stem-like cells and increased the expression of stem cell markers such as Oct4, Sox2, and CD44. Transcriptional levels of c-Met was increased in cells with high aldehyde dehydrogenase (ALDH) 1 activity, a putative marker for HNSCC stem-like cells, compared to cells with low activity. In contrast, knockdown of c-Met attenuated the sphere-forming capacity and stem cell markers expression in HNSCC stem-like cells, and augmented cisplatin chemosensitivity by decreased side population cells and suppression of an ABCG2 transporter gene. Furthermore, knockdown of c-Met in HNSCC stem-like cells inhibits tumor formation of mice in a xenograft model and increases mice survival. Conclusion Our results suggest that inhibition of the c-Met pathway could serve as a potent therapeutic strategy to target HNSCC stem-like cells.

CD44 is generally accepted as a surrogate marker for head and neck squamous carcinoma cancer stem cells (HNSC CSCs) and only CD44+ HNSC cells have tumour initiating capacity. However, a recent report suggested that CSCs themselves might be heterogenous due to various genetic alterations. Here, we compared in vitro stem-like cell characteristics, chemoresistance and in vivo tumour formation capacity of CD44+ and CD44- HNSC cells obtained from primary HNSC patient specimens. CD44- HNSC spheroid cells generated spheroid cells again after seeding of single-dissociated spheroid CD44- HNSC cells. Immunocytochemistry assays revealed that various stem cell markers, including octamer-binding transcription factor 4 (OCT4), sex determining region Y-box 2 (SOX2) and nestin were up-regulated in CD44- spheroid cells, similar to CD44+ spheroid cells. Furthermore, CD44- spheroid cells appeared to be chemoresistant to cisplatin and showed increased levels of ABCG2, similar to CD44+ spheroid cells. Of most interest, as few as 1000 CD44- spheroid cells were able to give rise to tumours in nude mice. The collective data indicate that the cell surface marker CD44 cannot be used as a selective marker of spheroid-forming, tumour-initiating or chemoresistant cell populations, and further indicate the limitation of current HNSC CSC identification methods using the CD44 cell surface marker.

Transforming growth factor β (TGFβ) ligands, including TGFβ1, are multifunctional cytokines known as key regulators of cell growth, differentiation and inflammation. Dysregulated TGFβ signaling is common in numerous solid tumors, including head and neck squamous cell carcinoma (HNSCC). Previously, TGFβ ligands were also reported to be associated with an enhancement of stemness in glioma stem-like cells. However, their role in HNSCC cancer stem cells (CSCs) has not been explored. The present study demonstrated that TGFβ1 enriches the properties of HNSCC CSCs. TGFβ1 promoted sphere formation and increased stemness-associated gene expression (Oct4 and Sox2) of primary HNSCC CSCs. Additionally, the population of aldehyde dehydrogenase (ALDH)-positive cells was increased subsequent to exogenous treatment of cells with TGFβ1. In addition, following stimulation with TGFβ1, the cells exhibited more resistance to cisplatin and elevated expression of Twist, Snail and Slug. Mechanistically, TGFβ1 acts as an upstream stimulator of Wnt/β-catenin signaling. Collectively, the present findings provide insights toward the development of TGFβ1 signaling inhibition strategies for treating HNSCC CSCs.

There are many conflicting reports about the clinical implications of BRAFCarcinoma tissues from 60 patients with PTC were genotyped for BRAFThe BRAFA high extent more than 25% of BRAF

c-Met proto-oncogene, which is a receptor of ligand hepatocyte growth factor (HGF), has been associated with cancer cell invasion. There have been no reports on the relationship between the expression of c-Met and tumor invasion and metastasis in small (T(1-2)) squamous cell carcinoma of the oral tongue (SCCOT). We analyzed the relationship between c-Met expression and tumor invasion depth and lymph node metastasis in 71 surgically treated patients with small SCCOT using immunohistochemistry. Furthermore, we investigated the associations between the c-Met expression status and patient survival. In addition, we explored whether overexpression of c-Met enhances tumor growth and invasion of tongue cancer cells in vitro and in vivo. Positive immunohistochemical staining of c-Met was observed in 39 (55%) samples. Presence of neck metastasis, and >4mm depth of tumor invasion, strongly correlated with c-Met expression in small SCCOT both by the univariate and multivariate analysis (p

Differentiation therapy is a novel approach to eradicate cancer stem cells (CSCs), including head and neck squamous carcinoma CSC (HNSC CSC). All-trans-retinoic acid (ATRA) is a potent differentiating agent. We studied the anti-tumour effect of ATRA on HNSC CSC. HNSC CSCs were differentiated by ATRA in a serum-free conditioned medium. The effect of differentiation on tumour growth was assessed in vitro and in vivo, and chemosensitisation was examined using a colorimetric viability assay. In addition, the involvement of Wnt/β-catenin signalling as an underlying mechanism of the anti-tumour effect of retinoic acid (RA) on HNSC CSCs was assessed. ATRA suppressed the expression of the stem cell markers Oct4, Sox2, Nestin and CD44 in HNSC CSCs and inhibited the proliferation of HNSC CSCs in vitro and in vivo. Furthermore, ATRA treatment augmented the chemosensitising effects of cisplatin. The anti-tumour effects of ATRA may be associated with down-regulation of Wnt/β-catenin signalling. In conclusion, ATRA may be potentially valuable in treatment of HNSC CSC, especially in combination with cisplatin.

Although head and neck squamous carcinoma cancer stem cells (HNSC-CSCs) can be enriched in serum-free suspension cultures, it is difficult to stably expand HNSC-CSC lines in suspension due to spontaneous apoptosis and differentiation. Here, we investigated whether HNSC-CSCs can be expanded without loss of stem cell properties by adherent culture methods. Cell culture plates were coated with type IV collagen, laminin, or fibronectin. We examined cancer stem cell traits of adherent HNSC-CSCs grown on these plates using immunocytochemistry for stem cell marker expression and analyses of chemo-resistance and xenograft tumorigenicity. We also assessed the growth rate, apoptosis rate, and gene transduction efficiency of adherent and suspended HNSC-CSCs. HNSC-CSCs grew much faster on type IV collagen-coated plates than in suspension. Adherent HNSC-CSCs expressed putative stem cell markers (OCT4 and CD44) and were chemo-resistant to various cytotoxic drugs (cisplatin, fluorouracil, paclitaxel, and docetaxel). Adherent HNSC-CSCs at the limiting dilution (1000 cells) produced tumors in nude mice. Adherent HNSC-CSCs also showed less spontaneous apoptotic cell death and were more competent to lentiviral transduction than suspended HNSC-CSCs. In conclusion, compared to suspension cultures, adherence on type IV collagen-coated culture plates provides better experimental conditions for HNSC-CSC expansion, which should facilitate various refined cellular studies.

Inflammatory microenvironment signalling plays a crucial role in tumour progression (i.e. cancer cell proliferation, survival, angiogenesis and metastasis) in many types of human malignancies. However, the role of inflammation in brain tumour pathology remains poorly understood. Here, we report that interferon regulatory factor 7 is a crucial regulator of brain tumour progression and heterogeneity. Ectopic expression of interferon regulatory factor 7 in glioma cells promotes tumorigenicity, angiogenesis, microglia recruitment and cancer stemness in vivo and in vitro through induction of interleukin 6, C-X-C motif chemokine 1 and C–C motif chemokine 2. In particular, interferon regulatory factor 7-driven interleukin 6 plays a pivotal role in maintaining glioma stem cell properties via Janus kinase/signal transducer and activator of transcription-mediated activation of Jagged-Notch signalling in glioma cells and glioma stem cells derived from glioma patients. Accordingly, the short hairpin RNA-mediated depletion of interferon regulatory factor 7 in glioma stem cells markedly suppressed interleukin 6-Janus kinase/signal transducer and activator of transcription-mediated Jagged-Notch-signalling pathway, leading to decreases in glioma stem cell marker expression, tumoursphere-forming ability, and tumorigenicity. Furthermore, in a mouse model of wound healing, depletion of interferon regulatory factor 7 suppressed tumour progression and decreased cellular heterogeneity. Finally, interferon regulatory factor 7 was overexpressed in patients with high-grade gliomas, suggesting its potential as an independent prognostic marker for glioma progression. Taken together, our findings indicate that interferon regulatory factor 7-mediated inflammatory signalling acts as a major driver of brain tumour progression and cellular heterogeneity via induction of glioma stem cell genesis and angiogenesis. * Abbreviations : CCL2 : C–C motif chemokine 2 CXCL1 : C-X-C motif chemokine 1 GSC : glioma stem cell IL6 : interleukin 6 IRF7 : interferon regulatory factor 7 JAK : Janus kinase shRNA : short hairpin RNA STAT : signal transducer and activator of transcription TNFα : tumour necrosis factor α

Glioma stem cells (GSCs) are known to be maintained within a "vascular niche"; thereby, disruption of this microenvironment using antiangiogenesis agents is a promising therapeutic modality. However, this regimen leads to treatment failure and tumor recurrence in patients with glioblastoma multiforme (GBM). Therefore, more effective therapeutic approaches that can eradicate GSCs and the bulk tumors are needed. Toward this goal, we examined the antitumor effects of an antiangiogenesis approach combined with conventional chemotherapy on suppressing glioma xenograft growth. We established three genetically engineered mesenchymal stem cell (MSC) lines (GE-AF-MSCs) by stably transducing the gene encoding endostatin (an antiangiogenesis factor), the gene encoding secretable form of carboxylesterase 2 (sCE2, a prodrug-activating enzyme), or a mixture of both genes. Among the three GE-AF-MSC cell lines, injection of amniotic fluid (AF)-MSCs-endostatin-sCE2 cells into U87MG-EGFRvIII-driven orthotopic brain tumor and postsurgery tumor recurrence models, and subsequent CPT11 treatment yielded the strongest antitumor responses, including diminished angiogenesis, increased cell death, and a reduced Nestin-positive GSC population. Therefore, our antitumor strategy provides a novel basis for designing stem cell-mediated therapeutic approaches to target and eradicate GSCs and the bulk tumors.

Background The frequencies, pattern, and predictive factors for occult contralateral central lymph node (LN) metastases in papillary thyroid carcinoma (PTC) patients with unilateral lateral neck metastases are still unsettled. Study Design We reviewed the medical records of 70 consecutive PTC patients with unilateral positive lateral neck who have initially received total thyroidectomy and comprehensive neck dissection including bilateral central LN dissection. The relationships between occult LN metastases to the contralateral central neck compartment and preoperative image findings and clinicopathologic factors were analyzed. Results Central neck LN metastases were present in 82.9%, in which 34.3% had bilateral central neck involvement and 48.6% had unilateral ipsilateral central neck involvement. Isolated contralateral central LN metastases without ipsilateral central LN metastases were not found. Multivariate analysis showed that the multifocality of primary thyroid tumor (p = 0.010, odds ratio=5.120) and the presence of metastases in all lateral neck levels (p = 0.017, odds ratio=5.130) were independent risk factors for the presence of contralateral central LN metastases. Conclusions The rate of occult contralateral central LN metastases was relatively high (34.3%) in PTC with ipsilaterally positive lateral neck, and multifocal primary tumor and positive LN involvement in all lateral neck levels are associated with contralateral central LN metastases.

Anaplastic thyroid carcinoma (ATC) is one of the most lethal solid tumors arising thyroid gland with dismal prognosis. One of the constituents of garlic, diallyl sulfide (DAS) was shown to inhibit chemically induced carcinogenesis in many animal models. This study examined whether DAS could induce growth inhibition and apoptosis in ATC cells. In MTT assay, DAS treatment inhibited the proliferation of ARO cells in a dose-dependent manner. Flow cytometric analysis showed that DAS treatment increased the accumulation of sub-G1 DNA and concomitant accumulation of cells in the G2/M phase in a dose-dependent manner. In addition, DAS-induced apoptosis was associated with a decrease in the level of Bcl-2 expression and an increase in the level of Bax expression, and cytochrome c was remarkably released from mitochondrial into the cytosol by DAS. Furthermore, caspase-9 and caspase-3 were activated by DAS, and DAS cleaved PARP. Taken together, DAS decreased cell proliferation and induced apoptosis via mitochondrial signaling pathway in ATC cells.

Background The extent of lateral neck dissection for clinically evident nodal metastases in the lateral neck in a patient with papillary thyroid cancer (PTC) continues to remain controversial. Methods We reviewed retrospectively the medical records between March 2005 and March 2008 of 70 patients with PTC who underwent therapeutic lateral neck dissections (level II–V) to establish indications for omission of a level V lymphadenectomy. No patient in the study had a clinically positive level V lymph node. Neck dissection specimens were obtained for histologic analysis for node metastasis with respect to the individual neck levels. Results Thirty-four (49%), 52 (74%), and 48 (69%) patients had histologically positive lymph nodes in levels II, III, and IV, respectively. Occult metastases in level V were observed in 11 (16%) patients. Isolated positive level V lymph nodes were never found, while all patients with positive level V lymph nodes had simultaneous positive level IV lymph nodes. In addition, there was no instance of a pathologically positive lymph node in level V without a suspicious metastatic lymph node in level IV by preoperative ultrasonography. In multivariate analysis, simultaneous multilevel involvement (level II, III, and IV) of lymphatic metastases was associated with level V metastasis. Conclusion Level V lymphadenectomy may be omitted in the treatment of PTC patients if positive nodes are not found on histologic exam (frozen section analysis) or by ultrasonography in level IV.

The optimal resection extent for papillary thyroid microcarcinoma (PTMC) confined within a unilateral lobe remains controversial.We reviewed the medical records of 132 consecutive patients who underwent total thyroidectomy for the treatment of clinically unilateral PTMC between March 2005 and March 2009. The frequency, pattern, and predictive factors for occult contralateral carcinoma in these patients were analyzed with respect to the following variables: age, gender, tumor size, multifocality of primary tumor, presence of perithyroidal invasion, lymphovascular invasion or capsular invasion, presence of central lymph node metastasis, and the presence of coexistent benign nodules in the contralateral lobe based on preoperative evaluation and final pathology.A total of 22 patients (16.7%) had occult PTMC in the contralateral lobe. In multivariate analysis, multifocality of the primary tumor (P = 0.026, odds ratio = 7.714) and the presence of coexistent benign nodule in the contralateral lobe by preoperative evaluation (P = 0.036, odds ratio = 3.500) were independent predictive factors for occult contralateral PTMC presence. However, there were no significant differences between the presence of occult contralateral carcinomas and age, gender, tumor size, perithyroidal invasion, lymphovascular invasion, capsular invasion, central lymph node metastasis, and coexistent benign nodules by final pathology.Based on our findings, total thyroidectomy, including the contralateral lobe, should be considered for the treatment of unilateral PTMC if it presents as a multifocal tumor in the unilateral lobe and/or if nodules are found in the contralateral lobe during preoperative evaluation.

Summary To evaluate treatment outcomes and the role of primary definitive surgery for T 1–2 , clinically N 0 oropharyngeal squamous cell carcinoma (OPSCC) patients, we performed a retrospective analysis of 46 consecutive cases treated primarily by surgery and/or postoperative radiotherapy at Yonsei University between May 1992 and December 2006. Twelve patients were T 1 and 34 were T 2 . The most common location was the tonsil (54%), followed by the soft palate (19%), the base of the tongue (BOT) (15%) and the posterior wall (12%). Occult lymph node metastasis was noted in 12 cases (26%). Seventeen patients (37%) received adjuvant radiotherapy. The 5-year disease-specific survival rate (DSSR) was 83%: 100% for clinical stage I (T 1 N 0 ) and 74% for clinical stage II (T 2 N 0 ). The 5-year DSSR of patients with surgery alone was 86%. Thirteen of 14 patients (93%) treated with conservative surgery alone without mandible-splitting or adjuvant radiotherapy attained disease-free status. In addition, 25 of 40 patients (63%) with disease-free status were treated with surgery alone. Almost 30% of all patients may be candidates for adjuvant chemotherapy through histopathologic analysis according to the National Comprehensive Cancer Network (2007) guidelines. The results of the present study demonstrate excellent oncologic outcomes with primary surgery for the treatment of early-stage OPSCC and suggest that surgery offers the best opportunity to identify patients in whom adjuvant radio- or chemotherapy may be most appropriately applied.

The extent of neck dissection (ND) appropriate for necks yielding clinical evidence of metastases of papillary thyroid carcinoma (PTC) is controversial. The need for level IIb lymph node (LN) dissection is particularly uncertain in view of its association with postoperative shoulder dysfunction. In the present study, we examined the frequency, pattern, and predictive factors of level IIb LN metastases in PTC patients with clinically positive lateral neck nodes.We reviewed the medical records of 76 PTC patients who underwent therapeutic lateral ND for the treatment of clinically positive lateral neck nodes between March 2005 and July 2008. ND specimens were separately obtained for analyzing LN involvement with respect to neck level.Metastatic disease at levels II, III, IV, and V, was seen in 40 (52.6%), 55 (72.4%), 52 (68.4%), and 12 (15.8%) of the patients, respectively. The metastasis rate in level IIb was 11.8% (9 of 76). By univariate analysis, the rate of level IIb LN metastasis was significantly higher in patients with positive level IIa LNs and positive LNs in all lateral neck levels (levels IIa + III + IV) (P.05). Multivariate analysis showed that positive LN involvement in all lateral neck levels (IIa + III + IV) was an independent predictive factor of level IIb LN metastasis (P = .044, odds ratio = 9.692).Level IIb LN dissection may be omitted in the treatment of positive neck nodes in PTC patients if multilevel involvement including level IIa involvement is absent.

This study demonstrates that the incidence of submandibular gland metastasis in oral cavity squamous cell carcinoma (SCC) is extremely rare and its involvement is through direct extension from a primary lesion. Therefore, if the primary lesion of the oral cavity carcinoma is not in close proximity and hence does not provide suspicion of direct extension, it may be safe to preserve the submandibular gland.Radiotherapy may lead to injury to the salivary glands resulting in xerostomia. This study aimed to determine whether and how the submandibular gland is involved in metastases of SCC of the oral cavity and to provide an oncological basis for preservation of the submandibular gland.This study reviewed the records and pathologic specimens of 201 patients who were diagnosed as having oral cavity SCC and underwent surgery at our institution, from 1991 to 2006, and pathologic metastasis to submandibular gland was evaluated.In all, 44 cases (21.9%) were found to show ipsilateral level I metastasis on pathologic examination. Only two cases (1%) had carcinoma involvement in the submandibular gland. Both these two cases had direct extension from a primary lesion (retromolar trigone and floor of mouth) and no submandibular glands showed pathologic evidence of isolated metastasis or local extension of metastatic lymph nodes.

Our study suggests that routine level I dissection may not be necessary in the surgical management of clinically N + hypopharyngeal squamous cell carcinoma (SCC) in patients who do not have a positive lymph node in neck level I.To determine whether level I lymph node dissection can be saved in patients with clinically N + hypopharyngeal SCC.Retrospective analysis of 64 consecutive clinically N + patients with untreated hypopharyngeal SCC between 1994 and 2006. Forty-seven patients underwent level I lymph node dissection and the remaining 17 did not. Forty-five of the 64 patients were followed for a minimum of 2 years, if alive, or until death. Of these 45 patients, 35 underwent ipsilateral level I dissection of the neck.The incidence of occult metastases to level I was 6% (3 of 47). Six (17%) of 35 patients with level I dissection and 1 (10%) of 10 patients without level I dissection experienced regional recurrence (p0.05). The 2-year disease-specific survival in 47 patients undergoing level I neck dissection was 44% compared with 37% in 17 patients who did not undergo level I neck dissection (p0.05).

Hepatocyte growth factor (HGF) has recently attracted a considerable amount of attention as a stromal-derived mediator in tumor-stromal interactions, particularly because of its close involvement in cancer invasion and metastasis, and (-)-epigallocatechin-3-gallate (EGCG) can modulate the cell signaling associated with angiogenesis, metastasis, and migration of cancer cells. In the present study, we have investigated the effects of HGF on invasion and metastasis of hypopharyngeal carcinoma cells and the effect of EGCG on blocking HGF-induced invasion and metastasis in these cells. We found that HGF promoted the autophosphorylation of c-Met, HGF receptor, and that HGF-induced proliferation, colony dispersion, migration and invasion of tumors. We also observed that HGF enhanced the activity of matrix metalloproteinase (MMP)-9 and urokinase-type plasminogen activator (uPA) in hypopharyngeal carcinoma cells. In addition, HGF-induced the activation of Akt and Erk pathway as a downstreaming pathway of invasion. On the other hand, EGCG at physiologically relevant concentration (1 microM) suppressed HGF-induced tumor motility and MMP-9 and uPA activities, and the suppression of Akt and Erk pathway by EGCG was one of the downstream mechanisms to facilitate EGCG-induced anti-invasion effects. These results suggest that EGCG may serve as a therapeutic agent to inhibit HGF-induced invasion in hypopharyngeal carcinoma patients.