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The present study aimed to investigate expression of β2-adrenergic receptor (AR), the effect of the stress-related neurotransmitter norepinephrine (NE) on cell viability, proliferation and the therapeutic effect of propranolol, which is a typical β-blocker in various type of head and neck cancers for the first time. The β2-AR expression was investigated using immunohistochemistry and an immunoreactive scoring (IRS) system in 57 different head and neck cancer specimens, and reverse transcriptase-polymerase chain reaction and western blotting in four head and neck cancer cell lines (HNCCLs). Cell viability and proliferation assays were performed using 0, 1, 5 and 10 µM of NE and 1 µM of propranolol in four HNCCLs. The expression of β2-AR was positive in the majority of head and neck cancer tissues (55/57, 96.5%); however, it was significantly higher in oral cavity cancer than in pharyngeal cancer (median IRS: 9 vs. 3; P

BACKGROUND: Macrophages have been known to have diverse roles either after tissue damage or during the wound healing process; however, their roles in flap wound healing are poorly understood. In this study, we aimed to evaluate how macrophages contribute to the flap wound regeneration. METHODS: A murine model of a pedicled flap was generated, and the time-course of the wound healing process was determined. Especially, the interface between the flap and the residual tissue was histopathologically evaluated. Using clodronate liposome, a macrophage-depleting agent, the functional role of macrophages in flap wound healing was investigated. Coculture of human keratinocyte cell line HaCaT and monocytic cell line THP-1 was performed to unveil relationship between the two cell types. RESULTS: Macrophage depletion significantly impaired flap wound healing process showing increased necrotic area after clodronate liposome administration. Interestingly, microscopic evaluation revealed that epithelial remodeling between the flap tissue and residual normal tissue did not occurred under the lack of macrophage infiltration. Coculture and scratch wound healing assays indicated that macrophages significantly affected the migration of keratinocytes. CONCLUSION: Macrophages play a critical role in the flap wound regeneration. Especially, epithelial remodeling at the flap margin is dependent on proper macrophage infiltration. These results implicate to support the cellular mechanisms of impaired flap wound healing. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13770-019-00214-x) contains supplementary material, which is available to authorized users.

Intractable wound healing is the habitual problem of diabetes mellitus. High blood glucose limits wound healing by interrupting inflammatory responses and inhibiting neoangiogenesis. Oxidative stress is commonly thought to be a major pathogenic cause of diabetic complications. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one, EDV) is a free radical scavenger which suppress oxidative stress. This study investigates whether EDV can reduce oxidative stress in wound healing HaCaT/human dermal fibroblasts cells (HDFs) in vitro and in vivo animal model. Cell viability and wound healing assays, FACS flow cytometry, and Hoechst 33342 staining were performed to confirm apoptosis and cytotoxicity in H2O2 and EDV-treated HaCaT and HDFs. A streptozotocin-induced hyperglycemic animal model was made in adult C57BL6 mice. Full-thickness skin flap was made on dorsomedial back and re-sutured to evaluate the wound healing process. EDV was delivered slowly in the skin flap with degradable fibrin glue. The flap was monitored and analyzed on postoperative days 1, 3, and 5. CD31/DAPI staining was done to detect newly formed blood vessels. The expression levels of NF-κB, bcl-2, NOX3, and STAT3 proteins in C57BL6 mouse tissues were also examined. The wound healing process in hyper- and normoglycemic mice showed a difference in protein expression, especially in oxidative stress management and angiogenesis. Exogenous H2O2 reduced cell viability in a proportion to the concentration via apoptosis. EDV protected HaCaT cells and HDFs from H2O2 induced reactive oxygen species cell damage and apoptosis. In the mouse model, EDV with fibrin resulted in less necrotic areas and increased angiogenesis on postoperative day 5, compared to sham-treated mice. Our results indicate that EDV could protect H2O2-induced cellular injury via inhibiting early apoptosis and inflammation and also increasing angiogenesis. EDV might be valuable in the treatment of diabetic wounds that oxidative stress has been implicated.

Human papillomavirus (HPV) infects squamous epithelium and is a major cause of cervical cancer (CC) and a subset of head and neck cancers (HNC). Virus-induced tumorigenesis, molecular alterations, and related prognostic markers are expected to be similar between the two cancers, but they remain poorly understood. We present integrated molecular analysis of HPV-associated tumors from TCGA and GEO databases and identify prognostic biomarkers. Analysis of gene expression profiles identified common upregulated genes and pathways of DNA replication and repair in the HPV-associated tumors. We established 34 prognostic gene signatures with a universal cutoff value in TCGA-CC using Elastic Net Cox regression analysis. We were able to externally validate our results in the TCGA-HNC and several GEO data sets, and demonstrated prognostic power in HPV-associated HNC, but not in HPV-negative cancers. The HPV-related prognostic and predictive indicator did not discriminate other cancers, except bladder urothelial carcinoma. These results identify and completely validate a highly selective prognostic system and its cross-usefulness in HPV-associated cancers, regardless of the tumor’s anatomical subsite. IMPORTANCE Persistent infection with high-risk HPV interferes with cell function regulation and causes cell mutations, which accumulate over the long term and eventually develop into cancer. Results of pathway enrichment analysis presumably showed this accumulation of intracellular damage during the chronic HPV-infected state. We used highly advanced statistical methods to identify the most appropriate genes and coefficients and developed the HPV-related prognostic and predictive indicator (HPPI) risk scoring system. We applied the same cutoff value to training and validation sets and demonstrated good prognostic performance in both data sets, and confirmed a consistent trend in external validation. Moreover, HPPI presented significant validation results for bladder cancer suspected to be related to HPV. This suggested that our risk scoring system based on the prognostic gene signature could play an important role in the development of treatment strategies for patients with HPV-related cancer.

Purpose To evaluate the feasibility of using skeletal muscle mass (SMM) at C3 (C3 SMM) as a diagnostic marker for sarcopenia in head and neck cancer (HNC) patients. Methods We evaluated 165 HNC patients and 42 healthy adults who underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography scans. The paravertebral muscle area at C3 and skeletal muscle area at L3 were measured by CT. Pearson’s correlation was used to assess the relationship between L3 and C3 SMMs. The prediction model for L3 SMM was developed by multiple linear regression. Then the correlation and the agreement between actual and predicted L3 SMMs were assessed. To evaluate the diagnostic value of C3 SMM for sarcopenia, the receiver operating characteristics (ROC) curves were analyzed. Results Of the 165 HNC patients, 61 (37.0%) were sarcopenic and 104 (63.0%) were non-sarcopenic. A very strong correlation was found between L3 SMM and C3 SMM in both healthy adults (r = 0.864) and non-sarcopenic patients (r = 0.876), while a fair association was found in sarcopenic patients (r = 0.381). Prediction model showed a very strong correlation between actual SMM and predicted L3 SMM in both non-sarcopenic patients and healthy adults (r > 0.9), whereas the relationship was moderate in sarcopenic patients (r = 0.7633). The agreement between two measurements was good for healthy subjects and non-sarcopenic patients, while it was poor for sarcopenic patients. On ROC analysis, predicted L3 SMM showed poor diagnostic accuracy for sarcopenia. Conclusions A correlation between L3 and C3 SMMs was weak in sarcopenic patients. A prediction model also showed a poor diagnostic accuracy. Therefore, C3 SMM may not be a strong predictor for L3 SMM in sarcopenic patients with HNC.

Diagnosis of occult palatine tonsil squamous cell carcinoma (SCC) using conventional magnetic resonance imaging (MRI) is difficult in patients with cervical nodal metastasis from an unknown primary site at presentation. We aimed to establish a radiomics approach based on MRI features extracted from the volume of interest in these patients. An Elastic Net model was developed to differentiate between normal palatine tonsils and occult palatine tonsil SCC. The diagnostic performances of the model with radiomics features extracted from T1-weighted image (WI), T2WI, contrast-enhanced T1WI, and an apparent diffusion coefficient (ADC) map had area under the receiver operating characteristic (AUROC) curve values of 0.831, 0.840, 0.781, and 0.807, respectively, for differential diagnosis. The model with features from the ADC alone showed the highest sensitivity of 90.0%, while the model with features from T1WI + T2WI + contrast-enhanced T1WI showed the highest AUROC of 0.853. The added sensitivity of the radiomics feature analysis were 34.6% over that of conventional MRI to detect occult palatine tonsil SCC. Therefore, we concluded that adding radiomics feature analysis to MRI may improve the detection sensitivity for occult palatine tonsil SCC in patients with a cervical nodal metastasis from cancer of an unknown primary site.

Head and neck squamous cell carcinoma (HNSCC) metastasizes to the locoregional lymph nodes at high rates and is related to poor clinical outcomes. However, the mechanism by which cancer cells migrate to the lymph nodes is unclear. To address this, we established a conditioned medium culture system for HNSCC cells and lymphatic endothelial cells (LECs) and investigated their crosstalk. Stimulation with tumor-conditioned medium (TCM) activated LECs, resulting in a robust increase in cell proliferation to induce lymphatic hyperplasia. Further, stimulation of HNSCC cells with activated LEC Conditioned media (TCM-LEC CM) induced cell invasion. Among various chemokines, CXCL5 promoted the invasion of TCM-LEC CM-treated HNSCC cells. The level of CXCL5 protein was higher in cancer tissues than those in normal tissues from HNSCC patients. Furthermore, treatment with SB225002, a CXCR2 (CXCL5 receptor) inhibitor, resulted in decreased lymph node metastasis in vivo. In conclusion, inhibition of CXCL5-CXCR2 signaling between cancer cells and LECs suppresses cancer cell invasion and metastasis in vitro and in vivo. This novel therapeutic strategy might be a practical approach to the clinical management of HNSCC.

Purpose Radiation-induced oral mucositis limits delivery of high-dose radiation to targeted cancers. Therefore, it is necessary to develop a treatment strategy to alleviate radiation-induced oral mucositis during radiation therapy. We previously reported that inhibiting reactive oxygen species (ROS) generation suppresses autophagy. Irradiation induces autophagy, suggesting that antioxidant treatment may be used to inhibit radiation-induced oral mucositis. Materials and methods We determined whether treatment with N-acetyl cysteine (NAC) could attenuate radiation-induced buccal mucosa damage in vitro and in vivo. The protective effects of NAC against oral mucositis were confirmed by transmission electron microscopy and immunocytochemistry. mRNA and protein levels of DNA damage and autophagy-related genes were measured by quantitative real-time polymerase chain reaction and western blot analysis, respectively. Results Rats manifesting radiation-induced oral mucositis showed decreased oral intake, loss of body weight, and low survival rate. NAC intake slightly increased oral intake, body weight, and the survival rate without statistical significance. However, histopathologic characteristics were markedly restored in NAC-treated irradiated rats. LC3B staining of rat buccal mucosa revealed that NAC treatment significantly decreased the number of radiation-induced autophagic cells. Further, NAC inhibited radiation-induced ROS generation and autophagy signaling. In vitro, NAC treatment significantly reduced the expression of NRF2, LC3B, p62, and Beclin-1 in keratinocytes compared with that after radiation treatment. Conclusion NAC treatment significantly inhibited radiation-induced autophagy in keratinocytes and rat buccal mucosa and may be a potentially safe and effective option for the prevention of radiation-induced buccal mucosa damage.

Fibroblastic reticular cells (FRCs) are immunologically specialized myofibroblasts of lymphoid organ, and FRC maturation is essential for structural and functional properties of lymph nodes (LNs). Here we show that YAP and TAZ (YAP/TAZ), the final effectors of Hippo signaling, regulate FRC commitment and maturation. Selective depletion of YAP/TAZ in FRCs impairs FRC growth and differentiation and compromises the structural organization of LNs, whereas hyperactivation of YAP/TAZ enhances myofibroblastic characteristics of FRCs and aggravates LN fibrosis. Mechanistically, the interaction between YAP/TAZ and p52 promotes chemokine expression that is required for commitment of FRC lineage prior to lymphotoxin-β receptor (LTβR) engagement, whereas LTβR activation suppresses YAP/TAZ activity for FRC maturation. Our findings thus present YAP/TAZ as critical regulators of commitment and maturation of FRCs, and hold promise for better understanding of FRC-mediated pathophysiologic processes., Fibroblastic reticular cells (FRC) are important for lymph node (LN) structure and function. Here the authors show that the YAP/TAZ complex downstream of Hippo signalling regulates FRC commitment and maturation, with YAP/TAZ deficiency impairing FRC differentiation, while hyperactivation of YAZ/TAZ inducing myofibroblastic FRCs and LN fibrosis.

Purpose The present study investigated the dynamics and prognostic role of messenger RNA (mRNA) expression responsible for ¹⁸F-fluorodeoxyglucose (FDG) uptake in FDG positron emission tomography (PET) and radioactive iodine (¹³¹I) uptake in whole-body radioactive iodine scans (WBS) in papillary thyroid cancer (PTC) patients. Materials and methods The primary and processed data were downloaded from the Genomic Data Commons Data Portal. Expression data for sodium/iodide symporter (solute carrier family 5 member 5, SLC5A5), hexokinase (HK1-3), glucose-6-phosphate dehydrogenase (G6PD), and glucose transporter (solute carrier family 2, SLC2A1-4) mRNA were collected. Results Expression of SLC5A5 mRNA were negatively correlated with SLC2A1 mRNA and positively correlated with SLC2A4 mRNA. In PTC with BRAF mutations, expressions of SLC2A1, SLC2A3, HK2, and HK3 mRNA were higher than those in PTC without BRAF mutations. Expression of SLC5A5, SLC2A4, HK1, and G6PD mRNA was lower in PTC without BRAF mutation. PTCs with higher expression of SLC5A5 mRNA had more favorable disease-free survival, but no association with overall survival. Conclusion Expression of SLC5A5 mRNA was negatively correlated with SLC2A1 mRNA. This finding provides a molecular basis for the management of PTC with negative WBS using ¹⁸F-FDG PET scans. In addition, higher expression of SLC5A5 mRNA was associated with less PTC recurrence, but not with deaths.

As tissue engineering and regenerative medicine have evolved recently, stem cell therapy has been investigated in the field of impaired wound healing. Several studies have reported that mesenchymal stem cells derived from various tissues including bone marrow and adipose tissue can exert the regenerative efficacy in the wound healing. Previously, we have demonstrated the isolation and characterization of tonsil-derived mesenchymal stem cells (TMSCs) with excellent proliferative property. In the present study, we aimed to evaluate the regenerative efficacy of TMSCs in the wound healing process. Two distinct cutaneous surgical defects were generated in the dorsum of mice. Each wound was treated with TMSCs or phosphate-buffered saline (PBS), respectively. After sacrifice, the skin and subcutaneous tissues around the surgical defect were harvested and assessed for inflammation, re-epithelialization, dermal regeneration, and granulation tissue formation. The administration of TMSCs into wound beds significantly promoted the repair of surgical defects in mice. Especially, TMSCs efficiently contributed to the attenuation of excessive inflammation in the surgical lesion, as well as the augmentation of epidermal and dermal regeneration. To elucidate the underlying mechanisms, TMSCs were analyzed for their potency in immunomodulatory ability on immune cells, stimulatory effect on the proliferation of keratinocytes, and fibroblasts, as well as the regulation of fibroblast differentiation. TMSCs inhibited the non-specific or T-cell-specific proliferation of peripheral blood mononuclear cells, as well as the M1 polarization of macrophage-like cells. Moreover, TMSCs augmented the proliferation of skin-constituting fibroblasts and keratinocytes while they suppressed the differentiation of fibroblasts into myofibroblasts. Taken together, our findings demonstrate the regenerative potential of TMSCs in wound healing process through the regulation on inflammation, proliferation, and remodeling of various skin cells, implying that TMSCs can be a promising alternative for wound repair.

// Yun Hak Kim 1, 7 , Dae Cheon Jeong 2 , Kyoungjune Pak 3, 7 , Tae Sik Goh 1, 4, 7 , Chi-Seung Lee 5 , Myoung-Eun Han 1 , Ji-Young Kim 1 , Liu Liangwen 1 , Chi Dae Kim 6 , Jeon Yeob Jang 7, 8 , Wonjae Cha 7, 8 and Sae-Ock Oh 1 1 Department of Anatomy, School of medicine, Pusan National University, Yangsan, 50612, Republic of Korea 2 Department of Statistics, Korea University, Seoul 02841, Republic of Korea 3 Department of Nuclear Medicine, Pusan National University Hospital, Busan 49241, Republic of Korea 4 Department of Orthopaedic Surgery, Pusan National University Hospital, Busan 49241, Republic of Korea 5 Biomedical Research Institute, Pusan National University Hospital and School of Medicine, Pusan National University, Busan 49241, Republic of Korea 6 Department of Pharmacology, School of medicine, Pusan National University, Yangsan, 50612, Republic of Korea 7 BEER, Busan society of Evidence-based mEdicine and Research, Busan 49241, Republic of Korea 8 Department of Otorhinolaryngology-Head and Neck Surgery, Pusan National Hospital, Busan 49241, Republic of Korea Correspondence to: Sae-Ock Oh, email: hedgehog@pusan.ac.kr Keywords: prognosis, network-regularized high-dimensional Cox-regression (Net), breast cancer, gene network, gene signature Received: July 03, 2017 Accepted: August 04, 2017 Published: August 24, 2017 ABSTRACT Accurate prediction of prognosis is critical for therapeutic decisions regarding cancer patients. Many previously developed prognostic scoring systems have limitations in reflecting recent progress in the field of cancer biology such as microarray, next-generation sequencing, and signaling pathways. To develop a new prognostic scoring system for cancer patients, we used mRNA expression and clinical data in various independent breast cancer cohorts (n=1214) from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and Gene Expression Omnibus (GEO). A new prognostic score that reflects gene network inherent in genomic big data was calculated using Network-Regularized high-dimensional Cox-regression (Net-score). We compared its discriminatory power with those of two previously used statistical methods: stepwise variable selection via univariate Cox regression (Uni-score) and Cox regression via Elastic net (Enet-score). The Net scoring system showed better discriminatory power in prediction of disease-specific survival (DSS) than other statistical methods (p=0 in METABRIC training cohort, p=0.000331, 4.58e-06 in two METABRIC validation cohorts) when accuracy was examined by log-rank test. Notably, comparison of C-index and AUC values in receiver operating characteristic analysis at 5 years showed fewer differences between training and validation cohorts with the Net scoring system than other statistical methods, suggesting minimal overfitting. The Net-based scoring system also successfully predicted prognosis in various independent GEO cohorts with high discriminatory power. In conclusion, the Net-based scoring system showed better discriminative power than previous statistical methods in prognostic prediction for breast cancer patients. This new system will mark a new era in prognosis prediction for cancer patients.

// Gi Cheol Park 1,* , Ji Min Kim 2,* , Hee-Young Park 2 , Ji Min Han 3 , Sung-Chan Shin 2 , Jeon Yeob Jang 4 , Dawoon Jung 2 , In Joo Kim 5 , Jin-Choon Lee 6 and Byung-Joo Lee 2 1 Department of Otorhinolaryngology – Head and Neck Surgery, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea 2 Department of Otorhinolaryngology – Head and Neck Surgery, Pusan National University School of Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan, Korea 3 Department of Internal Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea 4 Department of Otorhinolaryngology - Head and Neck Surgery, Ajou University School of Medicine, Suwon, Korea 5 Department of Internal Medicine, Pusan National University School of Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan, Korea 6 Department of Otorhinolaryngology – Head and Neck Surgery, Pusan National University School of Medicine and Biomedical Research Institute, Pusan National University Yangsan Hospital, Yangsan, Gyeongnam, Korea * The first two authors have equally contributed to this paper Correspondence to: Byung-Joo Lee, email: // Keywords : aging, thyroid, cold exposure, rat, Gerotarget Received : May 18, 2017 Accepted : July 26, 2017 Published : August 03, 2017 Abstract Thyroid function decreases and cold exposure response becomes impaired with increasing age. We investigated the age-related changes in thyroid structure and function and cold-induced changes in the thyroid activity of aging rats. Thirty-two male Sprague–Dawley rats were randomly divided into four groups (8 rats per group): young (7 months) and old (22 months) groups exposed to room temperature and cold stress. The active follicle ratio and serum free T3, T4 and TSH, and TSH receptor (TSHR) concentrations in the thyroid tissues of the rats from each group were compared. At room temperature, old rats had significantly lower active follicle ratio and free T3 and T4 concentrations than young rats. Furthermore, old rats displayed higher TSH level than young. Exposure to cold temperature led to significantly increased active colloid ratio and free T3 and T4 concentrations among old rats, but no significant differences were found among young rats. Additionally, no significant changes in the TSH and TSHR levels were observed after cold exposure in both young and old rats. Old rats have lower thyroid function than young rats under normal temperature. Aging rats are more susceptible to cold stress than young rats, and cold-induced thyroid activation occurs independently of TSH. We investigated the age-related changes in the thyroid structure and function and cold-induced changes in the thyroid activity of aging rats. Aging rats have structurally less active thyroid follicles and functionally lower thyroid hormone levels than young rats. Furthermore, old rats are more susceptible to cold stress than young rats, and cold-induced thyroid activation occurs independently of TSH.

Thyroid gland vasculature has a distinguishable characteristic of endothelial fenestrae, a critical component for proper molecular transport. However, the signaling pathway that critically governs the maintenance of thyroid vascular integrity, including endothelial fenestrae, is poorly understood. Here, we found profound and distinct expression of follicular epithelial VEGF-A and vascular VEGFR2 that were precisely regulated by circulating thyrotropin, while there were no meaningful expression of angiopoietin-Tie2 system in the thyroid gland. Our genetic depletion experiments revealed that VEGFR2, but not VEGFR3, is indispensable for maintenance of thyroid vascular integrity. Notably, blockade of VEGF-A or VEGFR2 not only abrogated vascular remodeling but also inhibited follicular hypertrophy, which led to the reduction of thyroid weights during goitrogenesis. Importantly, VEGFR2 blockade alone was sufficient to cause a reduction of endothelial fenestrae with decreases in thyrotropin-responsive genes in goitrogen-fed thyroids. Collectively, these findings establish follicular VEGF-Avascular VEGFR2 axis as a main regulator for thyrotropindependent thyroid angiofollicular remodeling and goitrogenesis.

Objectives/hypothesis Anatomical variations of the recurrent laryngeal nerve (RLN), such as extralaryngeal branching, are a well-known risk factor for RLN injury during thyroid surgery. This study aimed to analyze the surgical anatomy and to investigate the existence of posterior branch motor fibers of extralaryngeal RLNs. Study design Prospective consecutive observational study. Methods This was a prospective cohort study of 366 patients between January 2014 and February 2016. Operative data included the type of operation, incidence of nerve bifurcation, the distances among anatomical landmarks. The motor fibers were evaluated using neurostimulation with laryngeal palpation. Results A total of 667 RLNs at risk were analyzed in this study, and of these 103 (14.5%) nerves were bifurcated or trifurcated before the laryngeal entry point (LEP). More extralaryngeal branched RLNs were observed on the right side than on the left (17.5% vs. 13.3%, P = .294). The mean distance of the LEP point of division was longer on the left side (16.2 ± 6.7 mm) than on the right (14.7 ± 5.9 mm, P = .132). All branched RLNs had a palpable laryngeal twitch when stimulating anterior branches. When stimulating posterior branches, 28.2%(29/103) of branched RLNs showed palpable laryngeal twitch. Overall incidence of posterior motor branch in total RLNs was 4.3% (29/667). Conclusions The motor fibers of the RLN are all located in the anterior branch, whereas some posterior branches have motor function. Identification of all of the branches of the RLN may be mandatory to decrease the risk of postoperative nerve injury. Level of evidence 4. Laryngoscope, 127:2678-2685, 2017.

Korean Society of Thyroid-Head and Neck Surgery appointed a Task Force to develop clinical practice guidelines for the surgical treatment of laryngeal cancer. This Task Force conducted a systematic search of the EMBASE, MEDLINE, Cochrane Library, and KoreaMed databases to identify relevant articles, using search terms selected according to the key questions. Evidence-based recommendations were then created on the basis of these articles. An external expert review and Delphi questionnaire were applied to reach consensus regarding the recommendations. The resulting guidelines focus on the surgical treatment of laryngeal cancer with the assumption that surgery is the selected treatment modality after a multidisciplinary discussion in any context. These guidelines do not, therefore, address non-surgical treatment such as radiation therapy or chemotherapy. The committee developed 62 evidence-based recommendations in 32 categories intended to assist clinicians during management of patients with laryngeal cancer and patients with laryngeal cancer, and counselors and health policy-makers.

Background This study aimed to investigate the relationships between serum vascular endothelial growth factor (VEGF)-A or VEGF-C levels and lymph node metastasis (LNM) status in patients with papillary thyroid carcinoma (PTC). Methods The study enrolled 150 patients with pathologically proven PTC who underwent surgery: PTC without LNM, PTC with central neck metastasis, and PTC with lateral neck metastasis. Results Preoperative serum VEGF-A levels were 300.12 ± 80.80 pg/mL overall and were not correlated with the presence of LNM. Preoperative serum VEGF-C levels were 132.41 ± 48.48 pg/mL overall and were significantly correlated with the presence of LNM. Serum VEGF-C levels were further increased in patients with lateral neck metastasis and positively correlated with the number of metastatic LNs (rho = 0.252, P = 0.002). Serum VEGF-C, but not VEGF-A, was identified as a significant predictor of lateral neck metastasis. Conclusion Serum VEGF-C might be a clinically relevant biomarker of lateral neck metastasis in patients with PTC.

Objectives To clarify the anatomical distribution of the lingual artery in normal adult subjects through histopathologic evaluations. Methods Eighteen healthy cadaveric tongues were used to produce 8 paraffin-embedded tissue sections each. Length from midline raphe, depth from dorsum of tongue and the whole transverse length tongue were measured. The lateral distance, depth, and proportion of lateral distance of deep lingual artery were determined from tip to base of tongue gradually. Lateral distance is length from median raphe to the center of deep lingual artery lumen. Depth is vertical distance from dorsal surface of tongue to the center of deep lingual artery. Proportion of lateral distance is obtained by dividing lateral distance with transverse length from median raphe to lateral border of tongue. The degree of symmetry between right and left sides and the difference between selected spots were evaluated. Results Right and left sides of the lingual artery were symmetric. The lingual artery was lateralized as it run posterior. The lingual artery runs gradually deeper from the surface as it goes near the base of tongue. Both length and depth of the lingual artery gradually increased between 0%-75% of the mobile tongue, but 75%-100% zone of the lingual artery showed no significant difference. There was no anastomosis between right and left side of the lingual arteries. The lingual artery was located within 50% of the transverse length of tongue from median raphe. Conclusion The present study reveals 3-dimensional information on the anatomical distributions of the lingual artery in normal adult subjects. These findings gives us beneficial information about the handling of the lingual artery during oral and base of tongue-related surgery.

Objectives/Hypothesis Office-based biopsy (OBB) is widely used to diagnose suspicious laryngeal lesions. However, its routine use is still controversial and the algorithm for clinical strategy is not concrete. We tried to evaluate the accuracy of OBB as a diagnostic tool for laryngeal malignancy. Methods Medical data of 581 patients undergoing OBB were reviewed. Diagnostic values of OBB were analyzed for malignancy and malignancy/premalignancy. False negative rates (FNRs) were analyzed according to subsites, lesion sizes, and morphology. Results The collection rate of adequate specimens was 99.1%, and there were no complications during OBB. The false omission rates for malignancy of benign lesion; mild, moderate, and severe dysplasia; and carcinoma in situ (CIS) were 5.1%, 11.9%, 14.3%, 50.0%, and 100.0%, respectively. Sensitivity, specificity, positive predictive value, and negative predictive value for malignancy in OBB were 78.2%, 100.0%, 100.0%, and 87.3%, respectively. Those for malignancy/premalignancy in OBB were 88.2%, 86.7%, 85.7%, and 89.1%, respectively. The high FNRs were reported in glottis lesions (27.0%) and small lesions below 1 cm (27.5%). Morphologically fungating lesions showed low FNR (9.1%) compared to nonfungating ones. Conclusion Office-based biopsy could be used as an initial diagnostic tool for laryngeal malignancy for early detection and avoidance of general anesthesia. However, operative re-biopsy should be considered when severe dysplasia or CIS were reported in OBB, or when the lesions are clinically suspicious for malignancy. Level of Evidence 4. Laryngoscope, 2016

Objectives/Hypothesis Recurrent laryngeal nerve (RLN) injury during thyroidectomy or parathyroidectomy is a challenging issue and causes significant morbidity. We adopted the supramaximal stimulation protocol for neurostimulation with laryngeal palpation (NSLP) and tried to evaluate the predictive values of supramaximal NSLP for immediate postoperative vocal fold (VF) mobility. Study Design Prospective cohort study. Methods Prospectively, 293 patients who underwent thyroid and parathyroid surgery and 542 RLNs at risk were enrolled in this study. During NSLP, the current was escalated to 3 mA until definite laryngeal twitch was observed. Immediate postoperative VF mobility was evaluated using flexible laryngoscopy. Results Diagnostic accuracy of NSLP is calculated according to cutoff values of minimal current intensity (1 mA, 1.5 mA, and 2 mA). At 2mA, sensitivity was 81.82%, specificity 100%, positive predictive value 100%, and negative predictive value 99.62%. Conclusions Supramaximal NSLP might be a simple and reliable method to predict immediate postoperative VF mobility in open thyroid and parathyroid surgeries when intraoperative neuromonitoring is unavailable. Level of Evidence 4. Laryngoscope, 2016

Background Osteosarcoma of the head and neck is aggressive malignancy that might be affected by growth hormone. The purpose of this study was to demonstrate an unusual case of osteosarcoma with acromegaly. Methods and results This case is about a 39-year-old woman with an osteosarcoma of the mandible, who had a history of exponential tumor growth in spite of chemotherapy at another hospital. She transferred to Samsung Medical Center and underwent a wide resection of tumor and free flap reconstruction. During postoperative care, a brain MRI and hormonal test revealed a growth hormone-secreting pituitary adenoma, and then a transsphenoidal approach pituitary tumor removal was performed. Immunohistochemistry of the osteosarcoma indicated positive for insulin-like growth factor (IGF)-2 and somatostatin receptor. Conclusion This study proved the IGF-2 and somatostatin receptor from the osteosarcoma of the patient with acromegaly, and this could explain that the growth hormone secreting from the pituitary adenoma might be a risk factor of therapeutic intractability and growth acceleration of osteosarcoma. © 2016 Wiley Periodicals, Inc. Head Neck 38: E2432-E2436, 2016.

Whether to administer surgical or non-surgical treatments (radiation or chemoradiation therapies) for the initial management of hypopharyngeal cancer (HPC) remains a topic of debate. Herein, we explored the differences between the two approaches in terms of oncological and functional outcomes in 332 HPC patients. The primary endpoint was survival probability; secondary outcomes included post-treatment speech and swallowing functions and necessity of additional surgical procedures for salvage or complication management. Cox proportional hazard models using clinical variables were constructed to identify significant factors. The 2- and 5-year overall survival (OS) rates in all patients were 64.9 and 40.9 %, respectively. In early-stage HPC patients (N = 52), initial surgery ± radiation therapy (RT) or RT alone yielded similar oncological (60 % 5-year OS rate) and functional outcomes. As for resectable advanced-stage cancers (N = 177), initial surgery ± RT/chemoradiation therapy (SRC) and initial concurrent chemoradiation therapy (iCRT) resulted in similar 45–50 % 5-year OS rates. After sacrificing the larynx, 60 % of SRC patients recovered their speaking ability through voice prosthesis, which was less than the rate for iCRT patients (76.6 %; p = 0.008). Additional surgical interventions were required in 28.0–28.6 % of patients in both groups; however, 60 % of patients undergoing additional surgery in the iCRT group received multiple (two or more) surgical interventions (p = 0.029). Our data revealed similar oncological outcomes, but different functional outcomes, between initial surgical and non-surgical treatments for HPC. In resectable advanced-stage HPC, iCRT resulted in better verbal communication outcomes than SRC; however, more iCRT patients required multiple surgical interventions during clinical courses.

Background High-grade salivary gland cancer is a distinct clinical entity that has aggressive disease progression and early systemic spread. However, because of the rarity of the disease, the clinical outcomes, prognostic factors and clinical decision on the optimal treatments have not been fully understood. Methods In this study, we retrospectively analyzed the clinical data of 124 patients with high-grade salivary gland cancers and performed multivariate survival analyses to evaluate the clinico-pathological factors affecting the treatment outcomes. Results The 5-year disease-specific survival was 63.4% in patients with high-grade salivary gland cancers. Among the clinico-pathological factors, presence of lymph node metastasis (hazard ratio 5.63, 95% confidence interval 2.64–12.03, P

Adequate and rapid mucosal regeneration is one of the most important factors in the healing process of nasal mucosa after surgery or trauma. In particular, delayed mucosal regeneration after surgery is an important cause of surgical failure. However, no effective treatment is available yet. Non-thermal plasma (NTP) has several medical effects, but the existing probe type is limited to local direct treatment. Therefore, we investigated the various effects using liquid type plasma to overcome this limitation. In addition, the therapeutic effects of non-thermal plasma treated solution (NTS) on nasal mucosa have yet to be determined. Experiments were carried out using BEAS-2B, a human bronchial epithelial cell line similar to nasal mucosa epithelium. NTS had no cytotoxicity to the BEAS-2B cells and enhanced cell proliferation. NTS also promoted migration of BEAS-2B cells. NTS increased cell proliferation and migration via epidermal growth factor receptor (EGFR) activities and epithelial-to-mesenchymal transition (EMT) signaling. Furthermore, NTS enhanced wound healing of nasal mucosa in an animal model. Accordingly, NTS promotes nasal mucosa wound healing by increasing cell proliferation and migration. These findings suggest the therapeutic potential of NTS in nasal mucosa wound healing.

We assessed patient discomfort and identified factors predictive of discomfort while receiving radioactive iodine (RAI) ablation.Between August 2015 and April 2016, 52 patients with differentiated thyroid cancer were enrolled in this study. All patients received recombinant human thyroid stimulating hormone (rhTSH) aided RAI ablation using 3.7 GBq or 5.55 GBq of RAI. Discomfort during their stay for RAI ablation was evaluated using a symptom questionnaire. We analyzed the relationship between the patient's clinical data and the scores for the 15 items of the symptom questionnaire. We compared scores of questionnaires between male and female, under 45 years old and 45 and older, RAI activity of 3.7 GBq and 5.55 GBq. Also, scores of daily questionnaires were tested for differences.Most patients did not have severe discomfort, but some patients had mild discomfort during their stay for RAI ablation, despite using rhTSH. Important determinants of discomfort were sex and age. Female patients reported more symptoms of fatigue, facial edema, cold intolerance, and nausea. Older patients (45 and older) complained of insomnia more often. However, the dose of RAI ablation (3.7 GBq vs 5.55 GBq) did not affect the scores of questionnaires.Sex and age were important predictors of patient's discomfort during RAI ablation. Clinicians need to explain more about treatment and predicted discomforts to such patients before RAI ablation.Wir untersuchten unter ablativer Ra- dioiodtherapie (RIT) auftretende Beschwerden und identifizierten prognostische Faktoren für Beschwerden bei den Patienten.Von August 2015 bis April 2016 wurden 52 Patienten mit differenziertem Schilddrüsenkarzinom in die Studie aufgenommen. Alle Patienten erhielten eine durch rekombinantes humanes Thyreoidea-stimulierendes Hormon (rhTSH) gestützte ablative RIT mit 3,7 GBq oder 5,55 GBq. Die Beschwerden während des Aufenthaltes wegen der RIT wurden anhand eines Symptom-Fragebogens evaluiert. Wir analysierten den Zusammenhang zwischen den klinischen Daten der Patienten und den Scores in den 15 Items des Fragebogens. Die Fragebogen-Scores wurden wie folgt verglichen: Männer vs. Frauen,45-jährige vs. ≥ 45-jährige sowie RIT-Aktivität von 3,7 GBq vs. 5,55 GBq. Außerdem wurden die Scores der täglichen Fragebögen auf Unterschiede getestet.Die meisten Patienten hatten keine wesentlichen Beschwerden, bei manchen traten im Laufe des RIT- Aufenthaltes trotz rhTSH-Gabe leichte Beschwerden auf. Wichtige Determinanten für Beschwerden waren das Alter und das Geschlecht. Patientinnen berichteten häufiger über Symptome wie Müdigkeit, Gesichtsödem, Kälteunverträglichkeit und Übelkeit. Ältere Patienten (≥ 45 Jahre) klagten häufiger über Schlaflosigkeit. Die Dosis der ablativen RIT (3,7 GBq vs. 5,55 GBq) hatte jedoch keinen Einfluss auf die Fragebogen-Scores.Geschlecht und Alter waren wichtige Prädiktoren für Beschwerden unter einer ablativen RIT. Daher sollten Ärzte die Patienten vor einer ablativen RIT besser über die Behandlung und vorhersehbare Beschwerden aufklären.

Summary Objective The purpose of this study was to analyze the acoustic characteristics associated with alternation deformation of the vocal tract due to large epiglottic cyst, and to confirm the relation between the anatomical change and resonant function of the vocal tract. Methods Eight men with epiglottic cyst were enrolled in this study. The jitter, shimmer, noise-to-harmonic ratio, and first two formants were analyzed in vowels /a:/, /e:/, /i:/, /o:/, and /u:/. These values were analyzed before and after laryngeal microsurgery. Results The F1 value of /a:/ was significantly raised after surgery. Significant differences of formant frequencies in other vowels, jitter, shimmer, and noise-to-harmonic ratio were not presented. Conclusion The results of this study could be used to analyze changes in the resonance of vocal tracts due to the epiglottic cysts.

BACKGROUND/AIM We aimed to explore the prognostic value of metabolic heterogeneity of 18F-FDG uptake in chemoradiotherapy-treated pharyngeal cancer patients. PATIENTS AND METHODS This study included 52 consecutive patients with pharyngeal cancer who underwent 18F-FDG PET/CT before definitive chemoradiotherapy. The heterogeneity factor (HF) was defined as the derivative (dV/dT) of a volume-threshold function for primary tumors and metastatic lymph nodes. The relationships between clinical parameters and HFs of primary tumors (pHF) and metastatic lymph nodes (nHF) were analyzed. RESULTS The pHF (range=∓1.367 - -0.027; median=-0.152) was significantly correlated with the maximum standardized uptake value, metabolic tumor volume, and total lesion glycolysis. Induction chemotherapy response was not correlated with HF, whereas response to radiotherapy was significantly better in patients with high pHF (low heterogeneity). Consistently, the 2-year locoregional recurrence-free survival was significantly better in patients with high pHF (82.9% for pHF>-0.152 vs. 30.5% for pHF

Objectives/Hypothesis Vocal fold injection is a minimally invasive technique for various vocal fold pathologies. The shortcomings of the cricothyroid (CT) membrane approach are mainly related to invisibility of the injection needle. If localization of the needle tip can be improved during vocal fold injection with the CT approach, the current problems of the technique can be overcome. We have conceptualized real-time light-guided vocal fold injection that enables simultaneous injection under precise localization. In this study, we developed a device for real-time light-guided vocal fold injection and applied it in excised canine larynx. Study Design Animal model. Methods A single optic fiber was inserted in an unmodified 25-gauge needle. A designated connector for the device was attached to the needle, the optic fiber, and the syringe. A laser diode module was used as the light source. An ex vivo canine larynx model was used to validate the device. Results The location of the needle tip was accurately indicated, and the depth from the mucosa could be estimated according to the brightness and size of the red light. The needle was inserted and could be localized in the canine vocal fold by the light of the device. Precise injection at the intended location was easily performed with no manipulation of the device or the needle. Conclusions Real-time light-guided vocal fold injection might be a feasible and promising technique for treatment of vocal fold pathology. It is expected that this technique can improve the precision of vocal fold injection and expand its indication in laryngology. Level of Evidence NA Laryngoscope, 2015

Purpose Lymph node metastasis (LNM) is a strong prognostic factor in many solid cancers, including head and neck squamous cell carcinomas (HNSCC), and LNM can be dependent upon primary tumor biology, as well as tumor dimension. Here, we investigate the relative risk of LNM in accordance to tumor dimension and biology in HNSCC subsites. Materials and methods Medical data of 295 HNSCC patients who had undergone the initial curative surgery (oral tongue 174, oropharynx 75, hypopharynx 46) were analyzed to identify the significant predictive factor for LNM. Tumor volume and thickness were set as tumor dimensional variables, and biological variables included lymphovascular, perineural invasion, and tumor differentiation. Statistical analyses were conducted to assess the predictability of LNM from variables, and subgroup analyses according to the tumor subsites. In addition, we evaluated the impacts of tumor dimension and biological variables on the treatment outcomes and survival in HNSCC subsites. Results The overall tumor dimension and biological variables had a similar impact on the prediction of LNM in HNSCC (area under the curve, 0.7682 and 0.7717). The prediction sensitivity of LNM in oral tongue cancer was mainly dependent on tumor dimension, while LNM in oro- and hypo-pharynx cancers was more influenced by biological factors. Survival analyses also confirmed that biological factor was more powerful in estimating disease-free survival of hypopharyngeal cancer patients, while tumor dimension was more significant in that of oral cancer patients. Conclusion Tumor dimension and biology have a significant, tumor subsite-dependent impact on the occurrence of LNM and disease-free survival in HNSCC.