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The clinical outcomes of surgical treatments for vocal cord paralysis and tracheal stenosis, such as medialization laryngoplasty and laryngotracheal reconstruction, vary owing to the complex anatomy and physiology of the human upper airway. However, advances in three-dimensional (3D) simulation and printing ushered its use on an office-based workstation to aid in several surgical areas.The preoperation neck computed tomography image was loaded into the InVesalius 3.0 software for manual segmentation of airway and nearby important anatomic landmarks including hyoid bone, thyroid cartilage, and cricoid cartilage. The 3D model of the desired anatomy structure was manufactured and used for presurgical planning and rehearsal of the surgery.We review cases of four patients: two cases of unilateral vocal palsy undergoing medialization laryngoplasty and two cases of tracheal stenosis patients who used the air-cartilage combined model.Preoperation planning of the medialization thyroplasty could be more precise by prevision of the paralyzed vocal cord plane. Tracheal surgery could benefit from a preoperative design of segmented length. The novel airway-cartilage combined model offers new insight into vocal cord and trachea surgery.

Table S3: List of antibodies used in this study.

Supplementary Figures S1-19 and legends. Figure S1: Overexpression of HIF-1α enhances BTIC characteristics. Figure S2: Characterizations of isolated BTICs by different parameters. Figure S3: The expression of TET1 and TET3 is upregulated by hypoxia. Figure S4: HIF-1α binding to TET1 and TET3 gene promoter in HIF-1α overexpressing cells. Figure S5: Knockdown of TET diminishes hypoxia induced activation of stemness related genes in breast cancer cell lines. Figure S6: Knockdown of TET1/3 represses tumorigenicity of isolated BTICs in vivo. Figure S7: Isotype control for IHC analysis. Figure S8: Gene specific changes in 5hmC level and TET proteins binding in hypoxic, HIF-1α overexpressing cells and isolated BTICs. Figure S9: Starvation is unable to affect the levels of 5hmC on the genome regions of TNFα gene and TNFα gene expression. Figure S10: TET proteins are essential for hypoxia activated TNFα-p38-MAPK signaling. Figure S11: TET proteins are required for hypoxia-induced 5hmC change on the genome regions of the TNFα gene. Figure S12: The enzymatic activity of TET proteins is required for establishing 5hmC signature upon hypoxia. Figure S13: The enzymatic activity of TET proteins is required for activation of TNFα-p38-MAPK signaling upon hypoxia. Figure S14: Protein-protein interaction between TET1 and TET3 in hypoxic cells and isolated BTICs. Figure S15: Co-occupancy of TET1 and TET3 on genome regions of the TNFα gene. Figure S16: Suppression of p38-MAPK signaling reduces BTIC properties. Figure S17: Certain downstream targets of TNFα-p38-MAPK signaling are regulated by hypoxia/TET. Figure S18: The levels of 5hmC and the bindings of TET proteins at pluripotent loci upon hypoxia. Figure S19: The landscape for 5hmC level and TET proteins binding on pluripotent loci upon hypoxia.

To compare the treatment outcome and severe late adverse effects (AEs) between conventional volume and dose (CVD) and simultaneously reduced volume and dose (SRVD) of clinical target volume treatments in patients with nasopharyngeal carcinoma.This retrospective cohort study enrolled patients with nonmetastatic stage II to IV nasopharyngeal cancer from a single institute. Survival endpoints and severe (≥grade 3) late AEs and comorbidity were compared between groups. The correlation of severe late AEs, comorbidity, and overall survival (OS) were evaluated using Kaplan-Meier and Cox regression methods.From January 2012 to June 2017, this study enrolled 178 patients, 64 in the CVD group and 114 in the SRVD group. The 2 groups did not differ significantly in patient characteristics except for mean follow-up time (37.6 vs 48.8 months; P = .01). The SRVD group did not significantly differ from the CVD group in local control survival (82.0% vs 78.4%; P = .85), regional control survival (89.9% vs 86.0%; P = .62), or disease-free survival (76.4% vs 66.9%; P = .67). The SRVD group had significantly better OS (93.9% vs 67.0%; P.001) and salvage survival (79.3% vs 20.7%; P.01) and a significantly lower ratio of severe lung infection (1 of 113 vs 5 of 59; P = .02). The SRVD group had a significantly lower risk of mortality (hazard ratio [HR], 0.3; P = .03). The factors associated with a significantly higher risk of mortality were N3 (regional lymph node stage status of N3) (HR, 3.0; P = .02); comorbidities of diabetes, coronary artery disease, or chronic kidney disease (grades 2-3) (HR, 3.8; P = .009), and severe lung infection (HR, 6.3; P = .007).Simultaneously reduced volume and dose of clinical target volumes did not impair locoregional control or disease-free survival. The benefits of SRVD treatment may include significant reduction in severe late AEs, particularly lung infection, dysphagia, and xerostomia. However, additional studies with longer patient follow-up are required to confirm these benefits.

In-laboratory, polysomnography (PSG) is the gold standard for diagnosing obstructive sleep apnea syndrome (OSAS). However, the long waiting list and sleeping at a hospital make patients hesitate to undergo the examination, thereby delaying diagnosis. During coronavirus disease 2019 (COVID-19) pandemic, sleep labs are almost closed, and the delay is worsening. The home sleep test (HST) enables subjects to be tested at home, a familiar and comfortable environment, without a long waiting list. This study assessed the accuracy of a type III HST in diagnosing OSAS in the Taiwanese population and identified factors affecting the diagnostic accuracy.This retrospective study included 67 patients with clinically suspected OSAS. All patients were allocated to receive both PSG and the HST. The apnea-hypopnea index (AHI) measured through PSG was used as the standard. The sensitivity, specificity, and accuracy of the HST in diagnosing and evaluating the severity of OSAS were analyzed.Among the 67 patients, no significant difference was noted in the average AHI values obtained using PSG and the HST ( p = 0.103). The AHI obtained from HST was significantly correlated with that obtained from PSG, with the correlation coefficient being 0.779 ( p0.001). The sensitivity, specificity, and accuracy of the HST in diagnosing OSAS were 94.9%, 62.5%, and 91.0%, respectively, and 80.0%, 74.1%, and 77.6% in diagnosing moderate to severe OSAS. Furthermore, the difference in AHIs measured using the two tests were positively correlated with the severity of sleep apnea.The HST used in preliminary screening of patients with suspected OSAS achieved an accuracy of90%. For patients with moderate to severe OSAS, the accuracy was below 80%. Therefore, for patients who receive an OSAS diagnosis through the HST, arrangement of PSG is recommended for determining the severity of the OSAS and giving proper treatment.

Warthin tumor with ulceration of the surrounding skin is extremely rare, making it difficult to differentiate from parotid cancer in the clinical setting. We report a 65-year-old man with a Warthin tumor in the right parotid gland that had ulceration of the overlying skin. The patient presented with right upper neck mass 2 years ago. Ultrasound and fine needle aspiration were done, and Warthin tumor was suspected. One year later, the mass was enlarged with ulceration of the skin. Superficial parotidectomy with fusiform excision of the skin was performed, and histopathological diagnosis revealed a Warthin tumor with inflammatory change. We proposed that this unique manifestation may have been induced by fine needle aspiration, enlargement of the tumor, and ischemic changes secondary to pulmonary arteriovenous malformations.

BACKGROUND Although the effect of induction chemotherapy (IC) is still controversial in cancers of the oral cavity, the oropharynx, and the sinonasal tract, it is still used in some inoperable cases and for organ preservation in laryngeal or hypopharyngeal cancers. Taxane has played a greater role and produces a better overall response but a higher rate of acute toxicity. We investigated the response and risk of IC with docetaxel-combined regimens in advanced head and neck cancers. METHODS We retrospectively reviewed the medical history of patients with advanced head and neck cancer between 2011 and 2017. We enrolled 40 patients who completed the initial tumor survey, ICs with docetaxel-combined regimens, and definite therapeutic strategies including concurrent chemoradiation or surgery. The demographic data, laboratory results, overall response, and acute toxicity were analyzed. RESULTS There were 14 patients (35.0%) with partial response at least. There were 24 (60.0%) with at least one acute toxicity beyond grade III. Univariate analysis and multivariate linear regression analysis showed that a platelet-lymphocyte ratio (PLR)

Background Amyloidosis is a rare and variable disease, characterized by extracellular deposits of amyloid protein in different tissues and organs. Patients may present with a range of symptoms, depending on the extent of involvement. Rapid, accurate diagnosis is still challenging in clinical practice. Case report A 72-y-old woman presented with a 1-y history of droopy upper left eyelid, resulting in decreased visual acuity, and progressive tongue swelling, resulting in dysarthria, dysphagia, and sleep apnea. Physical examination revealed puffy eyes, moderate swelling up to 1 cm of the upper left eyelid, swollen submental region, and protrusion of the tongue, causing an inability to close the mouth. An abnormal serum free light chain ratio implied the presence of monoclonal gammopathies, and Congo red staining revealed amyloid deposits in specimens from both the tongue and left eyelid. Therefore, a diagnosis of systemic light-chain (AL) amyloidosis was confirmed. The patient then received oral melphalan therapy and surgical intervention for macroglossia. Clinical symptoms including dysarthria, dysphagia, and sleep apnea were under control at 6-month follow-up. Conclusions We report an uncommon case presenting initially with both ptosis and macroglossia, for which a final diagnosis of systemic AL amyloidosis was made. Detailed history and laboratory investigation must be implemented on suspicion of amyloidosis, because early recognition of amyloid-associated diseases and appropriate treatment can improve clinical outcomes.

The tumor microenvironment (TME) plays a crucial role in tumor progression. One of its key stromal components, cancer-associated fibroblasts (CAFs), may crosstalk with cancer cells by secreting certain cytokines or chemokines. However, which important mediator(s) are released by CAFs, and the underlying molecular mechanism, remain largely unknown. In the present study, we isolated patient-derived CAFs and normal fibroblasts (NFs). Using microarray analysis, we detected chemokine ligand 11 (CCL11) overexpression in CAFs compared to NFs. CCL11 administration promoted the migration and invasion of head and neck cancer (HNC) cells with enhanced cancer stem cell-like properties and induction of epithelial-to-mesenchymal transition. Furthermore, neutralization of CCL11 activity reversed the aggressive phenotype of CAF-induced cancer cells. Confocal microscopy showed colocalization of CCL11 and CC chemokine receptor 3 (CCR3) on HNC cells. Moreover, immunohistochemical analysis of clinical samples from 104 patients with HNC showed that expression of CCL11 and CCR3 were significantly correlated with poor overall survival (p = 0.003 and 0.044, respectively). Collectively, CCL11 expressed on CAFs promotes HNC invasiveness, and neutralization of CCL11 reverses this effect. We propose that the CCL11/CCR3 signaling circuit is a potential target for optimizing therapeutic strategies against HNC.

Background: The development of a hyperglycemic crisis in platinum-based chemotherapy-treated head and neck cancer patients, such as hyperosmolar hyperglycemic state (HHS), has been reported. Hyperglycemic crises are associated with a high risk of comorbidity and may delay cancer treatment if not promptly managed. Methods: This is a retrospective study using cancer registry data from a tertiary medical center. Head and neck cancer patients who had been treated with platinum-based chemotherapy from January 2014 to December 2015 were enrolled for review. Exclusion criteria included patients with a known history of type 2 diabetes mellitus (DM). Characteristics of patients who developed type 2 DM after initiation of chemotherapy were compared with non-DM patients, following which the clinical course of the patients developing a hyperglycemic crisis were reviewed. Results: A total of 185 patients were enrolled, of which seven patients (3.8%) had developed type 2 DM after initiation of platinum-based chemotherapy. No statistically significant differences in age, body mass index, sex, cancer subsite, cancer stage, or chemotherapy regimen were found when comparing new-onset type 2 DM patients with the rest of the patients. Three patients developed diabetic ketoacidosis, HHS, or impending HHS after initiating chemotherapy treatment. The incidence of hyperglycemic crises was 3 out of 185 (1.6%) in this patient group. Conclusion: Hyperglycemic crisis after cisplatin may be underestimated and may lead to a life-threatening condition. We suggest regular weekly follow-ups of serum glucose level after platinum-based chemotherapy for early detection of hyperglycemia and prevention of a life-threatening crisis. Keywords: Diabetic ketoacidosis, Hyperglycemia, Hyperglycemic hyperosmolar nonketotic coma, Platinum, Squamous cell carcinoma

Background 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (18F-FDG PET) has the potential to detect various types of cancers, including thyroid cancer (TC), at a potentially curable stage. Increased uptake of 18F-FDG was observed in anaplastic and poorly differentiated thyroid cancer cells, and PET-positive tumors are more likely to be resistant to 131I treatment. As cancer stem cells (CSCs) possess a dedifferentiated phenotype and are resistant to many anticancer therapies, we hypothesized that the expression of CSC-related markers is correlated with the ability of tumor cells in TC to uptake FDG. Methods The present study cohort included 12 patients with TC, who underwent 18F-FDG PET/CT imaging before surgery. Quantitative polymerase chain reaction (QPCR) and immunohistochemical (IHC) staining were performed to analyze the expression patterns of gene markers related to embryonic stem (ES) cells and CSCs in TC. Results The mRNA expression levels of CSC- (CD133 and CD44) and ES-related genes (Oct4 and Nanog) were higher in TC tissue than in normal thyroid tissue, whereas the mRNA expression levels of thyroid-specific genes (Tg, TSHR, and TTF1) were higher in normal thyroid tissue than in TC tissue. There was a positive and statistically significant correlation between FDG uptake (SUV max ) of tumor and relative mRNA levels of CD133, CD44, Oct4, and Nanog. The IHC results demonstrated that CD133 and Nanog were expressed in TC tissue but not in normal thyroid tissue, however, CD44 expression was observed in both TC and normal thyroid tissue. Comparisons of the clinicopathological parameters between TC tissues with low and high SUV max demonstrated significant differences in protein level of CD133 but not in that of Nanog. Conclusions The pre-therapeutic tumor SUV max obtained from 18F-FDG PET/CT may be a potential predictor for evaluating the proportion of CSC population in individual patients with TC.

Surgical site infections (SSIs) are associated with considerable medical expenditure. While head and neck free flap reconstruction has gradually become routine management following an ablative oncologic resection, reports on factors contributing to the SSIs are lacking. We retrospectively analyzed 173 new patients with oral cancer without any antecedent treatment at a tertiary medical center from 2010 to 2015. We determined incidence rates of SSIs within 30 days postoperatively and identified independent risk factors using multivariate logistic regression analysis. Of 173 patients, 67 (38.7%) had SSIs. Multivariate analysis demonstrated operative time [odds ratio (OR) = 1.199, 95% confidence interval (CI) = 1.036–1.389], mandibulectomy (OR = 2.759; 95% CI = 1.245–6.111), and oro-neck communication (OR = 5.358; 95% CI = 2.150–13.355) as independent predictors for SSIs. For patients with oral cancer undergoing free tissue reconstruction, mandibulectomy, oro-neck communication, and prolonged operative time were associated with increased incidence of SSIs.

OBJECTIVE To reconstruct extensive head and neck defects usually necessitates double free flaps, which require a time-and-manpower-consuming surgical procedure. We present using a single fibula or peroneal flap with the novel design of obliquely-arranged double skin paddles to reconstruct an extensive head and neck defect. METHODS From 1998 to 2016, eight patients with the age of 52.25 (35-71) years old had extensive head and neck defects after oral cancer ablation. All of the defects were through and through with the size of 16.25 (12-24) cm × 8.8 (4.5-11) cm. Six of the defects were due to buccal cancer. One was due to tongue cancer, and another one was due to gingiva cancer. All the defects were reconstructed with obliquely-arranged double-paddle free fibula or peroneal flaps. The long axis of the skin paddles was arranged at certain angle (30-45 degrees) to the long axis of lower leg, and the two separate skin paddles were used as the form of island flaps by isolating the cutaneous perforators to create a true chimeric flap. RESULTS The skin paddle sizes were 14 cm × 3 cm-24 cm × 11 cm and 9.5 cm × 4.5 cm-13 cm × 8 cm. The average length of harvested fibula was 19 (10-30) cm. All of the eight flaps survived without obvious donor site morbidity. One patient had partial skin necrosis over recipient site, requiring surgical debridements and closure. One patient had superficial necrosis over the edge of outer skin paddle, which healed spontaneously. After the follow-up periods of 1 month to 3 year and 8 months, two patients died of sepsis. Six of them could resume soft diet and had no saliva drooling. The remaining two remained nasogastric diet and had saliva drooling. CONCLUSION With the design of obliquely-arranged double paddles, we may maximize the harvested skin area of lateral lower leg to reconstruct an extensive head and neck defect with a single free flap.

Introduction Today, reconstructive surgeons offer an array of options to reconstruct the lip defects. Herein we present our experience of using free double-paddle peroneal flaps for extensive lip defect reconstruction. Patients and Methods From 1996 to 2014, 16 patients with extensive lip defects after tumor ablation were included. Free double-paddle peroneal flaps were used for reconstructions. In terms of flap design, one skin paddle superiorly placed on the lateral lower leg was used to reconstruct intraoral defects, whereas the other was inferiorly located and was used to reconstruct extraoral defects. A part of the inner skin paddle was everted, and the suture line with the outer skin paddle became the new vermilion border. A portion of the outer skin paddle could be de-epithelized and tucked into the fold of the inner skin paddle, leading to greater fullness of the new lip. Results Skin paddle sizes were 10–15 cm × 3–13 cm and 4–10.5 cm × 2.5–10.5 cm. Venous thrombosis occurred in one patient but was salvaged, and one flap had superficial necrosis over the outer paddle that was conservatively treated. In the 0.5–33 month follow-up period, all patients were able to close their mouths without obvious drooling. Conclusion Free double-paddle peroneal flap transfer could augment lip definition, deepen the labial vestibule, and provide an acute-angle oral commissure, leading to satisfactory oral competency and improved cosmetic results. Therefore, this technique may be considered a viable option for extensive lip defect reconstruction.

BACKGROUND Hearing impairment is the most frequent sensory deficit in humans, affecting more than 360 million people worldwide. In fact, hearing impairment is not merely a health problem, but it also has a great impact on the educational performance, economic income, and quality of life. Hearing impairment is therefore an important social concern. OBJECTIVE We aimed to evaluate and compare the accuracy of self-perception, Hearing Handicap Inventory for the Elderly-Screening (HHIE-S) questionnaire, free-field voice test, and smartphone-based audiometry as tests for screening moderate hearing impairment in older adults in China. METHODS In this study, 41 patients were recruited through a single otology practice. All patients were older than 65 years. Patients with otorrhea and cognitive impairment were excluded. Moderate hearing impairment was defined as mean hearing thresholds at 500, 1000, 2000, and 4000 Hz >40 dB hearing loss (pure-tone average > 40 dB hearing loss). All patients completed 5 hearing tests, namely, the self-perception test, HHIE-S questionnaire test, free-field voice test, smartphone-based audiometry test, and standard pure-tone audiometry by the same audiologist. We compared the results of these tests to the standard audiogram in the better-hearing ear. RESULTS The sensitivity and the specificity of the self-perception test were 0.58 (95% CI 0.29-0.84) and 0.34 (95% CI 0.19-0.54), respectively. The sensitivity and the specificity of the HHIE-S questionnaire test were 0.67 (95% CI 0.35-0.89) and 0.31 (95% CI 0.316-0.51), respectively. The sensitivity and the specificity of the free-field voice test were 0.83 (95% CI 0.51-0.97) and 0.41 (95% CI 0.24-0.61), respectively. The sensitivity and the specificity of the smartphone-based audiometry test were 0.92 (95% CI 0.60-0.99) and 0.76 (95% CI 0.56-0.89), respectively. Smartphone-based audiometry correctly diagnosed the presence of hearing loss with high sensitivity and high specificity. CONCLUSIONS Smartphone-based audiometry may be a dependable screening test to rule out moderate hearing impairment in the older population.

Background: In nasopharyngeal carcinoma (NPC), the cut-off value of cumulative cisplatin dose (CCD) associated with survival benefits remains controversial. This study aimed to determine a CCD cut-off value for favorable survival outcomes and to identify specific patient groups benefitting from higher CCDs. Methods: We retrospectively reviewed the records of 161 patients (male-to-female ratio of 2.6:1.0) with NPC receiving concurrent chemoradiotherapy ± adjuvant chemotherapy (AC) from February 2006 through September 2015 at our referral center. The CCD was calculated for each patient, and 3-year locoregional-free survival (LRFS), distant-metastasis free survival (DMFS), disease-specific survival (DSS), and overall survival (OS) were analyzed using a multivariable Cox regression model. Results: Stage N3 patients and stage IV patients had lower DMFS, DSS, and OS. A CCD ≥ 200 mg/m 2 or AC was not associated with survival benefits. After adjusting for other factors, N3 status remained robustly correlated with DMFS ( p < 0.001) and DSS ( p = 0.001). In subgroup analyses, stage N3 patients treated with CCD ≥ 200 mg/m 2 exhibited evident trends toward higher OS (one-sided p = 0.062), DSS (one-sided p = 0.100), DMFS (one-sided p = 0.059), and LRFS (one-sided p = 0.059) than patients treated with CCD < 200 mg/m 2 . Conclusions: A CCD ≥ 200 mg/m 2 might result in better survival outcomes in stage N3 patients. Larger CCDs may be exclusively used in cases of regionally advanced disease to avoid rigorous toxicity.

Background Malignant tumors of the lacrimal gland and lacrimal sac are rare entities, and their incidence has been decreasing. In this study, the incidence trend was examined in relation to patient demographics of these rare tumors. Methods In patient data obtained from the NCI Surveillance Epidemiology and End Results (SEER) database, International Classification of Diseases for Oncology, third edition (ICD-O-3) codes for lacrimal gland and lacrimal sac tumors (C69.5) were used to identify patients with the aforementioned malignancies. Demographic data, tumor size, treatment, and outcomes were analyzed. Tumor–node–metastasis (TNM) staging subgroup analysis was conducted for patients who had received AJCC 6th edition staging at diagnosis. The trend of the incidence rate was calculated per 100,000 person-years by using the joinpoint analysis and age adjusted to the 2000 US standard population (single ages-census P25-1130). All tests of statistical significance were two-tailed, and p-value of

// Ting-Ying Fu 1, 2, * , Chao-Nan Wu 3, 4, * , Huei-Cin Sie 1 , Jiin-Tsuey Cheng 5 , Yaoh-Shiang Lin 6 , Huei-Han Liou 7 , Yu-Kai Tseng 8, 9 , Chih-Wen Shu 7 , Kuo-Wang Tsai 7, 10 , Leing-Ming Yen 1 , Hui-Wen Tseng 11, 12 , Ching-Jiunn Tseng 7, 13, 14, 15 , Luo-Ping Ger 7, 16 , Pei-Feng Liu 7, 17 1 Department of Pathology and Laboratory Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan 2 Department of Optometry, Shu-Zen Junior College of Medicine and Management, Kaohsiung, Taiwan 3 Department of Stomatology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan 4 Department of Dental Technology, Shu-Zen Junior College of Medicine and Management, Kaohsiung, Taiwan 5 Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan 6 Department of Otorhinolaryngology-Head & Neck Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan 7 Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan 8 Department of Orthopedics, Show Chwan Memorial Hospital, Changhua, Taiwan 9 Department of Orthopedics, National Cheng Kung University Hospital, Tainan, Taiwan 10 Department of Chemical Biology, National Pingtung University of Education, Pingtung, Taiwan 11 Department of Dermatology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan 12 Department of Nursing, Meiho University, Pingtung, Taiwan 13 Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan 14 Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan 15 Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan 16 Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan 17 Department of Biotechnology, Fooyin University, Kaohsiung, Taiwan * These authors have contributed equally to this work Correspondence to: Luo-Ping Ger, email: lpger@vghks.gov.tw Pei-Feng Liu, email: pfliu@vghks.gov.tw Keywords: DDX60, oral cancer, subsite-specific, tumorigenesis, prognosis Received: April 14, 2016 Accepted: October 28, 2016 Published: November 08, 2016 ABSTRACT The clinical significance and biological function of DEXD/H box helicase 60 (DDX60) in oral cancer remains unknown. Herein, we evaluated the association of DDX60 expression with tumorigenesis and the prognosis of oral squamous cell carcinoma (OSCC). DDX60 expression was examined by immunohistochemistry on tissue microarray slides of 494 OSCC patients, including 180 buccal mucosal SCC (BMSCC), 241 tongue SCC (TSCC), and 73 lip SCC (LSCC) patients. DDX60 expression was significantly increased in all three subsites of OSCC compared to its expression in tumor adjacent normal tissues. However, its association with tumorigenesis was specific to the oral cavity subsite after the stratification of betel quid chewing, smoking, and drinking. Among OSCC patients, higher levels of DDX60 expression were associated with the male gender, a well-differentiated tumor, advanced stage of disease, and a large tumor size with subsite specific features. LSCC patients with high DDX60 expression levels showed shorter disease-specific survival, particularly those with moderately or poorly differentiated tumors. Additionally, TSCC or OSCC patients with high DDX60 expression showed a poor disease-free survival (DFS), particularly those with moderately or poorly differentiated tumors. Therefore, DDX60 is a novel and unfavorable biomarker for tumorigenesis and prognosis of OSCC in a subsite-specific manner.

MicroRNAs (miRs) are a class of small endogenous non-coding RNAs of ~21–24 nucleotides in length. Previous studies have indicated that miR-196b has either an oncogenic or tumor-suppressive function in various types of cancer. However, the biological role of miR-196b in oral squamous cell carcinoma (OSCC) remains unclear. In the present study, the expression levels of miR-196b were examined in oral cancer tissues and corresponding adjacent normal tissues from 69 OSCC patients using stem-loop reverse transcription-quantitative polymerase chain reaction. The results indicated that miR-196b was significantly overexpressed in OSCC tissues compared with the corresponding adjacent normal tissue samples (64 of 69, 92.7%, P

Sinonasal organized hematoma (SNOH) is rarely encountered in clinical practice. The disease demonstrates a high tendency for occurrence in East Asian individuals, and in the majority of cases, is located in the maxillary sinus. The current report presents the case of an 81-year-old female who developed a space-occupying lesion, which masqueraded as a skull base malignancy, following surgery for the treatment of isolated sphenoid sinus aspergilloma. Subsequent endoscopic endonasal surgery confirmed the diagnosis of an OH of the sphenoid sinus. The patient recovered from all neurological deficits within two months, with the exception of the loss of visual perception. Although SNOH presents a diagnostic challenge, when physicians possess knowledge of its typical imaging features, this facilitates the achievement of a correct diagnosis and the prescription of optimal treatment.

A tobacco-specific component, 4-methylnitrosamino-1-3-pyridyl-1-butanone (NNK), is a major risk factor for many cancers. Recent reports have demonstrated that NNK exposure may be associated with tumor progression and chemoresistance in certain cancers. However, the underlying NNK-induced mechanism contributing to the aggressiveness of colorectal cancer (CRC) has not been thoroughly studied. In this study, we used HT29 cells treated with NNK to simulate the long-term exposure of cigarette smoke. A comparative analysis was performed to evaluate cell proliferation, migration, and invasion as well as epithelial-mesenchymal transition (EMT) markers and drug-resistance genes expression, cancer stem cell (CSC) properties, and anti-apoptotic activity. Signaling pathways related to chemoresistance were also investigated. As a result, NNK exposure dose-dependently stimulates cell proliferation, enhance abilities of migration and invasion, induce EMT phenomenon, and attenuate apoptosis. Furthermore, NNK exposure also promotes the capabilities of sphere formation, upregulation of Snail, and overexpression of CD133, Nanog, OCT4, and the drug-resistant genes. Knockdown of Snail results in upregulation of Raf kinase inhibitor protein (RKIP), increased apoptosis, reversal of EMT phenomenon, and reducation of expression of CSC markers, all of which contribute to a decrease of chemoresistance. Our study demonstrates a number of related mechanisms that mediate the effect of NNK exposure on increasing CRC therapeutic resistance via the Snail signaling pathway. Targeting Snail may provide a feasible strategy for the treatment of CRC.

// Chia-Lin Liu 1 , Su-Feng Chen 2, * , Min-Zu Wu 3 , Shu-Wen Jao 4 , Yaoh-Shiang Lin 5 , Chin-Yuh Yang 6 , Tsai-Yu Lee 4 , Lian-Wu Wen 7 , Guo-Lun Lan 7 , Shin Nieh 1, 7, * 1 Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan 2 Department of Dental Hygiene, China Medical University, Taichung, Taiwan 3 Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA 4 Institute of Environmental and Occupational Health Sciences, School of Medicine & Division of Colon and Rectum Surgery, Department of Surgery, National Yang-Ming University & National Defense Medical Center, Tri-Service General Hospital Songshan Branch, Taipei, Taiwan 5 Department of Otolaryngology-Head and Neck Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan 6 Department of Dentistry, Cheng Hsin Hospital & Taipei Medical University, Taipei, Taiwan 7 Department of Pathology, National Defense Medical Center & Tri-Service General Hospital, Taipei, Taiwan * These authors have contributed equally to this work Correspondence to: Shin Nieh, e-mail: niehshin1014@yahoo.com.tw Su-Feng Chen, e-mail: su374065@gmail.com Keywords: cisplatin-based chemotherapy, drug-resistant sphere, lung cancer, heat shock protein 27, treatment strategy Received: November 17, 2015 Accepted: January 29, 2016 Published: February 10, 2016 ABSTRACT Treatment failure followed by relapse and metastasis in patients with non-small cell lung cancer is often the result of acquired resistance to cisplatin-based chemotherapy. A cancer stem cell (CSC)-mediated anti-apoptotic phenomenon is responsible for the development of drug resistance. The underlying molecular mechanism related to cisplatin resistance is still controversial, and a new strategy is needed to counteract cisplatin resistance. We used a nonadhesive culture system to generate drug-resistant spheres (DRSPs) derived from cisplatin-resistant H23 lung cancer cells. The expressions of drug-resistance genes, properties of CSCs, and markers of anti-apoptotic proteins were compared between control cells and DRSPs. DRSPs exhibited upregulation of cisplatin resistance-related genes. Gradual morphological alterations showing epithelial-to-mesenchymal transition phenomenon and increased invasion and migration abilities were seen during induction of DRSPs. Compared with control cells, DRSPs displayed increased CSC and anti-apoptotic properties, greater resistance to cisplatin, and overexpression of p-Hsp27 via activation of p38 MAPK signaling. Knockdown of Hsp27 or p38 decreased cisplatin resistance and increased apoptosis in DRSPs. Clinical studies confirmed that the expression of p-Hsp27 was closely associated with prognosis. Overexpression of p-Hsp27 was usually detected in advanced-stage patients with lung cancer and indicated short survival. Summary: DRSPs were useful for investigating drug resistance and may provide a practical model for studying the crucial role of p-Hsp27 in the p38 MAPK–Hsp27 axis in CSC-mediated cisplatin resistance. Targeting this axis using siRNA Hsp27 may provide a treatment strategy to improve prognosis and prolong survival in lung cancer patients.

OBJECTIVE This study aimed to determine the impact or survival of low skeletal muscle mass (SMM) among patients with oral squamous cell carcinoma (OSCC) undergoing primary surgery. DESIGN This study was a retrospective cohort study. SETTING Oral squamous cell carcinoma patients treated at our referral centre from April 2005 to March 2014 were examined. PARTICIPANTS The cohort comprised 276 patients with OSCC undergoing primary surgery. MAIN OUTCOME MEASURES Estimated SMM was measured by calculating the cervical skeletal muscle mass from a CT scan of the head and neck. The 5-year overall survival (OS) and disease-specific survival (DSS) were analysed using a multivariable Cox regression model. RESULTS There were 276 patients with a male-to-female ratio of 12:1. A low SMM (

OBJECTIVE We examined whether dynamic margin criteria margin-to-thickness (MTR) ratio has superior predictive value compared with the resection margin or tumour thickness alone in the survival outcome in oral squamous cell carcinoma (OSCC). DESIGN This is a retrospective cohort study. SETTING Oral squamous cell carcinoma patients treated in Kaohsiung Veterans General Hospital Cancer Center between January 2006 and December 2013. PARTICIPANTS A cohort of 302 patients with OSCC who had undergone surgical management. MAIN OUTCOMES MEASURES Log MTR was calculated for each patient, and survival data were analysed using a multivariable Cox regression model. Discriminative analysis was performed using chi-square, Akaike information criterion (AIC) and Harrell's C tests. RESULTS After assessing for discriminative ability, the linear trend of log MTR surpassed those of resection margin and tumour thickness in chi-square, AIC and Harrell's C tests for the advanced pathologic T (pT) category. A multivariate Cox proportional hazard regression model revealed that log MTR

Background Recent studies suggest that long-term exposure of the carcinogen 4-methylnitrosamino-1–3-pyridyl-1-butanone (NNK) found in tobacco smoke is involved in the progression of head and neck squamous cell carcinoma (HNSCC). The underlying nicotine-mediated mechanism remains unclear. Methods An analysis of SCC-25 and Fadu cells with or without NNK exposure focusing on the evaluation of migration and invasion abilities, the expression of epithelial–mesenchymal transition, drug-resistance-related genes, properties of cancer stem cells (CSCs), and anti-apoptosis was performed. Results Long-term NNK exposure enhances migration and invasion with morphological alterations in a dose-dependently manner. Furthermore, NNK exposure also upregulates Snail, promotes sphere-forming ability, and overexpresses aldehyde dehydrogenase 1 (ALDH1), Nanog, OCT4, ABCG2, and MDR1. Conclusion The current study confirmed that long-term NNK exposure plays a role in HNSCC by increasing anti-apoptosis and therapeutic resistance via the Snail-RKIP signaling pathway. Our data also suggest that α7 nicotinic acetylcholine receptor (α7-nAChR) inhibition or targeting Snail may provide a feasible rationale for preventing the progression of HNSCC. © 2015 Wiley Periodicals, Inc. Head Neck 37: 1712–1721, 2015

The vascular anatomy of submental flaps (SFs) represents a determining factor in successful SF raising. However, little attention has been focused on the venous return of SFs. Thus, the present study aimed to investigate SF venous return. This study enrolled patients who underwent SF reconstructive surgery in a tertiary referral center between November 2009 and October 2016. The drainage pathway of the SF venous return was routinely identified during the course of our operations to prevent damage during head and neck surgery. The venous return data of 70 patients were reviewed. The size of the flaps ranged from 15 to 84 cm2, and total flap loss was not observed in the case series. All of the submental arteries originated from the facial artery; however, the submental veins of 70 patients returned to either the internal jugular vein (IJV, 72.9%) or the external jugular vein (EJV, 27.1%). Our data suggest that drainage of the submental vein into the EJV, which has been previously overlooked, should receive greater attention during SF surgeries. The results support mandatory preservation of the EJV and IJV and indicate that vascular anatomy is a determining factor for successful SF raising.

Yu-Hsuan Lin,1 Kuo-Ping Chang,2 Yaoh-Shiang Lin,2,3 Ting-Shou Chang2–4 1Department of Otolaryngology, Head and Neck Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 2Department of Otolaryngology, Head and Neck Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, 3Department of Otolaryngology, Head and Neck Surgery, National Defense Medical Center, Taipei, 4Institute of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China Background: Increased cancer-related inflammation has been associated with unfavorable clinical outcomes. The combination of platelet count and neutrophil–lymphocyte ratio (COP-NLR) has related outcomes in several cancers, except for nasopharyngeal carcinoma (NPC). This study evaluated the prognostic value of COP-NLR in predicting outcome in NPC patients treated with intensity-modulated radiotherapy (IMRT).Materials and methods: We analyzed the data collected from 232 NPC patients. Pretreatment total platelet counts, neutrophil–lymphocyte ratio (NLR), and COP-NLR score were evaluated as potential predictors. Optimal cutoff values for NLR and platelets were determined using receiver operating curve. Patients with both elevated NLR (>3) and platelet counts (>300×109/L) were assigned a COP-NLR score of 2; those with one elevated or no elevated value were assigned a COP-NLR a score of 1 or 0. Cox proportional hazards model was used to test the association of these factors and relevant 3-year survivals.Results: Patients (COP-NLR scores 1 and 2=85; score 0=147) were followed up for 55.19months. Univariate analysis showed no association between pretreatment NLR >2.23 and platelet counts >290.5×109/L and worse outcomes. Multivariate analysis revealed that those with COP-NLR scores of 0 had better 3-year disease-specific survival (P=0.02), overall survival (P=0.024), locoregional relapse-free survival (P=0.004), and distant metastasis-free survival (P=0.046). Further subgrouping by tumor stage also revealed COP-NLR to be an unfavorable prognostic indicator of 3-year failure-free survival (P=0.001) for locally advanced NPC.Conclusion: COP-NLR score, but not NLR alone or total platelet count alone, predicted survival in NPC patients treated with IMRT-based therapy, especially those with stage III/IVA, B malignancies. Keywords: nasopharyngeal carcinoma, intensity-modulated radiotherapy, inflammation-based marker, combination of platelet count and neutrophil–lymphocyte ratio, prognosis

Background For large tongue defects, reconstructive surgeons have devised a variety of feasible options, such as radial forearm free flap and anterolateral thigh (ALT) flap. In our institution, peroneal flap has been the workhorse flap for the soft tissue defect in head and neck reconstruction. We present our experience using peroneal flap in tongue reconstruction. Patients and Methods The study included 47 patients who had undergone tongue reconstructions with peroneal flaps after tumor resection. The size and location of the defect after tumor resection determined whether the peroneal flaps could be harvested as pure septocutaneous flaps to solely reconstruct the neotongue or to carry an additional muscle bulk to fill the adjacent defect. Retrospective chart review was used to look for postoperative complications and to perform functional assessments (which were also performed through telephone inquiry). Results Of the 47 patients, 3 (6%) had flap failure and 1 (2.1%) had partial flap necrosis. The hemiglossectomy group had better results than the total glossectomy group with respect to speech and diet, but neither of these results reached statistical significance (p = 1.0 for speech and p = 0.06 for diet). The results of the subtotal glossectomy group were better than those of the total glossectomy group with respect to diet (p = 0.03). No statistically significant differences were noted among the three groups with respect to cosmetic aspect (p = 0.64). Conclusions Considering its reasonable postoperative complication rates and functional results, peroneal flap can be considered a feasible option for tongue reconstruction.

The mechanisms by which hypoxic tumours evade immunological pressure and anti-tumour immunity remain elusive. Here, we report that two hypoxia-responsive microRNAs, miR-25 and miR-93, are important for establishing an immunosuppressive tumour microenvironment by downregulating expression of the DNA sensor cGAS. Mechanistically, miR-25/93 targets NCOA3, an epigenetic factor that maintains basal levels of cGAS expression, leading to repression of cGAS during hypoxia. This allows hypoxic tumour cells to escape immunological responses induced by damage-associated molecular pattern molecules, specifically the release of mitochondrial DNA. Moreover, restoring cGAS expression results in an anti-tumour immune response. Clinically, decreased levels of cGAS are associated with poor prognosis for patients with breast cancer harbouring high levels of miR-25/93. Together, these data suggest that inactivation of the cGAS pathway plays a critical role in tumour progression, and reveal a direct link between hypoxia-responsive miRNAs and adaptive immune responses to the hypoxic tumour microenvironment, thus unveiling potential new therapeutic strategies.

OBJECTIVES Monitoring the viability of buried free flaps in hypopharyngeal reconstruction is difficult. Various methods have been proposed to monitor these buried flaps, but limitations remain. METHOD We present a method of using double-paddle chimeric peroneal flaps that permanently externalizes a flap skin paddle as a monitoring paddle in hypopharyngeal reconstructions. This study was performed in a medical center in southern Taiwan; between 2013 and 2015, 10 patients underwent double-paddle chimeric peroneal flap reconstruction in advanced stages of hypopharyngeal cancer. We retrospectively reviewed the medical records from these surgeries, searching for either short-term postoperative complications or long-term follow-up morbidity and researched relevant articles for comparisons with other monitoring methods. RESULTS None of the 10 flaps underwent total loss. The rate of stenosis and that of fistula formation was 10%. The average postoperative hospital stay was 39 days. Six of 10 patients were able to resume at least a soft diet after reconstruction, and none of the patients experienced significant complications. CONCLUSIONS The peroneal flap is a useful flap because it is thin and pliable, has minimal donor site morbidity in patients without peripheral vascular disease, and has the potential of multiple skin paddles so that one skin paddle can be used for monitoring the buried flap. Using this method, direct clinical monitoring is feasible, and early detection of vascular complications is possible. Furthermore, the drawbacks of using a monitoring paddle produced by a deepithelialized bridge can be avoided.

Purpose Diabetes mellitus (DM) is a global pandemic metabolic disorder. In recent years, the amount of medical resources required for the treatment of diabetes has increased as diabetes rates have gradually risen. The combined effects of individual and neighbourhood socio-economic status (SES) on DM survival rates are still not clear, especially in patients of working age. In this paper, we aim to analyze the combined effects of neighbourhood and individual SES on DM survival rates in patients of working age in Taiwan. Methods The study of 23,781 people who were diagnosed with DM by using population—based study between 2002 and 2006. Each sample was followed up for 4 years or as a sensor case. We defined Individual SES and neighbourhood SES by each patient’s job category and household income which characterized as advantaged or disadvantaged. Then we compared the survival rates by SES group used Cox proportional hazards model for adjust risk factors. Results The 4-year overall survival rates of diabetic patients were worst for those with low individual SES who living in advantaged neighbourhoods. After adjustment for patient characteristics, DM patients with high individual SES living in disadvantaged neighbourhoods had the same risk of mortality as those patients with high individual SES living in advantaged neighbourhoods (hazard ratio: 1.11; 95% confidence interval [CI]: 0.81–1.51). The study found that DM patients with low individual SES who live in disadvantaged areas had a greater risk of mortality than those with high SES (odds ratio: 2.57; 95% CI: 2.04–3.24). There were significant differences in survival rates between patients with high individual SES and patients with low individual SES. In contrast, the results did not statistically significant differences in survival rates between advantaged and disadvantaged neighbourhood SES groups. Conclusion DM patients with low individual SES had the worst survival rate, regardless of whether they were living in a high or low SES neighbourhood area. The competitive cause of death, i.e., the fact that complications, rather than DM itself, are often the cause of death, may be the reason for the inverse relationship found between the effects of individual SES and neighbourhood SES on DM survival. We conclude that the socio-economic gradient in survival among DM patients may be the result of differences in access to medical treatment and attributes related to individual SES.

We aimed to investigate the association of the expression levels of five epithelial–mesenchymal transition (EMT)-related proteins (Snail, Twist, E-cadherin, N-cadherin, and Vimentin) with tumorigenesis, pathologic parameters and prognosis in tongue squamous cell carcinoma (TSCC) patients by immunohistochemistry of tissue microarray. The expression levels of Snail, E-cadherin, N-cadherin and Vimentin were significantly different between the tumor adjacent normal and tumor tissues. In tumor tissues, lower E-cadherin and higher N-cadherin levels were associated with a higher grade of cell differentiation, advanced stage of disease, and lymph node metastasis. However, higher Vimentin expression was associated with poor cell differentiation and lymph node metastasis. Patients with low E-cadherin expression had poor disease-specific survival (DSS). Conversely, positive N-cadherin and higher Vimentin expression levels were associated with poor DSS and disease-free survival. Notably, our multivariate Cox regression model indicated that high Vimentin expression was an adverse prognostic factor for DSS in TSCC patients, even after the adjustment for cell differentiation, pathological stage, and expression levels of Snail, Twist, E-cadherin, and N-cadherin. Snail, E-cadherin, N-cadherin, and Vimentin were associated with tumorigenesis and pathological outcomes. Among the five EMT-related proteins, Vimentin was a potential prognostic factor for TSCC patients.

Background: This retrospective study was conducted to describe and compare the clinical characteristics of primary mucoceles occurring in patients without a previous history of sinus surgery, the cause of mucoceles and secondary mucoceles resulting as a complication following endoscopic sinus surgery, and the Caldwell-Luc operation. Materials and Methods: This study reviewed 18 cases of primary mucoceles and 21 cases of secondary mucoceles, who were diagnosed and had received surgical intervention between 1995 and 2012. Results: The most common presenting symptoms in primary mucoceles were: Visual disturbance (18.6%), nasal obstruction (12.5%), and headache (12.5%). In secondary mucoceles, the most common symptoms were: Nasal obstruction (27.5%), rhinorrhea (15%), and postnasal drip (12.5%). The most common sites of origin for primary mucoceles were the ethmoid sinus (31.5%) and sphenoid sinus (31.5%). In secondary mucoceles, the maxillary sinus was the most common site of origin (40.7%), followed by the ethmoid sinus (29.6%). All patients with secondary mucoceles had a history of sinus surgery. Conclusions: Mucoceles are benign lesions of the paranasal sinus. Cases of secondary mucoceles that occur following sinus endoscopic surgery develop more frequently in the ethmoid sinus compared to those following the Caldwell-Luc procedure. Endoscopic intranasal surgery of mucoceles is a reliable therapeutic measure with a favorable long-term outcome.

During pharyngeal phase of swallowing, related muscles work together to produce wave-like contractions and to move food into esophageal phase. How the peristaltic contraction of muscles and movement of bolus coordinate can significantly strengthen or weaken one’s swallowing functions. This study uses the spectral moment analysis to investigate the acoustic effects of the peristaltic contraction wave during pharyngeal phase of swallowing. Four spectral moments describe features of the energy spectrum: the first moment (mean, centre of gravity) and the second moment (standard deviation) represent the spectrum's central tendency and dispersion respectively. Skewness and kurtosis (moment 3 and 4 ) represent spectrum's tilt and peak in relation to the central tendency. Results indicate that spectral moment measures may be one acoustic index sensitive to peristaltic contraction properties of swallowing. The statistical interpretation in accord with swallowing evaluation will be discussed.During pharyngeal phase of swallowing, related muscles work together to produce wave-like contractions and to move food into esophageal phase. How the peristaltic contraction of muscles and movement of bolus coordinate can significantly strengthen or weaken one’s swallowing functions. This study uses the spectral moment analysis to investigate the acoustic effects of the peristaltic contraction wave during pharyngeal phase of swallowing. Four spectral moments describe features of the energy spectrum: the first moment (mean, centre of gravity) and the second moment (standard deviation) represent the spectrum's central tendency and dispersion respectively. Skewness and kurtosis (moment 3 and 4 ) represent spectrum's tilt and peak in relation to the central tendency. Results indicate that spectral moment measures may be one acoustic index sensitive to peristaltic contraction properties of swallowing. The statistical interpretation in accord with swallowing evaluation will be discussed.