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// Chih-Chia Yu 1, 2, * , Shih-Kai Hung 2, 3, * , Hon-Yi Lin 2, 3 , Wen-Yen Chiou 2, 3 , Moon-Sing Lee 2, 3 , Hui-Fen Liao 4 , Hsien-Bin Huang 1 , Hsu-Chueh Ho 5 and Yu-Chieh Su 6, 7 1 Department of Life Science and Institute of Molecular Biology, National Chung Cheng University, Chia-Yi, Taiwan, R.O.C 2 Department of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taiwan, R.O.C 3 School of Medicine, Tzu Chi University, Hualian, Taiwan, R.O.C 4 Department of Biochemical Science and Technology, National Chiayi University, Chia-Yi, Taiwan, R.O.C 5 Department of Otolaryngology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taiwan, R.O.C 6 Division of Hematology and Oncology, E-Da Hospital, Kaohsiung, Taiwan 7 School of Medicine, I-Shou University, Kaohsiung, Taiwan, R.O.C * These authors (Chih-Chia Yu and Shih-Kai Hung) contributed equally to this work Correspondence to: Yu-Chieh Su, email: hepatoma@gmail.com Keywords: PI3K/mTOR pathway, radiation, radiosensitization, radioresistant, oral cancer Received: September 23, 2016 Accepted: June 20, 2017 Published: August 02, 2017 ABSTRACT Radiation therapy (RT) is the current standard adjuvant approach for oral squamous cell carcinoma (OSCC) patients. Radioresistance is a major contributor to radiotherapy failure. In this study, we used patient-derived cells and a radiation-resistant cell line in vitro and in vivo for two purposes: evaluate the anti-tumor effects and understand the mechanisms in the dual PI3K/mTOR signaling pathway regulation of radiosensitization. Our findings indicate that in OML1-R cells, the radioresistance phenotype is associated with activation of the PI3K/AKT/mTOR signaling pathway. Compared to a combination of PI3K or mTOR inhibitors and radiation, dual blockade of the PI3K and mTOR kinases significantly improved radiation efficacy in oral cancer and patient-derived OSCC cells. Dual PI3K/mTOR inhibition enhanced the effect of radiation by inhibiting AKT/mTOR signaling pathways and caused G1 phase arrest, which is associated with downregulation of cyclin D1/CDK4 activity, leading to growth inhibition. In nude mice xenografted with radioresistant OML1-R cells, the combined treatment was also more effective than RT alone in reducing tumor growth. This treatment was also demonstrated to be dependent on the inhibition of protein kinase-dependent S6 kinase pathway and eIF4E-mediated cap-dependent translation. These findings indicate that activation of the PI3K/AKT/mTOR signaling pathway has a role in radioresistance of OSCC. We determined that a PI3K/mTOR inhibitor combined with radiation exhibits synergistic inhibition of the AKT/mTOR axis and induces cell cycle arrest. Our results show the therapeutic potential of drugs targeting the PI3K/AKT/mTOR signaling pathway should be new candidate drugs for radiosensitization in radiotherapy.

Determine the extent to which pre-fitting acceptable noise level (ANL), with or without other predictors such as hearing-aid experience, can predict real-world hearing-aid outcomes at three and 12 months post-fitting.ANLs were measured before hearing-aid fitting. Post-fitting outcome was assessed using the international outcome inventory for hearing aids (IOI-HA) and a hearing-aid use questionnaire. Models that predicted outcomes (successful vs. unsuccessful) were built using logistic regression and several machine learning algorithms, and were evaluated using the cross-validation technique.A total of 132 adults with hearing impairment.The prediction accuracy of the models ranged from 61% to 68% (IOI-HA) and from 55% to 61% (hearing-aid use questionnaire). The models performed more poorly in predicting 12-month than three-month outcomes. The ANL cutoff between successful and unsuccessful users was higher for experienced (∼18 dB) than first-time hearing-aid users (∼10 dB), indicating that most experienced users will be predicted as successful users regardless of their ANLs.Pre-fitting ANL is more useful in predicting short-term (three months) hearing-aid outcomes for first-time users, as measured by the IOI-HA. The prediction accuracy was lower than the accuracy reported by some previous research that used a cross-sectional design.

Background:Voriconazole is a broad-spectrum azole exhibiting strong anti-Aspergillus activity and good long-term tolerance. However, the evidence for voriconazole efficacy against refractory Aspergillus otomycosis is weak.Method:We reviewed the medical records of patients with Aspergillus otomycosis treated with voriconazole from January 2008 to June 2012 in a Taiwanese regional hospital. Demographic data and information regarding underlying diseases, clinical features, treatment and outcome were assessed.Results:In total, 14 cases of Aspergillus otomycosis were treated with voriconazole, including 5 patients with Aspergillus invasive otitis externa. All patients had failed to respond to local treatment, antibiotics or topical agents. One case was lost to follow up. The symptoms of two patients recurred after voriconazole treatment: one patient received a second 12-week course of voriconazole and was cured; and symptoms of the other patient recurred after a second 12-week course of voriconazole, leading to surgical debridement. The remaining 11 patients were cured by voriconazole treatment without extensive surgical debridement.Conclusion:This study demonstrates that voriconazole can be a very effective and convenient therapeutic option for the management of refractory Aspergillus otomycosis.

The objective of this prospective study was to investigate the relationship between acceptable noise level (ANL), which was measured using Taiwanese and the international speech test signal (ISTS), and real-world hearing-aid success for listeners who were representative of the population commonly seen in clinics.Unaided ANLs were measured pre-hearing-aid fitting. Hearing-aid success was assessed three months post-fitting using the international outcome inventory for hearing aids (IOI-HA) and a hearing-aid use questionnaire.Eighty adults with hearing impairment completed the study.Both Taiwanese and ISTS ANLs were significantly associated with hearing-aid success, with higher ANLs suggesting poorer outcomes. However, the ANL's prediction accuracy for the probability of hearing-aid success was either much lower than that suggested by some literature, or was not much different from that of simply predicting all listeners as successful users.The current study suggested the possibility of using ANL to predict hearing-aid success. However, the usefulness of ANL as a clinical tool is unlikely to be as great as indicated by the literature.

Acceptable noise level (ANL) determines the maximum noise level that a listener is willing to accept while listening to speech. The objective of this study was to determine the equivalence of ANL measured using different speech stimuli for native speakers who lived in the U.S. and Taiwan.ANLs were measured using English, Mandarin, and the international speech test signal (ISTS) at each site. The same babble noise was used across speech stimuli. The ANLs were considered equivalent if the difference was unlikely to be greater than 3 dB.Thirty adults with normal hearing were recruited at each site.For each site, the equivalence test suggested that the native-language and foreign-language ANLs were equivalent. Between the two sites, ANLs measured using the listener's native language were also equivalent. Although the ISTS ANL obtained within each site was equivalent to, and highly correlated to, the native-language ANL, the data were unable to confirm the equivalence of the ISTS ANLs obtained from the two sites.The results suggested the possibility of directly comparing ANL measures carried out in different countries using different languages. However, it remains unclear if the ISTS can serve as an international ANL stimulus.

Background: The aim of this study was to determine the influence of inflammation on acute phase protein and epithelial-mesenchymal transition (EMT) in buccal cancer. Methods: Western blotting was carried out to investigate the expression of haptoglobin and epithelial-mesenchymal transition in oral cancer cell lines with or without IL-6 stimulation. We studied patients with buccal cancer patients without distant metastasis at diagnosis. Correlation between cellular haptoglobin, EMT, and clinical characteristics of buccal cancer was analyzed to assess the prognostic value of cellular haptoglobin level and EMT. The relationship of haptoglobin, and EMT expression with survival was assessed using Cox proportional hazard models. Results: Western blotting analysis showed that increased haptoglobin protein was associated with overexpression of vimentin. Under IL-6 stimulation, overexpression of haptoglobin, EMT-associated motile phenotype was noted in OC2 cell lines. Overexpression of haptoglobin was also associated with an increased risk for locoregional recurrence [hazard ratio (HR) 1.04; p=0.011] after adjusting for age, gender, disease site, stage, and treatment modality. Conclusions: Increased cellular expression of haptoglobin is associated with EMT in oral cancer cell lines and this phenomenon could be exaggerated with IL-6. Cellular expression of haptoglobin is related to locoregional recurrence rate in buccal cancer patients.

Olfactory neuroblastoma, also known as esthesioneuroblastoma, is a rare malignant head and neck tumor. Olfactory neuroblastoma accounts for approximately 3–5% of all malignant nasal tumors. We present a case of olfactory neuroblastoma in a 61-year-old man who underwent endoscopic surgery followed by postoperative irradiation. Right neck metastasis was diagnosed about 6 months after endoscopic surgery. Supraomohyoid dissection of the right side of the neck was performed, but right parotid metastasis was identified about 3 months later. Boost radiotherapy was applied to the right metastatic parotid. There was no evidence of recurrence on head and neck magnetic resonance imaging and endoscopic examination during the 2-year follow-up.

Summary Background Chemo-radiotherapy-induced carotid stenosis and cerebrovascular events in head and neck cancer patients can cause severe disability and death. We aimed to estimate the risk of stroke in such patients over a six-year follow-up period. Patients and methods The study cohort consisted of head and neck cancer patients ( n = 10,172). Cox proportional hazard model was used to compare the stroke-free survival rate between the patients treated with radiotherapy or chemotherapy, surgery alone, and surgery with adjuvant therapy after adjusting for possible confounding factors. Results At the end of follow-up, 384 patients had strokes: 126 (4.3%) from the surgery alone group, 167 (3.8%) from the radiotherapy or chemotherapy group, and 91 (3.2%) from the surgery with adjuvant therapy ( P = 0.222). Head and neck cancer patients aged less than 55 years treated with radiotherapy or chemotherapy conferred a 1.8-fold higher risk for stroke (95% CI, 1.22–2.56; P = 0.003) after adjusting for patient characteristics, co-morbidities, geographic region, urbanization level, and socio-economic status. There was no statistical difference in stroke risk between different treatment modalities in head and neck cancer patients aged 55 years and more. Conclusions Young head and neck cancer patients treated with radiotherapy or chemotherapy have higher risks for stroke. Different treatment strategies should be considered in such patients.

Patients with oral cancer utilize considerable health care resources, particularly when wide resection of the tumor and reconstruction with pedicle flap/free flap is performed. This study was conducted to explore the relationship between survival rates and surgeon volume. A total of 1256 patients who underwent resections for oral cancer in 2005 were identified from the Taiwan National Health Insurance Research Database. Survival analysis, the Cox proportional regression model, and propensity score were used to evaluate the association between 3-year survival rates and surgeon caseloads. Oral cancer patients treated by high-volume surgeons (caseload 22-117) had better survival rates (hazard ratio [HR]=0.656; 95% confidence interval [CI], 0.484-0.89; P=0.007) using the Cox proportional regression model after adjusting for patients' comorbid conditions, hospital, and surgeon characteristics. When analyzed by propensity score, the adjusted 3-year survival rate was 74% for patients treated by high-volume surgeons compared to 58% in the low/medium-volume group (P=0.019). We concluded that for patients who underwent oral cancer resection and reconstruction, after adjusting for differences in the case mix, high-volume surgeons had better 3-year survival rates. Treatment strategies adopted by high-volume surgeons should be analyzed further and utilized more widely.

The aim of this study is pursue the effect of herbal point-patch treatment on allergic rhinitis patients by investigation of the changes of serum total IgE (T-IgE) and eosinophile cationic protein (ECP) levels and through assessment of the results of SF-36 and rhinitis severity questionnaires. A prospective, randomized, single-blind, parallel, controlled study was used. Forty- three eligible participants were selected from outpatients of the Dept. of Ear, Nose, and Throat and Chinese medicine clinic, and 33 eligible participants completed the treatment satisfactorily. Participants used a Chinese herbal point-patch or a placebo patch once a week, for three hours at a time, after being randomly assigned to a control or an experimental group. Each treatment course was three weeks in duration, and each participant underwent two courses of treatment. Before and after each course, participants evaluated the effectiveness of the treatment by completing a questionnaire, and blood samples were collected for T-IgE and ECP analysis. The data revealed that the acupoint herbal patch is a valuable treatment for allergic rhinitis, especially in the symptoms of sneezing, running and itchy nose. The results of the SF-36 indicate a distinct improvement in GH (general health) and VT (vitality) in patients treated with acupoint herbal patches. This study supports the belief that the acupoint herbal patch is an effective treatment for allergic rhinitis and can significantly improve general health, social life and vitality in quality of life.

Changes in tumor necrosis factor-alpha (TNF-alpha) and soluble interleukin-2 (sIL-2R) levels appear to be closely related to tumor progression and prognosis in nasopharyngeal carcinoma (NPC). Further investigation is suggested.The study examined whether changes in TNF-alpha and sIL-2R in NPC can be used to predict tumor progression and prognosis.The study was carried out in 58 patients with NPC newly diagnosed from December 2003 to December 2006 at a single institution and 60 control subjects of comparable age. Blood levels of TNF-alpha and sIL-2R were monitored before, during, and 3 months and 1 year after treatment.Differences in TNF-alpha level between patients with NPC in all four stages and healthy controls and in sIL-2R level between patients with advanced stage NPC and healthy controls were significant (p0.05). Furthermore, 1 year after completing radiotherapy, levels of TNF-alpha and sIL-2R in patients with recurrent tumors were significantly different from those in patients without recurrence and healthy control subjects.

Objectives To elucidate the effect of primary tumor volume (PTV) on treatment outcomes in patients with nasopharyngeal carcinoma (NPC) who were treated with radiotherapy or concurrent chemoradiotherapy. The TNM staging system developed by American Joint Committee of Cancer (AJCC) is universally used and accepted but its prediction of prognosis in NPC receives a lot of challenge. Primary tumor volume had been reported to have close relationship with prognosis of head and neck cancer. We may predict prognosis of NPC with PTV. Methods From 1999 to 2006, 91 patients with newly diagnosed NPC who were treated with radiotherapy or CCRT were enrolled in the study. Computed tomography-derived or magnetic resonance-derived primary tumor volume was calculated. The correlation between AJCC disease stage, primary tumor volume and disease-specific survival were analyzed. Multivariate analyses using the Cox proportional hazard model was performed. Results The median primary tumor volume for the whole series was 11.39 ml (range 1.25–166.58 ml). The median primary tumor volume was 2.69 ml in T1 disease, 10.14 ml in T2 disease, 15.41 ml in T3 disease, and 26.69 ml in T4 disease. Hazard ratio increased with tumor volume, ranging from 5.91 (95% confidence interval (95% CI) 1.13–26.43) for tumor volumes between 20 ml and 40 ml, and 15.72 (95% CI, 3.82–61.05) for tumor volumes >40 ml. With both tumor volume and T classification in the same Cox regression model, only tumor volume remained statistically significant in the prognosis of NPC. Conclusion Primary tumor volume has closer relationship with survival rates of patients with NPC. Calculation of primary tumor volume may be further considered to improve the current staging system.

Objective To evaluate the auditory brainstem responses (ABRs) in patients with asymmetric hearing loss (ASHL). Methods Data on 245 patients (men = 106; women = 139) with ASHL were gathered, retrospectively. Effects of sex, age, stimulation side, and hearing level on ipsilateral ABRs were carried out by multivariate linear regression. Results Waves III and V latencies were only significantly affected by sex and hearing level but not by age and stimulation side, in patients with ASHL. In addition, wave V latencies were positively correlated with age in men, but not in women; III–V intervals were significantly affected only by sex and age but not by stimulation side or hearing level. Conclusion Effects of clinical factors on ABR were different between patients with ASHL and normal-hearing subjects.

A weekly regimen of cisplatin 30 mg/m2 as concurrent chemoradiation (CCRT) was effective in elderly nasopharyngeal carcinoma (NPC) patients, with acceptable and reversible acute toxicity following CCRT therapy.The purpose of this retrospective study was to evaluate the efficacy, toxicity, and tolerability of a multi-modal treatment strategy in elderly NPC patients. Subsequent systemic adjuvant chemotherapy was administered to achieve systemic control.From December 2002 to December 2006, 26 NPC patients over 60 years of age who had stage IIB to IV NPC were evaluated in this retrospective analysis. The CCRT chemotherapy protocol consisted of eight weekly doses of cisplatin 30 mg/m2 administered in an outpatient setting. Adjuvant systemic chemotherapy consisted of four monthly cycles of cisplatin (20 mg/m2/day) plus 5-fluorouracil (1000 mg/m2/day) for 5 consecutive days. Study end points included treatment outcome, compliance, and toxicity.The 2-year overall survival, disease-free survival, local control, and distant metastasis-free rate were 87%, 73%, 92%, and 76%, respectively. Over 80% of patients were able to take more than six doses of weekly cisplatin during CCRT; however, nearly half of the patients had grade 3 hematological toxicity during adjuvant therapy requiring treatment modification or cessation of further adjuvant therapy.

Objective Several comorbid measures have been developed and demonstrated the predictive ability for cancer mortality. We conducted a retrospective study on oral squamous cell carcinoma (OSCC) patients to compare the Charlson comorbidity index score (CCIS) to the Elixhauser comorbidity index score (ECIS). Methods Newly diagnosed OSCC patients ( n = 232) post major surgery with or without adjuvant therapy were identified from the cancer registry database between 2006 and 2011. Comorbidities present prior to the cancer diagnosis were obtained and adapted to the CCIS and ECIS. The prevalence of comorbid conditions and the influence on disease-specific survival (DSS) rate were calculated and analyzed by Cox regression model. The discriminatory ability of these two comorbid measures was evaluated by using the adjusted hazard ratio and Akaike information criterion (AIC) in a multivariate regression model. The prediction accuracy was assessed using Harrell's c -statistic. Results Most of the patients (93.5%) were male with a mean age of 54 ± 11 years and 77 of them (33.1%) had at least one comorbid condition. The ECIS was associated DSS, with an additional 10% increased risk observed for mortality for each increased score (HR, 1.10; 95% confidence interval [CI], 1.03–1.18) after adjusting with pathological risk features. However, the CCIS was not an independent prognostic factor for these patients. The ECIS increased discriminatory ability but the CCIS did not improve discrimination. Conclusions Comorbid conditions significantly influenced the clinical outcomes of patient with OSCC post major surgery. A higher ECIS was associated with worse disease specific survival indicative of a valuable prognostic indicator. The ECIS may be considered in further clinical trials for a variety of cancers, including head and neck cancers.

Several histopathological characteristics have a significant prognostic impact on recurrence and survival rates in head and neck squamous cell carcinoma (HNSCC). We conducted a retrospective study on patients with HNSCC to compare traditional pathological T (pT) classification to a new T classification system that incorporates these histopathological characteristics. Newly diagnosed patients with HNSCC (n = 349) post major surgery were identified from the cancer registry database between 2004 and 2013. The pT and new T classification systems were compared with respect to recurrence-free survival (RFS), disease-specific survival (DSS), and survival rates using the Cox proportional hazards model with adjustments. The discriminatory ability of these 2 classification systems was evaluated using the adjusted hazard ratio (HR) and Akaike information criterion (AIC) in a multivariate regression model. The prediction accuracy was assessed using Harrell's C-statistic. The new T classification, which incorporated tumor size, extent, and location with histopathological features had better discriminatory ability and monotonicity of gradients than did pT classification. The new T4 classification yielded a higher adjusted HR in RFS (HR, 4.11; 95% confidence interval [CI], 7.75–9.65) and in DSS (HR, 4.39; 95% CI, 1.6–12.03), and a lower AIC in recurrence (927 vs 969) and survival rates (791 vs 833). The new T classification system had better discriminatory ability in RFS and DSS compared with the routinely used American Joint Committee on Cancer (AJCC) pT classification system. Therefore, this new T classification system, which includes tumor size, location, extent, and histopathological features, could be used as an alternative to AJCC pT classification for patients with HNSCC.

Supplemental digital content is available in the text, Recently, log odds of positive lymph nodes (LODDS) was proven a better prediction of outcomes than other methods in gastric cancer, pancreatic cancer, and colon cancer. However, the validity is not yet tested in oral cavity squamous cell carcinoma (OSCC). We conducted a retrospective study to compare the predictive ability of LODDS, traditional pN classification and lymph node ratio (rN) in OSCC patients. In total, 347 OSCC patients receiving surgery with or without adjuvant therapy at the time of diagnosis between 2004 and 2013 were identified from the cancer registry database of the Dalin Tzu Chi Hospital. Cox proportional hazards models were used to compare the disease-specific survival (DSS) rates for pN, rN, and LODDS after adjusting for possible confounding risk factors. The discriminatory ability of different classification systems was evaluated using the adjusted hazard ratio and Akaike information criterion (AIC) by multivariate regression model. The prediction accuracy of the model was assessed by Harrell's c-statistic. The 347 OSCC patients had a mean age of 57 years old. Among them, 322 patients (92.8%) were male and 189 patients (54.5%) were in stages III to IV. LODDS showed better discriminatory ability for patients with

To explore whether monocyte chemotactic protein-1 (MCP1) is associated with the epithelial-mesenchymal transition (EMT) and neck metastases in head and neck cancer (HNC).MCP1 and its related protein were evaluated using western blotting, and a migration assay for HNC cell lines. Thirty-five patients with HNC were recruited for the evaluation of MCP1 expression and pathologically-proven neck metastases from their tissue specimens.MCP1 changed the phenotype of OML-1 cells to a spindle shape, with increased mobility. In OML3 cells, MCP1 knockdown with siRNA blocked EMT. Activation of protein kinase B (AKT) was positively associated with the EMT phenotype, and this transition was abrogated with a phosphoinositide 3 kinase (PI3K) inhibitor. By comparing clinical outcomes, the histological MCP1 score was associated with pathological neck metastases (p=0.027).The overexpression of MCP1 in HNC cells may partially induce EMT through the AKT pathway. A high cellular expression of MCP1 was associated with pathological neck metastases.

Paradoxical vocal cord motion (PVCM) is an unusual cause of stridor, which is associated with some underlying causes, such as central nervous system lesion, gastroesophageal reflux or psychogenic problem. Once a diagnosis of PVCM is made, acute management with reassurance and sedation instead of aggressive airway intervention is required. Speech therapy, psychotherapy combination with anti-reflux medication is considered to be useful in long-term management. We present a 58 year-old male patient who had suffered from several episodes of acute onset of stridor, short of breath and tachypnea since one year ago. He was initially treated as an asthmatic patient with poor response. Aneurysm of ascending aorta by angiography, and mild gastroesophageal reflux with hiatal hernia by panendoscopy were noted. Then, the paradoxical vocal cord motion during inspiration phase was confirmed by flexible fiberoptic nasopharyngoscope after the consultation with an otolaryngologist. The emergency of his air-hunger was relieved quickly after psychological intervention. Now, he is free of stridor attack under anti-reflux therapy and psychotherapy.

Aspergillus invasive otitis externa (IOE) is rare and often occurs in the immunocompromised hosts. An immunocompetent case of Aspergillus IOE complicated by herpes zoster oticus is described in this report. The patient presented with refractory otorrhea and otalgia that continued for a long time after resolution of the herpes zoster oticus. She was successfully treated for 8 weeks with oral voriconazole. To our knowledge, this is the first description of an immunocompetent case of Aspergillus IOE complicated by herpes zoster oticus. Copyright 2011, Buddhist Compassion Relief Tzu Chi Foundation. Published by Elsevier Taiwan LLC. All rights reserved.

Inhibition of mammalian target of rapamycin (mTOR) kinase enhances the radiosensitivity of some cancer cells. We investigated the effect of RAD001, an mTOR inhibitor, on irradiated oral cancer cell lines.Clonogenic assays were performed to determine the radiosensitivity of SCC4 and SCC25 cells after treatment with RAD001. Target protein phosphorylation, apoptosis, and cell-cycle progression were assessed in SCC4 cells treated with RAD001 with and without ionizing radiation.RAD001 increased the radiosensitivity of SCC4 cells without affecting cell death; it also inhibited phosphorylation of mTOR, S6, and factor 4E binding protein 1 and reduced the clonogenic survival of irradiated cancer cells. RAD001 combined with radiation increased G2 arrest by activating CHK1, which phosphorylates CDC25C at Ser216, thereby inhibiting CDC2-cyclin B 1 complex formation.RAD001 enhances the radiosensitivity of SCC4 cells by inhibiting mTOR signaling and inducing G2 cell-cycle arrest through disruption of the G2 checkpoint.

Primary tympanic membrane cancer is very rare; metastatic cancer to the tympanic membrane is extremely rare and presents diagnostic challenges. We report a case of metastatic hepatocellular carcinoma in the tympanic membrane. The presenting symptom was hearing loss. Physical examination revealed a friable granulomatous mass over the left anterior tympanic membrane extended from the external auditory canal. Computed tomography scan of the temporal bone revealed one soft tissue mass involving the left external auditory canal and tympanic membrane. A left middle ear mass biopsy was performed. The tumor cells were uniformly positive for cytokeratin and hepatocyte paraffin-1, confirming a diagnosis of metastatic tympanic membrane. A tympanic membrane mass might easily be misdiagnosed and improperly treated. This case serves as a reminder that the differential diagnosis of acute hearing loss in cancer patients should include the metastasis occurring in the auditory canal or tympanic membrane, and that tissue biopsies are necessary to establish the definitive diagnosis for such lesions.

OBJECTIVES: To examine the risk of adverse effects of special interest in persons vaccinated against seasonal influenza compared with unvaccinated persons aged 65 and above. METHODS: We retrospectively observed 41,986 vaccinated elderly persons and 50,973 unvaccinated elderly persons in Taiwan from October 1, 2008, through September 30, 2009, using the National Health Insurance database. Neurological and autoimmune disorders and one-year hospitalization rates and in-hospital mortality rates were analyzed according to the vaccination status. Propensity score analysis was used to assess the relationship between adverse outcomes, hospitalization rates, and vaccination status. RESULTS: 45% of the elderly received influenza vaccination. Multiple logistic regression showed that the probability of being vaccinated was related to more patients visiting for URI symptoms (odds ratio (OR), 1.03; 95% CI, 1.02-1.03), men (OR, 1.15; 95% CI, 1.12-1.17), increased age (OR, 1.02; 95% CI, 1.02-1.03), and more comorbidities (OR, 1.2; 95% CI, 1.17-1.23). There were no statistical differences in neurological and autoimmune diseases between the vaccinated and unvaccinated individuals using propensity score analysis, but vaccinated persons had a reduced hospitalization rate of 19% (odds ratio [OR], 0.81; 95% CI, 0.77-0.84) for the first six-months and 13% for one-year of follow-up (OR, 0.87; 95% CI, 0.85-0.9). CONCLUSIONS: Based on data from the one-year follow-ups among 93,049 elderly persons in Taiwan, reassuring results for selected neurological and autoimmune diseases were found among the vaccinated individuals after adjusting other factors. Influenza vaccination decreased the risk for hospitalization. Public health strategies must continue to improve the influenza vaccination rate among the elderly with information based upon tangible evidence.

Background and purpose To investigate the risk of stroke development following a diagnosis of Bell's palsy in a nationwide follow-up study. Methods and materials Information on Bell's palsy and other factors relevant for stroke was obtained for 433 218 eligible subjects without previous stroke who had ambulatory visit in 2004. Of those, 897 patients with Bell's palsy were identified. Over a median 2.9 years of follow-up, 4581 incident strokes were identified. We estimated hazard ratios (HR) and 95% confidence intervals [CI] with Cox proportional hazard models adjusting for age, sex, co-morbidities, and important risk factors. Standardized incidence ratio of stroke amongst patients with Bell's palsy was analyzed. Results Compared with non-Bell's palsy patients, patients with Bell's palsy had a 2.02-times (95% CI, 1.42–2.86) higher risk of stroke. The adjusted HR of developing stroke for patients with Bell's palsy treated with and without systemic steroid were 1.67 (95% CI, 0.69–4) and 2.10 (95%, 1.40–3.07), respectively. Conclusions Patients with Bell's palsy carry a higher risk of stroke than the general population. Our data suggest that these patients might benefit from a more intensive stroke prevention therapy and regular follow-up after initial diagnosis.

Oral cancer has emerged as one of the fastest growing malignancies in Taiwan. However, biomarkers that reliably predict clinical outcomes have yet to be identified. This study was aimed to identify tumor-associated proteins that could be prognostic biomarkers for oral cancer. We compared the protein expression between oral squamous cell carcinoma (OSCC) tissues and adjacent non-cancerous matched tissues (NCMTs) by proteomics. We found that Rho GDP-dissociation inhibitor alpha (RhoGDIα) was differentially expressed in frozen cancerous samples and OSCC cell lines but not in NCMTs. Furthermore, our results indicated that RhoGDIα was selectively upregulated in 78 OSCC tissue sections (p0.001), and this high expression was significantly correlated with increased tumor size (p0.05) and poor overall survival (p0.01). There was a trend that RhoGDIα expression was localized in the cytoplasm of cancer cells but was localized in the plasma membrane of NCMTs. Finally, expression of RhoGDIα was validated to be an independent prognostic indicator for overall survival (p0.01). These results have identified a novel biomarker that may be useful for prediction of poor prognosis in OSCC patients.

Purpose Radiation/chemoradiotherapy-induced carotid stenosis and cerebrovascular events in patients with nasopharyngeal carcinoma (NPC) can cause severe disability and even death. This study aimed to estimate the risk of ischemic stroke in this patient population over more than 10 years of follow-up. Methods and Materials The study cohorts consisted of all patients hospitalized with a principal diagnosis of NPC ( n = 1094), whereas patients hospitalized for an appendectomy during 1997 and 1998 ( n = 4376) acted as the control group and surrogate for the general population. Cox proportional hazard model was performed as a means of comparing the stroke-free survival rate between the two cohorts after adjusting for possible confounding and risk factors. Results Of the 292 patients with ischemic strokes, 62 (5.7%) were from the NPC cohort and 230 (5.3%) were from the control group. NPC patients ages 35–54 had a 1.66 times (95% CI, 1.16–2.86; p = 0.009) higher risk of ischemic stroke after adjusting for patient characteristics, comorbidities, geographic region, urbanization level of residence, and socioeconomic status. There was no statistical difference in ischemic stroke risk between the NPC patients and appendectomy patients ages 55–64 years (hazard ratio=0.87; 95% CI, 0.56–1.33; p = 0.524) after adjusting for other factors. Conclusions Young NPC patients carry a higher risk for ischemic stroke than the general population. Besides regular examinations of carotid duplex, different irradiation strategies or using new technique of radiotherapy, such as intensity modulated radiation therapy or volumetric modulated arc therapy, should be considered in young NPC patients.

We determined whether expression of haptoglobin by head and neck squamous cell carcinoma (HNSCC) cells is associated with prognosis.Western blotting was carried out to investigate the expression of haptoglobin in oral cancer cell lines. We study patients with HNSCC without distant metastasis at diagnosis. Correlation between cellular haptoglobin and clinical characteristics of HNSCC was analyzed to assess the prognostic value of cellular haptoglobin level. Kaplan-Meier survival curves and log-rank test were used to evaluate differences in recurrence, distant metastasis, and overall survival rates between patients grouped according to cellular haptoglobin level in cancer tissues. The relationship of haptoglobin expression with survival was assessed using Cox proportional hazard models.Western blotting analysis showed that haptoglobin protein was expressed in 4 oral cancer cell lines. The recurrence rate was higher in HNSCC patients with over-expression of haptoglobin (50%) (P=0.045). Over-expression of haptoglobin was also associated with an increased risk for recurrence (hazard ratio [HR] 3.2; 95% confidence interval [CI], 1.127-8.895; P=0.029) after adjusting for age, gender, disease site, stage, and treatment modality.Altogether, the data presented show that cellular expression of haptoglobin is closely related to recurrence rate in HNSCC patients. The elevated risk of relapse was confirmed in a multivariate analysis. The cellular expression of haptoglobin may be a prognostic factor in HNSCC.

Aim Haptoglobin polymorphisms are associated with different cancers; however, the occurrence of nasopharyngeal carcinoma (NPC) in relation to haptoglobin polymorphisms has not been reported. In this study, the distribution of haptoglobin genotypes among patients with NPC was investigated and the prognostic significance of haptoglobin genotypes was further analyzed. Material and methods Haptoglobin genotypes were analyzed using polymerase chain reaction and electrophoresis. The genotypes were determined in the sera of 49 NPC patients and in 134 controls. Results The haptoglobin genotypes of patients with NPC were as follows: Hp 1–1, 2%; Hp 2–1, 39%; Hp 2–2, 59%. The frequency of the Hp 2–2 genotype was much higher in NPC patients than in control individuals (p=0.044). Furthermore, NPC patients with the Hp 2–2 genotype had advanced T stages (p=0.001) and larger primary tumor volumes (p=0.035) than those with Hp 2–1 or 1–1. Conclusion An increased frequency of the Hp 2–2 genotype was associated with NPC. The Hp 2 allele was also overexpressed in NPC patients. NPC patients with the Hp 2–2 genotype had advanced T stage and a larger primary tumor volume. Hp 2–2 may be a negative prognostic factor in NPC.

The aim of this study was to determine whether haptoglobin (Hp) genotypes are associated with prognosis in patients with squamous cell carcinoma of the head and neck (HNSCC).We studied patients with HNSCC without distant metastasis at diagnosis. The Hp genotype of each patient was determined and the prognostic significance of the Hp genotype was further analyzed. Pearson's chi(2)-test or Fisher's exact test were used to analyze correlations between Hp genotype and clinical characteristics of HNSCC. Eighty patients with newly diagnosed HNSCC who were treated with curative modality were enrolled in this study. Kaplan-Meier plots and log-rank test were used to compare locoregional recurrence-free survival, distant-metastasis-free survival and overall survival of patients according to Hp genotype. Survival analysis was performed using Cox proportional hazard models.Eighty patients with newly diagnosed HNSCC were enrolled in this study. There was no significant difference in the distribution of Hp genotypes in HNSCC patients and healthy individuals (p=0.959). Matched-pair analysis showed that locoregional recurrence-free survival was poor (p=0.02) for HNSCC patients with Hp 2-2 or 2-0. There was no significant difference in distant metastasis-free survival and overall survival (p=0.422 and 0.509, respectively). Multivariate analysis showed that Hp 2-2 or 2-0 was associated with an increased risk of locoregional recurrence [Hazard ratio (HR) 5.9; 95% confidence interval (CI), 1.1-6.65; p=0.038]. The risk was still higher in patients with Hp 2-2 or 2-0 after further adjusting for age and treatment modality (HR 7.6; 95% CI, 1.2-46; p=0.028) in locoregional recurrence-free survival.The present data show that the Hp genotype is closely related to recurrence rate in patients with HNSCC. Patients with Hp 2-2 or 2-0 have greater locoregional recurrence and significantly increased HRs in multivariate analysis. The Hp genotype may be a prognostic factor in patients with HNSCC.

We report on a case of recurrent nasal NK/T-cell lymphoma in a patient who presented with a penile mass. No obvious other recurrent site except the penile lesion was noted. Metastatic penile lymphoma is extremely rare. We describe the image findings and clinical course of this case.

Background The discovery of molecular biomarkers is crucial to the diagnosis of head and neck squamous cell cancer (HNSCC). Methods Proteins from pre-surgery serum samples of patients with HNSCC and healthy individuals were analyzed by 2-dimensional gel electrophoresis (2-DE) using a 17 cm-long immobilized pH gradient gel strip (large gel). The differentially expressed protein spots were detected by statistical analysis. Because 2 haptoglobin (Hp) α chains were found to be differentially expressed, the genotypic distribution of Hp α chains in patients and healthy individuals was assayed by polymerase chain reaction. The protein expression levels of Hp α chains in individuals carrying different Hp alleles were analyzed by 2-DE with a small gel. Results Two isoforms of haptoglobin α2 chain (Hp α2) in patients' sera were found from 2-DE analysis to be up-regulated, while the isoforms of haptoglobin α1 chain (Hp α1) were significantly down-regulated. Apolipoprotein AII and 2 isoforms of apolipoprotein CII were also differentially expressed in the sera of patients with HNSCC. The Hp α2 chain was significantly up-regulated in the patients carrying at least one haptoglobin 2 allele, according to the spot intensities from scanned images of small-gel 2-DE. Conclusions The expression pattern of seven differentially expressed polypeptides and the up-regulation of Hp α2 in individuals with the Hp 2 allele are potential biomarkers.

Objective Many of the medico-legal patients who claimed compensation may exaggerate hearing loss that varies in degree, nature, and laterality. The purpose of this study was to investigate whether Auditory Steady-State Response (ASSR) could be used to predict the hearing level of adults, and whether ASSR could become a better testing method than Auditory brainstem response (ABR) in audiometric assessment of adults with sensorineural hearing loss. Methods This was a prospective study, which was conducted in a tertiary referral hospital. From January to June 2007, 142 subjects (284 ears) with varying degrees of sensori-neural hearing impairment were included in this study. Four commonly used frequencies (500, 1000, 2000, 4000 Hz) were evaluated. All subjects received pure-tone audiometry, multi-channel ASSR, and ABR tests for threshold measurement. The correlation of pure tone thresholds with ASSR and ABR thresholds were assessed. Results Between multi-channel ASSR and pure tone thresholds, a difference of less than 15 dB was found in 71% while a difference of less than 25 dB was found in 89% of patients. The correlation coefficient ( r ) of multi-channel ASSR and pure tone thresholds were 0.89, 0.95, 0.96, and 0.97 at 500, 1000, 2000, and 4000 Hz, respectively. The strength of the relationship increased with increasing frequency. On the other hand, between ABR and pure-tone thresholds, a difference of less than 15 dB was found in 31%; a difference of less than 25 dB was found in 62% of patients. The r correlation value for ABR and pure tone thresholds was 0.83. Conclusion ASSR is a more reliable test for the accurate prediction of auditory thresholds than ABR. It can be a powerful and convenient electro-physiologic examination tool for clinically assessing of adults with sensorineural hearing loss.

We suggest that concurrent chemoradiation (CCRT) is an effective definitive treatment for patients with advanced hypopharyngeal carcinoma who are unfit for or refuse surgery. A high dose of radiation (70 Gy) should be given to achieve acceptable local control rates and survival.The purpose of this retrospective study was to compare the treatment results of locally advanced hypopharyngeal carcinoma with two different protocols.From December 1995 to December 2004, 74 patients with locally advanced hypopharyngeal cancer were treated with CCRT or surgery plus postoperative radiotherapy (SRT). Their treatment results were reviewed by retrospective analysis. The study points included outcome, toxicity, and prognostic factors.There was no significant difference in T and N status between the two treatment groups, nor were there significant differences in overall or disease-free survival or the incidence of distant metastasis (p0.05). In the CCRT group and SRT group, the estimated 3-year overall survival was 39% and 44%, respectively. The SRT group had better local control than the CCRT group (p0.05). Relatively, 27% patients retained their larynx function for more than 2 years in the CCRT group. Radiation doses70 Gy yielded significantly better survival and local control than doses70 Gy (p0.05).

Conclusions. Young patients with squamous cell carcinoma (SCC) of the oral tongue developed fewer locoregional recurrences. The overall survival and disease-specific survival rates were better in the young patient population. Objectives. To compare the survival rates of patients under 45 years of age and diagnosed with SCC of the oral tongue with those of patients older than 45 years. Patients and methods. A retrospective review of 20 patients under 45 years of age with SCC of the oral tongue was performed. These patients were matched to an older population by sex and clinical stage. Overall survival, disease-free survival, disease-specific survival, and rates of local, regional and distant metastases were determined for both populations. Results. Stage and treatment modality were similar in the two age groups. There were significant differences in overall survival (p=0.013) and disease-specific survival (p=0.046) favoring young patients. Rates of locoregional recurrence and distant metastasis were higher...

There is an increased incidence of oral squamous cell carcinoma (SCC) in young patients. However, the literature concerning prognosis for young patients with oral SCC is conflicting. The aim of this study was to compare the survival rates of patients under 45 years of age and diagnosed with SCC of the oral cavity with those of patients older than 45 years. A retrospective review of 28 patients under 45 years of age with SCC of the oral cavity was performed. We matched each of these patients by sex, tumor site, and overall stage with two patients older than 45 years. Overall survival, disease-free survival, disease-specific survival, rates of local, regional and distant metastasis were determined for both populations. Survival analysis was performed using Cox proportional hazard models. Stage and treatment modality were similar in the two groups. There were significant differences in overall survival (P=0.024) and disease-specific survival (P=0.03) favoring young patients. Locoregional recurrence and distant metastasis were higher in the older patients. Furthermore, matched survival analysis demonstrated a difference in overall survival rate [risk ratio (RR) 2.457; P=0.033] and disease-specific survival [RR 2.475; P=0.048]. Young patients with SCC of the oral cavity developed fewer locoregional recurrences and distant metastasis. The overall survival and disease-specific survival rates were better in the young patient population.

Epithelial papillae may occasionally occur in association with pleomorphic adenomas. When combined with hyperchromasia and pleomorphism, they present the potential for misinterpretation of the cytology results, which appear to be indicative of papillary carcinoma. Ectopic salivary gland tissue is relatively common in cervical lymph nodes, particularly near the parotid gland. If these lesions stem from ectopic salivary glands in the neck region, they may be easily misdiagnosed as metastatic papillary carcinoma, particularly in fine-needle aspiration cytology (FNAC). A 60-year-old woman suffered for more than 1 month from a painless, slowly growing mass in the left upper neck. Sonography revealed a round hypoechoic nodule with a cystic component, which was approximately 1.5 1.1 cm in size and had no direct relation with the submandibular or parotid glands. FNAC with three passes for this mass revealed only some epithelial papillae composed of crowded slightly hyperchromatic high cuboid cells without apparent fibrovascular cores (Fig 1). Under the suspicion of metastatic papillary carcinoma, the mass was totally excised. Histology showed a well-demarcated pleomorphic adenoma with components of papillary, trabecular, and cystic formations (Fig 2). Some residual ductal structures embedded in the neighboring lymphoid tissue were also noted. There was no evidence of malignancy. The patient gave her informed consent for this presentation.

A 26-year-old primigravida having suffered from dry cough, dyspnea and orthopnea for two months came to our hospital for a check up at 34 weeks gestation. Physical examination and ultrasonic study showed a lot of lymph nodes around her neck. After close coordination of opinion from responsible doctors, it was decided to deliver the baby first. After anesthetic induction, bronchoscopy revealed that the lower trachea was totally collapsed with obvious tracheobronchial mucosal swelling. A high inspiratory pressure was applied, and high-dose corticosteroid and bronchodilator were immediately given, but the airway resistance was still high and her SpO2 level was falling down. Fortunately, after we changed the patient's position from supine to semi-sitting, ease of ventilation was reestablished and SpO2 rose up from 40% to 100%. We then delivered a healthy baby, and malignant lymphoma was proven by biopsy of the cervical lymph nodes performed immediately after delivery. In this case, the change to semi-sitting position and relevant medication helped reestablish her ventilation and save her life. At the moment we write she is undergoing chemotherapy and does her follow-up at our hospital as advised.

This article describes a 59-year-old woman with a rare malignant schwannoma invading the left mandible. The clinical, radiological, pathological findings, treatment, and prognosis of our patient are discussed in detail. A 4-year cure was achieved by radical surgery and concurrent chemoradiotherapy (CCRT). In addition, we also review and summarize relevant literature on malignant schwannoma.

Fine-needle aspiration cytology (FNAC) is a highly accurate tool for the diagnosis of pleomorphic adenomas. However, this common salivary gland neoplasm can be diagnostically challenging, causing pitfalls in cytodiagnosis because ectopic salivary gland tissue is relatively common in cervical lymph nodes, particularly near the parotid gland. Any of them, therefore, may be the source of salivary gland tumors, or may be confused with metastasis (by finding extraneous tissue in an unexpected site). If pleomorphic adenomas with papillary features stem from ectopic salivary glands in the neck region or other ectopic locations, they may be easily mistaken for metastatic papillary carcinoma, particularly if the aspiration smears only show the papillary components composed of cells with hyperchromatic, pleomorphic, and crowded nuclei. Foci of squamous metaplastic changes may occur occasionally in pleomorphic adenomas. Similarly, if pleomorphic adenomas or other benign salivary gland lesions with extensive squamous metaplasia are found in the neck region or other ectopic locations, they may be easily mistaken for metastatic well-differentiated squamous cell carcinoma, particularly when the aspiration smears are primarily composed of squamous metaplastic components.

Fine-needle aspiration cytology (FNAC) is a highly accurate tool for the diagnosis of pleomorphic adenomas. However, this common salivary gland neoplasm can be diagnostically challenging, causing pitfalls in cytodiagnosis because ectopic salivary gland tissue is relatively common in cervical lymph nodes, particularly near the parotid gland. Any of them, therefore, may be the source of salivary gland tumors, or may be confused with metastasis (by finding extraneous tissue in an unexpected site). If pleomorphic adenomas with papillary features stem from ectopic salivary glands in the neck region or other ectopic locations, they may be easily mistaken for metastatic papillary carcinoma, particularly if the aspiration smears only show the papillary components composed of cells with hyperchromatic, pleomorphic, and crowded nuclei. Foci of squamous metaplastic changes may occur in pleomorphic adenomas. Similarly, if pleomorphic adenomas or other benign salivary gland lesions with extensive squamous metaplasia are found in the neck region or other ectopic locations, they may be easily mistaken for metastatic well-differentiated squamous cell carcinoma, particularly when the aspiration smears are primarily composed of squamous metaplastic components. We have been confronted with both type of cases and are willing to share with colleagues.

To evaluate the relationship of emotional status and health-related quality of life (HRQOL) in disease-free head and neck cancer (HNC) patients post treatment and to explore their predictive factors.Seventy-three HNC patients, post treatment at least 1 year, were recruited to complete three questionnaires, EORTC QLQ-C30, EORTC-HN35 cancer module, and the Beck Depression Inventory-II (BDI-II).Patients with depression demonstrated significantly poor global health status/QoL (score 41.7 vs. 71.9, P0.001) and almost all functioning, except for role functioning. Besides, depressive patients presented statistically significant worse symptoms in all QLQ-C30 items, except constipation and financial problems, and in all QLQ-HN35 symptoms except for teeth and coughing problems. Depression was significantly negative correlated with all functional scales and global health status/QoL (r = -0.341 to -0.750, all P0.05), and was significantly positive correlated with symptom scales (r = 0.348 to 0.793, all P0.05), except for constipation. Stepwise multiple linear regression analyses showed that physical functioning and physical distressful symptoms play an important role in the perception of HRQOL (total 46% explained). Global health status and impaired social functioning could explain depression in addition to emotional functioning (total 64% explained).HNC patients with depression were noted to have poorer HRQOL in almost every functioning symptom. HNC patients may get benefit from early interventions to improve HRQOL, emotional status, or both by a more rapid and friendly questionnaire to earlier identify patients with poor HRQOL or depressive status.

Sonographic texture analysis can reflect histopathological components and their arrangement in metastatic and common benign lymph nodes. It is helpful in differentiation between metastatic and benign lymph node lesions for target selection during biopsy of multiple lymph nodes and the strategy of the management. Two ultrasound systems, 107 sonographic regions of interest (ROIs) of metastases and 174 sonographic ROIs of common benign lymph nodes, were recruited in the study. Thirteen texture features derived from co-occurrence matrix were used in characterization of above ROI ultrasound images. Support vector machine (SVM) was used as a classifier and a feature selector. The experimental results show that the entropy gains the best cross-validation accuracy of 94.66% and 87.73% in both ultrasound systems 1 and 2 for the classification of metastatic and benign lymph nodes disease. The accuracy can be further increased to 97.86% and 100% by the combination of the sum average in the study. There are significantly higher entropy and sum average values of the metastatic lymph nodes than of the benign lymph nodes, which are due to the heterogeneous compositions and arrangement of larger cancer cells, lymphocytes, and stroma in metastatic lymph nodes that contrast with simple inflammatory cells infiltration in common benign lymph nodes.

Background Most treatment failure of buccal mucosal cancer post surgery is locoregional recurrence. We tried to figure out how close the surgical margin being unsafe and needed further adjuvant treatment. Methods Between August 2000 and June 2008, a total of 110 patients with buccal mucosa carcinoma (25 with stage I, 31 with stage II, 11 with stage III, and 43 with Stage IV classified according to the American Joint Committee on Cancer 6th edition) were treated with surgery alone (n = 32), surgery plus postoperative radiotherapy (n = 38) or surgery plus adjuvant concurrent chemoradiotherapy (n = 40). Main outcome measures: The primary endpoint was locoregional disease control. Results The median follow-up time at analysis was 25 months (range, 4-104 months). The 3-year locoregional control rates were significantly different when a 3-mm surgical margin (≤3 versus >3 mm, 71% versus 95%, p = 0.04) but not a 5-mm margin (75% versus 92%, p = 0.22) was used as the cut-off level. We also found a quantitative correlation between surgical margin and locoregional failure (hazard ratio, 2.16; 95% confidence interval, 1.14 - 4.11; p = 0.019). Multivariate analysis identified pN classification and surgical margin as independent factors affecting disease-free survival and locoregional control. Conclusions Narrow surgical margin ≤3 mm, but not 5 mm, is associated with high risk for locoregional recurrence of buccal mucosa carcinoma. More aggressive treatment after surgery is suggested.