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Objectives A combination of platinum-based chemotherapy and radiotherapy is the standard treatment for nasopharyngeal carcinoma (NPC). However, the efficacy of chemotherapy has reached a plateau. Many autophagy studies suggest that autophagy can either promote or suppress to cancer progression. Thus, a role of autophagy in the acquisition of chemoradioresistance has recently been a notable event. Therefore, we examined the relationship between autophagy and chemotherapy in NPC. Methods The expression of Beclin 1 and microtubule-associated protein light chain 3 (LC3), a marker of autophagy, was determined by immunohistochemistry in the biopsy samples of patients with NPC before and after the first course of chemotherapy. Additionally, to investigate in the effect of autophagy suppression in chemotherapy, NPC cell line C666-1 cells were treated with cisplatin and/or chloroquine, an inhibitor of autophagy. Results The expression of Beclin 1 increased after chemotherapy in all patients. In NPC cell line C666-1, compared to cisplatin alone, combination therapy (cisplatin and chloroquine) reduced cell viability, and promoted cell apoptosis. Conclusions These results suggest that autophagy, represented by Beclin 1, is upregulated after chemotherapy in both in vitro and in vivo NPC studies. Inhibition of autophagy could therefore be new strategy for NPC treatment.

Tracheoesophageal fistula (TEF) is a serious complication associated with impaired quality of life. However, a successful TEF closure is difficult owing to the high incidence of recurrence. We utilized a prefabricated deltopectoral (DP) flap for closure of a TEF that occurred after an extended total thyroidectomy. Prefabrication of the inner soft tissue lining the DP flap with a split skin graft was performed prior to surgical closure of a TEF. Esophageal and tracheal mucosa were sutured to the split thickness side and full thickness side of the prefabricated DP flap, respectively. A successful closure of the fistula was achieved with this procedure. Prefabricated DP flap is a useful procedure for the surgical treatment of TEF. © 2014., Embargo Period 12 months

Objective The treatment of recurrent respiratory papillomatosis (RRP) continues to be difficult. Adjuvant pharmacological treatment is increasingly being used, and intralesional cidofovir injection remains the leading option. Almost all papers regarding the treatment come from the United States and Europe. The present study demonstrated it for the first time from Asia. Methods Ten patients with RRP were treated with intralesional cidofovir injection. The severity of papillomatosis and adverse events including blood leukocytes, blood neutrophils, and serum creatinine were evaluated before and after the completion of treatment. Results Human papillomavirus (HPV) type 6 was detected in nine patients, and no types of HPV were detected in a remaining patient. Severity scores significantly improved after treatment ( p = 0.005). However, complete resolution was achieved in only one patient. No significant differences were observed between before and after treatment with respect to adverse events ( p = 0.866 for blood leukocytes, p = 0.866 for blood neutrophils, and p = 0.933 for serum creatinine). Squamous cell carcinoma occurred three and half years after the completion of treatment in a patient without HPV detection. However, the link between cidofovir and the occurrence of carcinoma in the case remains questionable. Conclusion This initial report of intralesional cidofovir injection for RRP from Asia demonstrated acceptable efficacy without obvious adverse events. However, the uncontrolled spread of this treatment should be avoided, and eighteen statements approved by the task force of the United States should be referred to while planning this treatment.

Objective Dysphagia eventually occurs in amyotrophic lateral sclerosis (ALS). Swallowing in patients with ALS at their initial diagnosis was evaluated using videofluoroscopy (VF). Methods Nineteen consecutive patients with ALS, 14 with bulbar symptoms, and 5 without them, underwent VF. Fourteen physiologic components, 6 oral and 8 pharyngeal components, were assessed during the examination. Results Significantly poorer scores were observed in three of the 6 oral components and 3 of the 8 pharyngeal components in patients with bulbar symptoms. Furthermore, bolus transport from the oral cavity to pharynx, pharyngeal constriction, oral residue and pharyngeal residue were impaired in patients even without bulbar symptoms. On the other hand, pharyngoesophageal segment opening was preserved in patients even with bulbar symptoms. Bolus transport and initiation of pharyngeal swallow were correlated with the swallowing category of the ALS severity scale. Conclusion Defining types of impairment in patients with or without bulbar symptoms is useful for evaluating dysphagia in this disease. Although VF showed impairment of oral and pharyngeal phases of swallowing, the oral phase affected the eating habit in ALS at the initial diagnosis.

Primary myoepithelial carcinoma of the hypopharynx is an extremely rare malignant tumor that was first classified as a separate neoplasm by the World Health Organization in 1991. We present an unusual case arising in a 1-year-old boy. He underwent microsuspension direct laryngoscopy with organ preservation. The tumor cells were arranged in nests and lobules separated by thin fibrovascular septae in a background of fibromyxoid stroma. Immunohistochemically, the tumor was positive for S-100 protein, AE1/AE3, and synaptophysin. The tumor was diagnosed as myoepithelial carcinoma. During follow-up for 12 months, there was no clinical or radiological evidence of recurrence or distant metastasis.

Objective: The aim of this study was to clarify the role of IL-33 in tumor progression. Methods: Surgical specimens from 81 patients with squamous cell carcinoma of the tongue were studied using immunohistochemistry. Primary tumor sections were analyzed for IL-33 and ST2 expression. To examine the influence of IL-33 on the microenvironment of the tumor, we determined the mast cell density (MCD) and microvessel density of the stroma. Results: Patients with high IL-33 expression had a significantly worse prognosis (p = 0.004). IL-33 expression was significantly elevated in patients with local and nodal recurrence (p = 0.014 and p = 0.019). ST2 expression was also associated with a worse prognosis (p = 0.024) and was significantly elevated in patients with nodal recurrence (p = 0.004). MCD was associated with worse prognosis (p = 0.038) and correlated significantly with IL-33 expression (r = 0.626, p < 0.001). Micovessels in the stroma were significantly increased in the high IL-33 group (p < 0.001). Conclusion: These data suggest that the IL-33/ST2 axis contributes to tumor aggressiveness and affects the tumor microenvironment. Immunohistochemical evaluation of IL-33 and ST2 is useful for identifying patients at a high risk for poor prognosis. © 2014 Elsevier Ireland Ltd. All rights reserved.

Objective Recurrent respiratory papillomatosis (RRP) has historically been and still continues to be a difficult disease to treat. The present study aimed to characterize current practices in the treatment of RRP in Japan. Methods A questionnaire was posted to the Department of Otolaryngology of all 80 central university hospitals in Japan. Results A total of 56 universities responded to the survey. Regarding the use of surgical instruments, a trend toward a preference for lasers (50 hospitals) rather than a microdebrider (16 hospitals) or cold instruments (20 hospitals) was observed. Among the 50 hospitals frequently performing laser surgery, a carbon dioxide (CO 2 ) laser was most commonly used, followed by a potassium-titanyl-phosphate (KTP) laser. The most favored adjuvant therapy was traditional Chinese medicine. Eight of the 56 university hospitals had an experience of using cidofovir, involving a total of 28 patients. Conclusion The present study demonstrated the current trends in the management of RRP based on a questionnaire survey in a geographical area other than the US and UK for the first time. Treatment trends were generally similar in all three areas except for the least popular use of cidofovir in Japan.

Undifferentiated nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated malignant tumor. A consistent elevation in EBV antibody titers is a well-established risk factor for the development of NPC. The pathophysiological relationship and molecular mechanisms of EBV-mediated carcinogenesis have not been fully elucidated. While NPC tumors are known to express three EBV-encoded proteins, EBNA1, LMP1, and LMP2, they also express a large number of virus-encoded small RNAs (EBERs) and microRNAs (miRNAs). Among them, LMP1 may be a central player in the development of NPC. LMP1, an EBV-encoded primary oncogene, functions as a viral mimic of the TNFR family member, CD40, and engages in a number of signaling pathways that induce morphological and phenotypic alterations in epithelial cells. LMP1 upregulates EMT, and contributes to the highly metastatic features of NPC. Moreover, LMP1-associated EMT is accompanied by the expression of cancer stem cell (CSC)/cancer progenitor cell (CPC) markers (CD44high/CD24low) and the acquisition of stem cell/progenitor cell-like properties. BART miRNAs, encoded from the BamHI-A region of the viral genome, are the most abundant transcripts. They modulate apoptosis and host innate immune defense mechanisms. Some BART1 miRNAs are considered to negatively regulate LMP1 protein expression. LMP1 is secreted via exosomes, is incorporated into EBV-uninfected cells by endocytosis, and affects the environment surrounding the tumor. Here we reviewed the contribution of EBV gene products to NPC pathogenesis in relation with LMP1.

The contribution of the lymphatic system to tumor metastasis is being increasingly appreciated through studies of human cancers. As the biological behavior of nasopharyngeal carcinoma (NPC) depends on its nodal status, patients with advanced nodal status show a higher tendency toward a poor outcome. Here, we examined the role of lymphangiogenesis on lymphatic spread of NPC. We also evaluated the involvement of vascular endothelial growth factor (VEGF)-C/VEGF receptor 3 (VEGFR3) signaling pathway on lymphangiogenesis in NPC. Furthermore, we tested whether Epstein-Barr virus (EBV)-latent membrane protein (LMP) 1 induces VEGF-C. Forty-one patients with NPC were evaluated for expressions of VEGF-C and its receptor, VEGFR3, and LMP1 proteins and lymphatic vessel counts (LVC) highlighted by anti-podoplanin employing immunohistochemistry. The VEGF-C induction by LMP1 was then tested with Western blotting and enzyme-linked immunosorbent assay in vitro. The LVC and VEGF-C expression were significantly higher in cases with advanced regional lymph node metastasis (N2,3) than those with no or limited lymph node involvement (N0,1) (p = 0.0380 and p = 0.0109, respectively). In VEGF-C/VEGFR3-positive cases, the LVC were significantly increased compared with VEGF-C/VEGFR3-negative cases (p = 0.0007). However, LMP1 expression did not show significant associations with LVC and VEGF-C-expression scores (p = 0.1210 and p = 0.1324, respectively). Induction of VEGF-C protein by LMP1 was not detected in vitro. These results suggest the involvement of the VEGF-C/VEGFR3 axis in the induction of lymphangiogenesis which results in lymphatic spread of NPC. However, EBV-LMP1 was not associated with the mechanism. © 2011 Elsevier Ltd. All rights reserved.

Objective It has become clear through epidemiological analysis that the incidence of cancers of the lung, liver, colon, and rectum are increasing in Japan every year. However, there have been few epidemiological analyses of nasopharyngeal carcinoma (NPC) in Japan. The aim of this study was to analyze the epidemiology and current incidence of NPC in the Chubu region of Japan during the period from 1996 to 2005. Methods Takeshita et al. conducted a similar investigation in the Chubu region 10 years ago, and, as a result, this is a comparative study. The Chubu region is the central region of Japanese main island. We researched NPC patients treated in hospitals in each prefecture over a 10-year period (1996–2005) using a questionnaire. Results A total of 525 cases (male:385, female:134, unknown:6) were analyzed epidemiologically, histologically, serologically, and clinically in this study. The incidence per 105 population per year was 0.29. For the period of 1986–1995, the age-standardized incidence of NPC was 0.28 per 105 persons per year in Takeshita's report. There was no significant difference between the two periods. The ages of the patients ranged from 13 to 90 years. The mean age of was 55.2 years. On the basis of the World Health Organization (WHO) histological criteria, 36% of the patients were classified as WHO I, 27% as WHO II, and 37% as WHO III. Carcinoma was located in the posterosuperior region in 56%, lateral in 41%, and inferior in 3%. Tumor staging showed that 6% to belonged to stage I, 25% to stage II, 31% to stage III, and 38% to stage IV. A neck mass was present in 52% of the patients, ear symptoms in 48%, nasal symptoms in 27%, headaches in 10%, pharyngeal symptoms in 9%, ophthalmologic symptoms in 9%, and cranial neurological symptoms in 9%. The positive rates of serum titers of the antibodies to Epstein-Barr virus (EBV)-related antigens were calculated. The positive rate of anti-EBV-viral capsid antigen (VCA) immunoglobulin (Ig) G titers was 58.6%, that of anti-EBV-VCA IgA titers was 53.6%, and that of EBNA was 81%. The five-year survival rate for all patients was 67.6%, and that for those in stage I, II, III, and IV was 75%, 84%, 69%, and 53%, respectively. The five-year survival rate for stage IV was significantly lower than those for the other stages (P Conclusion The age-standardized annual incidence of NPC in our survey was 0.29 per 105 persons per year, being relatively low and stable.

金沢大学附属病院耳鼻咽喉科, Objectives: Although organ-preserving radiotherapy or chemoradiotherapy has offered good locoregional control, many patients still experience recurrent disease requiring salvage laryngectomy. The pharyngocutaneous fistula (PCF) is a common and troublesome complication in the early post-operative period after laryngectomy. Here, we evaluated the cause of PCF after laryngectomy, with special emphasis on radiotherapy and/or chemotherapy. Patients and methods: A total of 63 consecutive patients undergoing salvage total laryngectomy for squamous cell carcinoma of the larynx at Kanazawa University Hospital from 1990 to 2005 were reviewed. Forty of the 63 had received primary total laryngectomy (PL). Ten patients underwent radiotherapy alone (SL-RT) and 13 patients underwent concurrent chemoradiotherapy (SL-CRT) followed by salvage laryngectomy. Results: Overall, 17 of the 63 patients (27.0%) developed PCF after laryngectomy. Fisher's exact test showed a significant increase of PCF formation in SL-CRT (7/13, 53.8%) compared with PL (7/40, 17.5%) (p = 0.0252). There were non-significant increases of PCF formation both in SL-CRT (7/13, 53.8%) compared with SL-RT (3/10, 30.0%) (p = 0.4015), and also in SL-RT (3/10, 30.0%) compared with PL (7/40, 17.5%) (p = 0.3969). The Mann-Whitney U-test showed that the duration of PCF was significantly longer for SL-CRT PCF (121.2 ± 95.0 days) compared with those for PL (39.0 ± 55.3 days) (p = 0.0298) or SL-RT (28.0 ± 16.2 days) (p = 0.0325). However, we did not find a significant difference in the duration of PCF with respect to PL (39.0 ± 55.3 days) and SL-RT (28.0 ± 16.2 days) (p = 0.4367). Conclusions: Although radiotherapy or chemotherapy has only a limited impact on PCF formation, concurrent chemoradiotherapy significantly increases PCF formation. The addition of chemotherapy to irradiation delays PCF closure. © 2007 Elsevier Ireland Ltd. All rights reserved.

Well differentiated squamous cell carcinoma of the nasal septum developed in a 55-year old man with Wegener's granulomatosis. It is suggested that the malignancy was induced by immunosuppressive state from an increased and prolonged use of cyclophosphamide and corticosteroids. Although the efficacy of the therapeutic concept using cyclophosphamide and corticosteroids is well established, there have been some few reports that cyclophosphamide could be implicated in the genesis of malignancies. The pathophysiology of Wegener's granulomatosis should be better understood, and effective and less toxic alternative protocol should be established.