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Purpose: The EBV oncoprotein, latent membrane protein 1 (LMP1), contributes to the metastasis of nasopharyngeal carcinoma (NPC) by inducing factors to promote tumor invasion and angiogenesis. The receptor for advanced glycation end products (RAGE) is associated with abnormal angiogenesis in diabetic microangiopathies. Moreover, some papers have suggested the association of RAGE overexpression with tumor metastasis; thus, the associations of RAGE with LMP1 and angiogenesis in NPC were examined.Experimental Design: Forty-two patients with NPC were evaluated for expressions of LMP1, RAGE, and S100 proteins and for microvessel counts by immunohistochemistry. Then, the RAGE induction by LMP1 was examined with Western blotting and luciferase reporter assay.Results: The microvessel counts were significantly higher in patients with high LMP1 expression or high RAGE expression compared with cases with low expressions (P = 0.0049 and P < 0.0001), respectively. Patients with advanced N classification were also significantly increased in these groups (P = 0.0484 and P = 0.0005). The expressions of LMP1 and RAGE proteins were clearly correlated in NPC tissues (P = 0.0093). Transient transfection with LMP1 expression plasmid induced RAGE protein in Ad-AH cells. The expression of LMP1 transactivated the RAGE promoter as shown by luciferase reporter assay. Mutation of the reporter at nuclear factor-κB binding site (−671 to −663) abolished transactivation of the RAGE promoter by LMP1.Conclusion: These results suggest that LMP1-induced RAGE enhances lymph node metastasis through the induction of angiogenesis in NPC. Nuclear factor-κB binding site (−671 to −663) is essential for transactivation of the RAGE promoter by LMP1.

Supplementary Table S1 from Induction of Receptor for Advanced Glycation End Products by EBV Latent Membrane Protein 1 and Its Correlation with Angiogenesis and Cervical Lymph Node Metastasis in Nasopharyngeal Carcinoma

A multicenter, randomized controlled phase III trial was conducted on sentinel lymph node biopsy (SLNB) and elective neck dissection for T1 (depth of invasion ≥ 4 mm)-T2N0M0 oral cavity squamous cell carcinoma. This study identified factors associated with poor prognosis in patients who underwent SLNB based on a subgroup analysis of this trial. We analyzed 418 sentinel lymph nodes (SLNs) from 132 patients who underwent SLNB. The metastatic SLNs were classified into three categories based on size—isolated tumor cells

Several epidemiological studies have suggested that Epstein-Barr virus (EBV) lytic infection is essential for the development of nasopharyngeal carcinoma (NPC), as the elevation of antibody titers against EBV lytic proteins is a common feature of NPC. Although ZEBRA protein is a key trigger for the initiation of lytic infection, whether its expression affects the prognosis and pathogenesis of NPC remains unclear. In this study, 64 NPC biopsy specimens were analyzed using immunohistochemistry. We found that ZEBRA was significantly associated with a worsening of progression-free survival in NPC (adjusted hazard ratio, 3.58; 95% confidence interval, 1.08-11.87; p = 0.037). Moreover, ZEBRA expression positively correlated with key endocrinological proteins, estrogen receptor α, and aromatase. The transcriptional level of ZEBRA is activated by estrogen in an estrogen receptor α-dependent manner, resulting in an increase in structural gene expression levels and extracellular virus DNA copy number in NPC cell lines, reminiscent of lytic infection. Interestingly, it did not suppress cellular proliferation or increase apoptosis, in contrast with cells treated with 12-O-tetradecanoylphorbol-13-acetate and sodium butyrate, indicating that viral production induced by estrogen is not a cell lytic phenomenon. Our results suggest that intratumoral estrogen overproduced by aromatase could induce ZEBRA expression and EBV reactivation, contributing to the progression of NPC.

Nasopharyngeal carcinoma (NPC) is one of the Epstein–Barr virus (EBV)-associated malignancies. NPC is highly metastatic compared to other head and neck carcinomas, and evidence has shown that the metastatic features of NPC are involved in EBV infection. The prognosis of advanced cases, especially those with distant metastasis, is still poor despite advancements in molecular research and its application to clinical settings. Thus, further advancement in basic and clinical research that may lead to novel therapeutic modalities is needed. Farnesylation is a lipid modification in the C-terminus of proteins. It enables proteins to attach to the lipid bilayer structure of cellular membranes. Farnesylation was initially identified as a key process of membrane association and activation of the RAS oncoprotein. Farnesylation is thus expected to be an ideal therapeutic target in anti-RAS therapy. Additionally, more and more molecular evidence has been reported, showing that proteins other than RAS are also farnesylated and have significant roles in cancer progression. However, although several clinical trials have been conducted in cancers with high rates of ras gene mutation, such as pancreatic carcinomas, the results were less favorable than anticipated. In contrast, favorable outcomes were reported in the results of a phase II trial on head and neck carcinoma. In this review, we provide an overview of the molecular pathogenesis of NPC in terms of the process of farnesylation and discuss the potential of anti-farnesylation therapy in the treatment of NPC.

An Epstein‐Barr virus (EBV)—encoded latent membrane protein 1 (LMP1) is a principal oncogene that plays a pivotal role in EBV‐associated malignant tumors including nasopharyngeal cancer (NPC). Recent genomic landscape studies revealed that NPC also contained many genomic mutations, suggesting the role of LMP1 as a driver gene for the induction of these genomic mutations. Nonetheless, its exact mechanism has not been investigated. In this study, we report that LMP1 alters the expression profile of APOBEC3s(A3s), host deaminases that introduce consecutive C‐to‐U mutations (hypermutation). In vitro, LMP1 induces APOBEC3B (A3B) and 3F(A3F), in a nasopharyngeal cell line, AdAH. Overexpression of LMP1, A3B, or A3F induces mtDNA hypermutation, which is also detectable from NPC specimens. Expression of LMP1 and A3B in NPC was correlated with neck metastasis. These results provide evidence as to which LMP1 induces A3s and mtDNA hypermutation, and how LMP1 facilitates metastasis is also discussed., EBV LMP1 induces host cytidine deaminases, APOBECs, in nasopharyngeal cells. TES2 domain is important for LMP1‐induced LMP1 hypermutates host mitochondrial genome.

Nasopharyngeal carcinoma (NPC) is Epstein-Barr virus (EBV)-associated invasive malignancy. Increasing evidence indicates that epigenetic abnormalities, including DNA methylation, play important roles in the development of NPC. In particular, the EBV principal oncogene, latent membrane protein 1 (LMP1), is considered a key factor in inducing aberrant DNA methylation of several tumour suppressor genes in NPC, although the mechanism remains unclear. Herein, we comprehensively analysed the methylome data of Infinium BeadArray from 51 NPC and 52 normal nasopharyngeal tissues to identify LMP1-inducible methylation genes. Using hierarchical clustering analysis, we classified NPC into the high-methylation, low-methylation, and normal-like subgroups. We defined high-methylation genes as those that were methylated in the high-methylation subgroup only and common methylation genes as those that were methylated in both high- and low-methylation subgroups. Subsequently, we identified 715 LMP1-inducible methylation genes by observing the methylome data of the nasopharyngeal epithelial cell line with or without LMP1 expression. Because high-methylation genes were enriched with LMP1-inducible methylation genes, we extracted 95 high-methylation genes that overlapped with the LMP1-inducible methylation genes. Among them, we identified DERL3 as the most significantly methylated gene affected by LMP1 expression. DERL3 knockdown in cell lines resulted in significantly increased cell proliferation, migration, and invasion. Lower DERL3 expression was more frequently detected in the advanced T-stage NPC than in early T-stage NPC. These results indicate that DERL3 repression by DNA methylation contributes to NPC tumour progression.

Nasopharyngeal carcinoma (NPC) is caused by infection with Epstein-Barr virus (EBV) and endemic in certain geographic regions. EBV lytic gene, BALF2, closely associates with viral reactivation and BALF2 gene variation, the H-H-H strain, causes NPC in endemic region, southern China. Here, we investigate whether such EBV variations also affect NPC in a non-endemic region, Japan. Viral genome sequencing with 47 EBV isolates of Japanese NPC were performed and compared with those of other EBV-associated diseases from Japan or NPC in Southern China. EBV genomes of Japanese NPC are different from those of other diseases in Japan or endemic NPC; Japanese NPC was not affected by the endemic strain (the BALF2 H-H-H) but frequently carried the type 2 EBV or the strain with intermediate risk of endemic NPC (the BALF2 H-H-L). Seven single nucleotide variations were specifically associated with Japanese NPC, of which six were present in both type 1 and 2 EBV genomes, suggesting the contribution of the type 2 EBV-derived haplotype. This observation was supported by a higher viral titer and stronger viral reactivation in NPC with either type 2 or H-H-L strains. Our results highlight the importance of viral strains and viral reactivation in the pathogenesis of non-endemic NPC.

Background Large cervical lymph nodes and the extranodal extension of metastatic lymph nodes are considered poor prognostic factors in head and neck squamous cell carcinoma (HNC). Aims/objectives The efficacy of intra-arterial chemotherapy (iaCT) targeting lymph node (LN) in HNC was examined. Materials and methods We performed a retrospective review of 41 patients with laryngeal and hypopharyngeal cancer showing metastatic cervical LN larger than 20 mm treated with iaCT with concurrent radiotherapy. The administration of cisplatin into LN was divided into three groups: no administration (NO), via the same artery as that supplying the primary tumor (SAME), and via a different artery from that supplying the primary tumor (DIFFERENT). Results A trend toward a more favorable three-year regional control in DIFFERENT compared to NO was observed, although the mean size of LN in DIFFERENT was larger than in the other groups. A better regional control was obtained in both DIFFERENT (p Conclusions/significance Targeting lymph node may be helpful to avoid neck dissection when iaCT was planned in HNC with relatively large LNs.

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.

Rodent models mimic the heterogeneity of head and neck cancer (HNC) malignancies and are used to investigate HNC-associated biomarkers and evaluate drug responses. To assess the utility of patient-derived xenografts (PDXs) as an HNC model, 18 tumour samples were obtained from surgical specimens of patients with HNC and implanted into non-obese diabetic severe combined immunodeficient mice. The histological features of PDXs and corresponding patient samples were compared. Furthermore, the present study investigated how PDX responses to anticancer drugs mimic patient clinical responses, as well as the expression of adenosine triphosphate-binding cassette transporters through chemotherapy in an HNC-PDX model. A total of five PDXs from patients with HNC exhibiting high correspondence with histopathological features of the original patient samples were established (establishment rate, 28%). The responses of three PDXs to cisplatin were associated with clinical responses of the patients. ABC transporter expression was augmented in one PDX model after anticancer drug treatment, but not in PBS-treated passaged PDXs. PDX models exhibited similar biological and chemosensitive characteristics to those of the primary tumours. PDXs could be a useful preclinical tool to test novel therapeutic agents and identify novel targets and biomarkers in HNC.

OBJECTIVES This study aimed to investigate whether pretreatment skeletal muscle mass index (SMI) is a predictor for the risk of aspiration pneumonia and to explore the relationship between low SMI and overall survival (OS) in patients with head and neck squamous cell carcinoma (HNSCC) receiving chemoradiotherapy (CRT). METHODS We retrospectively reviewed the data of patients with HNSCC who received CRT during 2010-2019. Patients received a combination of radiotherapy and cisplatin-based chemotherapy (3 cycles of 80 mg/m2 cisplatin on days 1, 22, and 43). Aspiration pneumonia were defined as the presence of both subjective and objective symptoms. Kaplan-Meier curves were generated to analyze survival. RESULTS Among the 159 patients, 36 (22.6%) developed aspiration pneumonia during treatment. Median SMI in patients with and without pneumonia was 12.4 cm2 /m2 (9.0-20.7) and 13.6 cm2 /m2 (8.1-19.7), respectively (P

Human papillomavirus (HPV) infection is now identified as a major etiologic factor for oropharyngeal cancer (OPC), and HPV positivity is well established better prognostic marker in OPC. Now, predictable markers for the prognosis of the patients who are stratified by HPV has been investigated in. Semaphorin 3A (SEMA3A) is a well-known axon guidance molecule in the nervous system. It is also known as a tumor suppressor in various cancers. In the present study, we examined the relationships between SEMA3A and clinicopathologic features, especially HPV status, and neoangiogenesis, and its prognostic significance for OPC patients. Thirty-two OPC patients and 17 normal patients were analyzed for SEMA3A expression by immunohistochemical analysis. We also analyzed 22 OPC specimens for CD34 expression as a marker of neoangiogenesis. SEMA3A was significantly downregulated in OPC compared with chronic tonsillitis tissues (p = 0.005). SEMA3A expression was negatively correlated with CD34 expression (r = &minus, 0.466, p = 0.033). Moreover, the higher SEMA3A expression cohort showed better survival than the lower SEMA3A expression cohort regardless of HPV status (p = 0.035). These results suggest that SEMA3A expression is a prognostic marker for survival regardless of HPV status and is associated with anti-angiogenesis in OPC.

Semaphorin 3A (SEMA3A) is a well-known axon guidance molecule in the nervous system. It is also known as a tumor suppressor in various cancers. In the present study, we examined the relationships between SEMA3A and clinicopathologic features and neoangiogenesis and its prognostic significance for oropharyngeal cancer (OPC) patients. Thirty-two OPC patients who underwent biopsy and 17 normal patients who underwent tonsillectomy were analyzed for SEMA3A expression by immunohistochemical analysis. We also analyzed 22 OPC specimens for CD34 expression as a marker of neoangiogenesis. SEMA3A was significantly downregulated in OPC compared with normal tonsil tissues (p = 0.005). SEMA3A expression was negatively correlated with CD34 expression, which suggested that a higher microvascular density corresponded to a lower expression of SEMA3A (r = -0.466, p = 0.033). Moreover, the higher SEMA3A expression cohort showed better survival than the lower SEMA3A expression cohort regardless of human papillomavirus (HPV) status (p = 0.035). These results suggest that SEMA3A expression is a prognostic marker for survival and is associated with antiangiogenesis in OPC.

Semaphorins were discovered as guidance signals that mediate neural development. Recent studies suggest that semaphorin 3A (Sema3A), a member of the semaphorin family, is involved in the development of several cancers. This study aimed to analyze the association of Sema3A with the clinical features of nasopharyngeal carcinoma (NPC), an Epstein−Barr virus-associated carcinoma, and the Epstein−Barr virus primary oncogene latent membrane protein 1 (LMP1). The expression of Sema3A and LMP1 was immunohistochemically examined in the 35 NPC specimens. The mean expression scores for Sema3A and LMP1 were 20.8% ± 14.5% and 13.9% ± 14.8%, respectively. The expression of Sema3A significantly correlated with that of LMP1 (r = 0.41, p = 0.014). In addition, the Sema3A high cohort showed significantly poorer prognosis than the Sema3A low cohort. Sema3A expression was higher in the LMP1-positive KH-1 and KR-4 cell lines compared to the LMP1-negative HeLa cells. Overexpression of LMP1 in the LMP1-negative AdAH cell line upregulated Sema3A expression, both at the transcriptional and translational level. Finally, Sema3A expression was associated with poor prognosis in patients with NPC. Our data suggest that LMP1 induces the expression of Sema3A, which may promote tumor progression in NPC.

Latent membrane protein 1 (LMP1) is a primary oncogene encoded by the Epstein‐Barr virus, and various portions of LMP1 are detected in nasopharyngeal carcinoma (NPC) tumor cells. LMP1 has been extensively studied since the discovery of its transforming property in 1985. LMP1 promotes cancer cell growth during NPC development and facilitates the interaction of cancer cells with surrounding stromal cells for invasion, angiogenesis, and immune modulation. LMP1 is detected in 100% of pre‐invasive NPC tumors and in approximately 50% of advanced NPC tumors. Moreover, a small population of LMP1‐expressing cells in advanced NPC tumor tissue is proposed to orchestrate NPC tumor tissue maintenance and development through cancer stem cells and progenitor cells. Recent studies suggest that LMP1 activity shifts according to tumor development stage, but it still has a pivotal role during all stages of NPC development.

Nasopharyngeal carcinoma (NPC) is very common in southern China and Southeast Asia. In regions where NPC is endemic, undifferentiated subtypes constitute most cases and are invariably associated with Epstein-Barr virus (EBV) infection, whereas the differentiated subtype is more common in other parts of the world. Undifferentiated NPC is a unique malignancy with regard to its epidemiology, etiology, and clinical presentation. Clinically, NPC is highly invasive and metastatic, but sensitive to both chemotherapy and radiotherapy (RT). Overall prognosis has dramatically improved over the past three decades because of advances in management, including the improvement of RT technology, the broader application of chemotherapy, and more accurate disease staging. Despite the excellent local control with modern RT, distant failure remains a challenging problem. Advances in molecular technology have helped to elucidate the molecular pathogenesis of NPC. This article reviews the contribution of EBV gene products to NPC pathogenesis and the current management of NPC.

Interferon regulatory factor 7 (IRF7) has oncogenic properties in several malignancies such as Epstein-Barr virus (EBV)-associated lymphoma. However, there is no evidence whether IRF7 is associated with the oncogenesis of nasopharyngeal cancer (NPC), the pathogenesis of which is closely associated with EBV. Herein, we report that expression of IRF7 was increased in normal nasopharyngeal cells that expressed the EBV principal oncoprotein, latent membrane protein 1 (LMP1). In addition, IRF7 was mainly expressed in the nucleus in both normal nasopharyngeal cells and nasopharyngeal cancer cells that expresses LMP1. On immunohistochemical analysis, IRF7 was predominantly localized in the nucleus in biopsy samples of NPC tissues. In total, IRF7 expression was detected with 36 of 49 specimens of these tissues. Furthermore, the expression score of IRF7 correlated with the expression score of LMP1. Moreover, the expression score of IRF7 is associated with cervical lymph-node metastasis, which reflects the highly metastatic nature of this cancer. Taken together, our results suggest that expression of IRF7 is one of the metastatic effectors of LMP1 signalling in EBV-associated NPC.

Objective: Although Japan is a non-endemic area with nasopharyngeal carcinoma (NPC), the proportion of WHO type I NPC in Japan are different from that in non-endemic areas such as North America and Europe. Recently, it is said that not only Epstein-Barr virus (EBV) but also human papillomavirus (HPV) has an influence on NPC in non-endemic areas. The aim of this study is to clarify the influence of HPV on NPC in Japan. Methods: Paraffin-embedded tumor specimens were available for 59 patients with NPC diagnosed between 1996 and 2015. We detected the virus status by p16 immunohistochemistry, HPV PCR, and in situ hybridization for Epstein-Barr virus (EBV)-encoded RNA. Kaplan-Meier curves were used to compare the overall survival by viral status. Results: Among the 59 patients, 49 (83%) were EBV-positive/HPV-negative, 2 (3%) were EBV-positive/HPV-positive, and 8 (16%) were EBV-negative/HPV-negative. All HPV-positive NPCs were co-infected with EBV. There were no significant differences between the overall survival in the three groups (p=0.111). Conclusion: In Japan, HPV was detected in a few patients with NPC, and we suggest that HPV has no influence on NPC carcinogenesis in this population. © 2016 Elsevier Ireland Ltd., Embargo period 12 months

The present study aimed to clarify the incidence and clinical outcomes of nasopharyngeal carcinoma (NPC) in the Chubu region of Japan from 2006 to 2015, compared with previous reports. A retrospective analysis was conducted based on medical records from 40 hospitals located in the Chubu region in the central Japanese main island, with a population of around 22.66 million individuals. This study was designed in line with to two previous clinical studies into NPC conducted in the same area of Japan. We recruited NPC patients diagnosed in hospitals across this area over a 10-year period (2006&ndash, 2015) using a questionnaire about sex, age, primary site, clinical symptoms, pathology, Union for International Cancer Control (UICC) staging, serological exam, treatment, and survival. A total of 620 NPC patients were identified. The age-standardized incidence of NPC from 2006 to 2015 was 0.27 per 100,000 individuals per year. There were no significant differences between this study and the previous two studies conducted in the same area of Japan. The five-year overall survival rate for all patients was 75.9%, while those for patients with stages I, II, III, and IVA were 97%, 91%, 79%, and 68%, respectively. The age-standardized annual incidence of NPC in the present study was 0.27 per 100,000 individuals per year, which was relatively low and stable. The five-year overall survival rate for all NPC patients was significantly improved in this decade compared with previous studies. The smoking rates in male and female NPC patients were 64.5% and 18.8%, respectively, thereby suggesting the involvement of smoking in the incidence of NPC.

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.

Conclusion: Reduced-RADPLAT for HPC achieved comparative survival and locoregional control rates with lower toxicities compared with concurrent chemoradiotherapies including original RADPLAT. S-1 adjuvant chemotherapy showed a survival benefit. Objectives: To evaluate the efficacy and toxicities of targeted intra-arterial (IA) infusion of cisplatin with concurrent radiotherapy with a reduced dose (reduced-RADPLAT) for resectable hypopharyngeal cancer (HPC). Methods: Between 1999–2012, 50 patients with stage II–IVA HPC primarily treated by reduced-RADPLAT were analyzed. They were treated by 2–5 courses of IA cisplatin infusion (100 mg per body) with simultaneous systemic infusion of sodium thiosulfate concurrent with conventional radiotherapy (66–70 Gy). After 2003, S-1, an oral fluoropyrimidine, adjuvant chemotherapy was administered to all eligible patients. Results: During a median follow-up of 48.6 months, the estimated 3- and 5-year overall survival (OS), progression-free survival (PFS), locoregional control, and laryngoesophageal dysfunction-free survival (LEDFS) rates were 76.0% and 62.0%, 58.0% and 50.0%, 66.0% and 62.0%, and 56.0% and 54.0%, respectively. Grade 3 toxicities were observed in 30.0%. No patient had grade 4 or higher toxicities. No patient required tube feeding or tracheotomy at 3 months after treatment. T4-lesions and S-1 administration were significant factors predicting poor and good OS, PFS, and LEDFS, respectively. © 2016 Informa UK Limited, trading as Taylor & Francis Group, Embargo Period 12 months

Conclusion: SPARC-expression is an indicator of the prognosis in terms of OS, independent of HPV-infection. HPV-negative patients with SPARC-Low show survival as favorable as HPV-positive patients, probably because of their higher salvage rate after relapse than SPARC-High patients. Objective: The objectives of the study were to clarify the correlation between the expression of secreted protein acidic and rich in cysteine (SPARC) and HPV-status, and to determine the prognostic value of SPARC-expression in oropharyngeal squamous cell carcinoma (OPSCC) patients. Methods: Fifty-three formalin-fixed and paraffin-embedded tissues were obtained from patients with OPSCC who underwent curative treatment. The SPARC protein was detected by immunohistochemistry. SPARC-expression level was divided into two categories, SPARC-High and SPARC-Low, according to the staining index. Results: Twenty-two out of the 53 OPSCC patients were HPV-positive. There was no significant correlation between the HPV-status and SPARC-expression level. Multivariate Cox proportional hazards regression analysis revealed that the HPV-status and SPARC-expression are independent prognostic indicators of favorable and unfavorable overall survival (OS) (p = 0.021 and p = 0.012), respectively. For disease-free survival, the HPV-status was the only predictive factor (p = 0.022). After stratification by the HPV-status, high SPARC-expression was a significant predictor of poor OS in HPV-negative OPSCC patients using Kaplan-Meier analysis and the log-rank test (p = 0.014). Ten out of 28 SPARC-Low patients relapsed, among which six patients (60%) were salvaged. However, 14 out of 25 SPARC-High patients relapsed, and only three patients (21.4%) were salvaged. © 2015 Taylor & Francis., Embargo Period 12 months

In sentinel lymph node (SLN) biopsy for head and neck cancers, the radioisotope method has been the gold standard. However, this method has several problems, such as unavoidable radiation exposure and requirements of expensive equipment.To overcome these problems, we evaluated the contrast-enhanced ultrasonography (CEUS)-guided SLN-detection method, and predicted the SLN metastatic status using novel ultrasound technology, superb microvascular imaging (SMI).Ten patients (6 with oral and 4 with oropharyngeal cancers) without neck lymph node metastasis were enrolled in this study. Ultrasound contrast agent, SonazoidSLNs were successfully detected in 8 out of 10 cases. In 7 out of the 8 cases, in whom SLNs were successfully detected, the metastatic status of SLNs was correctly diagnosed with SMI.Although more clinical data are needed based on a larger cohort, establishing the CEUS-guided SLN-detection and criteria for the accurate diagnosis of SLN-metastases using SMI would be valuable as an alternative to radioisotope method, in oral and oropharyngeal cancers.

Human papillomavirus (HPV) has been identified as a causative agent of cervical cancer and oropharyngeal cancer (OPC). Intriguingly, estrogen and HPV were shown to play synergistic roles in cervical carcinogenesis. We recently demonstrated that the apolipoprotein B mRNA-editing catalytic polypeptide 3 (APOBEC3, A3) family, which is inducible by estrogen, could lead to HPV DNA hypermutation and cause viral DNA integration. In the present study, we examined the relationships between estrogen-estrogen receptor α (ERα) and A3s in HPV-positive OPC. ERα expression was associated with HPV positivity in OPC biopsy samples using immunohistochemical analysis and reverse-transcription quantitative polymerase chain reaction. In addition, ERα was significantly associated with improved overall survival in HPV-positive OPC (hazard ratio, 0.26; p = 0.029). APOBEC3A (A3A) mRNA was induced by estrogen in HPV and ERα-positive OPC cells. Furthermore, A3A mRNA and protein expression were significantly higher in ERα-positive cases than in ERα-negative ones, among HPV-positive biopsy samples (p = 0.037 and 0.047). These findings suggest that A3A is associated with a good prognosis in ERα-positive OPC, and indicate the prognostic significance of ERα in HPV-positive OPC. This is the first study to demonstrate the prognostic role of ERα in HPV-positive OPC.

Objectives Cancer-related fatigue impairs daily functioning and negatively impacts health-related quality of life (HRQoL). Our previous study revealed that cisplatin-based chemoradiotherapy (CRT) impairs the carnitine system and carnitine deficiency leads to poor physical functioning. This open label, randomized, controlled prospective study investigated the effects of l -carnitine administration on plasma carnitine concentration, CRT-induced fatigue, and decline in HRQoL in patients with head and neck squamous cell carcinoma (HNSCC). Methods Patients were divided into experimental group (received 1000 mg of oral liquid l -carnitine once daily for 8 weeks) and control group. The primary and secondary endpoints were the change in HRQoL scores and the change in carnitine levels, respectively, from baseline (pre-CRT) to after CRT. Results The mean total plasma carnitine concentration in the control group decreased significantly, 2 weeks after the end of chemotherapy, while no significant differences were seen in the l -carnitine group. l -carnitine administration, therefore, kept the physical functioning score unchanged. Conclusion Our study shows that patients who receive CRT experience chemotherapy-induced damage of carnitine homeostasis leading to deficiency of carnitine and impairment of HRQoL. l -carnitine administration is beneficial in improving the HRQoL in patients with HNSCC.

We used hemilaryngotracheal tissue without tumor involvement as a laryngotracheal flap (LTF) for immediate repair of a pharyngoesophageal defect following resection for hypopharyngeal cancer. Five cases of lateralized advanced hypopharyngeal cancer were treated in our department. The median age was 82 years, ranging from 64 to 90 years. Four tumors were T3 stage, and the other was T2. A pharyngocutaneous fistula developed in one patient. The postoperative swallowing function was satisfactory, but one patient developed difficulty in eating a normal diet, because of pharyngoesophageal stenosis at 7 months after chemoradiotherapy. During the follow-up period, there was no locoregional recurrence. One patient had lung metastasis, and died of the disease. One patient died of another cause. Three patients are alive without evidence of the disease. Reconstruction of the hypopharynx with an LTF is a minimally invasive method compared with the radial forearm free flap and free jejunal flap. For selected cases of advanced hypopharyngeal cancer, this method would be one of the choices to reconstruct the pharyngoesophageal defect.

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.

Since the publication of Intergroup Study 0099, representing a superiority of concurrent chemoradiotherapy with cisplatin followed by adjuvant chemotherapy to radiotherapy alone for the treatment of locoregionally advanced nasopharyngeal carcinoma, an efficacy of concurrent setting of cisplatin-based chemotherapy with radiotherapy has been repeatedly validated. In meanwhile, the role of adjuvant part of the protocol has been controversial. There is an increasing evidence for the positive role of neoadjuvant chemotherapy with following concurrent chemoradiotherapy whereas favorable contribution was not proven in the last century. This article reviews the role of chemotherapy in the treatment of locoregionally advanced nasopharyngeal carcinoma.

Objective: Locally advanced thyroid carcinoma is relatively rare; extrathyroid extension, such as to the trachea, is one of the most important prognostic factors. Surgical resection is the mainstay of treatment, and appropriate surgical planning is crucial for obtaining a reasonable prognosis and quality of life of the patients. Case Report: Herein, we report a case of advanced thyroid carcinoma involving the trachea. Total thyroidectomy and window resection of the trachea were performed. The tracheal defect was approximately 2.5 × 3.0 cm in size, extending from the first to the third tracheal cartilage, and was reconstructed with auricular cartilage and covered with the sternohyoid muscles of both sides in a single-stage surgical procedure. The tracheal stoma was closed 2 weeks after the surgery. There were no postoperative complications. Conclusion: This reconstruction of the relatively small defect of the trachea provided excellent functional and cosmetic results.

金沢大学医薬保健研究域医学系, Background: Multifocal human papillomavirus (HPV) infection into the palatine and pharyngeal tonsils, which might be linked to a second primary tumor of HPV-positive oropharyngeal cancer (OPC), was investigated. Patients and methods: One hundred and five patients with various head and neck diseases including 14 patients with OPC were enrolled in this study. Swabs from the palatine and pharyngeal tonsils were collected in each individual, and auto-nested GP5+/GP6+ PCR for HPV DNA was performed. Results: HPV DNA was detected in the palatine tonsil or the pharyngeal tonsil in a small subset of upper respiratory tract cancer other than OPC (URTC) and non-cancer diseases. Furthermore, HPV DNA was detected in both the palatine and pharyngeal tonsils in the same individual in 2 of 48 (4%) URTC cases, and 1 of 43 (2%) non-cancer cases. On the other hand, p16-positive OPC cases demonstrated a higher HPV DNA detection rate (4 of 9, 44.4%) compared with other disease groups. Conclusion: HPV DNA detection in both the palatine and pharyngeal tonsils in the same individual, especially in HPV-OPC, suggested the ability of HPV to infect tonsillar tissues of Waldeyer’s ring multifocally. © 2017 Acta Oto-Laryngologica AB (Ltd), Embargo Period 12 months

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.

Objectives: A subgroup of oropharyngeal squamous cell carcinoma (OPC) is infected with high-risk human papillomavirus (HPV). The object of this study is to evaluate the efficacy of adjuvant chemotherapy with S-1, an oral 5-fluorouracil prodrug, on survival of patients with OPC according to HPV status. Methods: Among OPC patients of stage III or IV who received definitive treatment from 1998 to 2008, 38 who were confirmed tumor-free after primary treatment were analyzed. Before 2003, none of the patients received S-1 adjuvant chemotherapy (S-1(-)-group); however, all patients who were eligible were administered S-1 (S-1(+)-group) after 2003. The expression of thymidylate synthase (TYMS) involved in 5-FU metabolism was also examined in protein and mRNA levels. Results: Although there was a trend to disease-free and overall survival benefit in HPV-negative patients with S-1, it did not achieve statistical significance ( P = .082 and P = .065, respectively). For the HPV-positive patients, the survivals were similar with or without S-1 administration. TYMS-expression in HPV-positive OPC tissues was significantly higher than in HPV-negative ones in both protein and mRNA levels ( P = .0489 and P = .0446, respectively). Conclusion: The current study provides a rationale to plan a randomized trial to compare the efficacy of S-1 according to the HPV status in OPCs.

We aimed to identify tumor- and treatment-related factors predicting gastrostomy tube dependence after concurrent chemoradiotherapy (CCRT) for hypopharyngeal cancer. We performed a retrospective review of all patients with hypopharyngeal cancer treated with CCRT between 2002 and 2012 except for those with residual or recurrent disease at evaluation. The incidence of gastrostomy tube dependence, defined as complete or almost complete dependence on tube feeding, at 6 months after the completion of treatment was the endpoint. A total of 75 patients were analyzed in this study. Twelve patients (16 %) showed gastrostomy tube dependence. Among tumor-related factors, the subsite (posterior wall versus pyriform sinus plus postcricoid) was the most significant factor correlated with gastrostomy tube dependence (p

The free jejunum flap technique has been regarded as the optimal approach during circumferential pharyngolaryngectomy reconstruction. Although classical patency tests are available, an intraoperative guarantee of the patency of anastomoses and microcirculations is inevitable. Indocyanine green near-infrared angiography (ICGA) was intraoperatively performed in six patients after reconstruction using the free jejunum flap. An adequate arterial as well as venous phase was observed. In addition to classical patency tests and doppler, we have successfully monitored the flap after total pharyngolalyngectomy intraoperatively using the ICGA. Our preliminary results implicate that this novel technique offers secure intraoperative monitoring of a free jejunum graft. This technique will provide us with advantages over regular patency test in selected cases. © 2014 Springer-Verlag Berlin Heidelberg.

Objective: Nasopharyngeal cancer (NPC) is radiosensitive and chemosensitive. We evaluated the efficacy of alternating chemoradiotherapy in patients with advanced NPC. Methods: Alternating chemoradiotherapy was initiated in 30 patients with NPC, and 27 patients with cancer stages II (n = 6), III (n = 8), IVA (n = 9), and IVB (n = 4) were retrospectively analyzed. Chemotherapy was initially administered followed by radiotherapy, and chemotherapy, radiotherapy, and chemotherapy were alternately administered. Of the 27 patients, 22 patients received cisplatin (50 mg/m2/day, days 6 and 7) and 5-fluorouracil (5-FU; 800 mg/m2/day, days 1-5), whereas 5 patients received carboplatin (AUC 4-5, day 6) and 5-FU. Results: Of the 27 patients, 19 (70%) received 3 chemotherapy courses. The total duration of alternating chemoradiotherapy was 81 to 101 days (median, 90 days). At a median follow-up of 53 months, the 5-year progression-free survival (PFS) was 71%. Multivariate analysis showed that weight loss and the number of chemotherapy courses had a significant effect on PFS. Conclusion: Alternating chemoradiotherapy led to similar or higher survival rates compared with concurrent chemoradiotherapy, which was characterized by good compliance and adaptable intensity.