Real-world treatment patterns and outcomes in Japanese patients with cervical esophageal cancer.

BACKGROUND: Cervical esophageal cancer (CEC) carries a poor prognosis; however, due to its low incidence, optimal treatment for CEC remains to be established. The purpose of this study was to clarify the current status of treatment of CEC in Japan and obtain evidence for establishing the appropriate treatment method. PATIENTS AND METHODS: We asked specialist training facilities accredited by the Japanese Broncho-Esophageal Society to register data on CEC cases that received curative treatment from January 2009 to December 2014, and conducted a retrospective review of the clinical data of 302 cases registered from 27 facilities. RESULTS: In regard to the initial therapy, of the 302 patients, 33 had undergone endoscopic resection, 41 had undergone surgery, 67 had received induction chemotherapy (IC), and 143 had received chemoradiotherapy (CRT). There were no significant differences in the 5-year overall survival rates among the patient groups that had received surgery, IC or CRT as the initial treatment; advanced stage and recurrent nerve invasion were identified as independent poor prognostic factors. Among the patients who had received IC or CRT as laryngeal-preserving surgery was not indicated at the time of the initial diagnosis, the functional laryngeal preservation rate at the end of the observation period was 34.8%. CONCLUSION: Even in patients with advanced CEC, there is the possibility of preserving the larynx by adopting IC or CRT. However, if the laryngeal function cannot be preserved, there is a risk of complications from aspiration pneumonia, so that the choice of treatment should be made carefully.

Influence of Epstein-Barr virus and human papillomavirus infection on macrophage migration inhibitory factor and macrophage polarization in nasopharyngeal carcinoma.

BACKGROUND: To assess the effects of Epstein-Barr virus (EBV) and human papillomavirus (HPV) infection on the tumor microenvironment, we examined the relationship between viral infection status, macrophage migration inhibitory factor (MIF), and tumor-associated macrophages in nasopharyngeal carcinoma (NPC). METHODS: A tissue microarray containing 150 cores from 90 patients with NPC and six with chronic inflammation was used. EBV and HPV status were detected using in situ hybridization with commercial EBER1 and HPV16/18 probes. Immunofluorescence double staining of MIF, pan-macrophage marker CD68, M1 macrophage marker CD11c, and M2 macrophage marker CD163 were analyzed using the same tissue microarray. The levels of these markers between NPC and inflammation cases and between tumor nests and stroma were compared. Correlations among these markers were analyzed. RESULTS: We found EBER1(+) cases in 90% of NPC patients, including 10% EBV/HPV co-infection. M1 macrophages mainly infiltrated the tumor nest, while M2 macrophages infiltrated the tumor stroma. We found a significant positive correlation between EBER1 levels and MIF levels in tumor nests and a significant positive correlation between HPV16/18 and CD11c(+) cell levels in NPC tissues. CONCLUSIONS: It is suggested that MIF is associated with EBV, and M1 macrophage infiltration is affected by HPV status in NPC.

A longitudinal study on circulating miR-21 as a therapeutic effect marker in head and neck squamous cell carcinoma.

The aim of the study is to investigate plasma miR-21 for a possible therapeutic effect determination marker in head and neck squamous cell carcinoma (HNSCC). Plasma samples are obtained from 86 HNSCC patients and 29 non-cancer volunteers who had been treated at Mie University Hospital between May 2015 and December 2016, and plasma miR-21 expression was measured using real-time quantitative reverse transcription polymerase chain reaction. In addition, plasma miR-21 level of advanced HNSCC patients including 22 non-recurrent cases and 11 recurrent cases before and after treatment was analyzed using a longitudinal design. Plasma miR-21 expression in 86 HNSCC patients was obviously higher than in 29 control patients (P < 0.0001). The area under the curve (AUC) for plasma miR-21 was 0.756 (95% confidence interval: 0.661-0.851). Furthermore, our longitudinal study of plasma miR-21 showed that the expression level of plasma miR-21 was significantly reduced at the time point of 2 months after treatment in case of no recurrence. On the other hand, plasma miR-21 was not decreased after treatment in case of 10 patients who had developed recurrences during the follow-up period. This study may provide new insights into the role of plasma miR-21 as a biomarker for HNSCC, and plasma miR-21 would be useful for early detection of tumor recurrence after operation or chemoradiotherapy.

Interleukin-33 induces mucin gene expression and goblet cell hyperplasia in human nasal epithelial cells.

We investigated whether IL-33 is involved in mucus overproduction and goblet cell hyperplasia in eosinophilic chronic rhinosinusitis (ECRS). IL-33 mRNA was significantly higher in the eosinophilic CRS group than in the non-eosinophilic CRS group from human nasal polyps. IL-33 induced MUC5AC mRNA and MUC5AC protein, and also goblet cell hyperplasia at air liquid interface culture in human nasal epithelial cells. In addition to that, IL-33 induced MUC5B and FOXA3, and reduces FOXJmRNA. In conclusion, our present study demonstrated that the direct evidence of IL-33 which lead to increase mucin gene and protein expression, as well as goblet cell hyperplasia. This study provides novel insights into the role of IL-33 on mucus overproduction in eosinophilic inflammation of human airways.

Oxytetracycline Inhibits Mucus Secretion and Inflammation in Human Airway Epithelial Cells.

Oxytetracycline is a broad-spectrum antibiotic, but its nonantibacterial effects in the human respiratory tract are unknown. In this study, the effects of oxytetracycline on mucus secretion and inflammation were examined by PCR and ELISA in the human airway epithelial cell line NCI-H292. Oxytetracycline (10 µg/mL) significantly inhibited TNF-α-induced MUC5AC gene expression and MUC5AC protein levels in NCI-H292 cells. It also downregulated IL-8 and IL-1ß gene expression and IL-1ß protein levels. Our findings demonstrated that oxytetracycline suppressed mucus production and inflammation in human respiratory epithelial cells, providing further evidence for the usefulness of oxytetracycline for human airway inflammatory diseases.

Endoscopic electrocauterization of pyriform sinus fistula.

To determine the efficacy of endoscopic electrocauterization for pyriform sinus fistula (PSF) using a flexible Bugbee cautery electrode. From 2009 to 2016, a total of eight patients with acute suppurative thyroiditis or cervical abscess secondary to PSF were retrospectively registered in our study (three males, five females; median age 6.5 years). All patients underwent endoscopic electrocauterization as treatment for PSF. Six of eight patients had no recurrence after the initial endoscopic electrocauterization of PSF. One patient with recurrence developed symptoms 9 days after cauterization and another experienced recurrence after 2 years. Mean follow-up for the eight patients was 50 months (range 5-96 months). No post-operative complication was reported. Endoscopic electrocauterization appears to be a less-invasive, safe, and effective method for the treatment of PSF.

[Intraoperative CT Is Useful in Diagnosing a Fish Bone Foreign Body Buried in the Tongue: A Case Report].

Fish bones as a foreign body are often present in the palatine tonsil and the base of the tongue. Such foreign bodies can often be diagnosed with inspection only. However, it is difficult to diagnose and extirpate a foreign body when it is buried in the oral/pharyngeal mucosa. We experienced a case of a fish bone foreign body buried in the tongue muscle layer. We report herein on the case of a 49-year-old man with a fish bone foreign body buried in his tongue. The patient had noticed a sore throat since eating a sea bream and was referred to our department. Visual inspection revealed no foreign body, but CT imaging revealed a fish bone in the tongue. We performed an emergency surgical exploration of tongue to locate the fish bone. Because the fish bone as a foreign body was unable to be confirmed by palpation, we identified the location of the fish bone by intraoperative CT. This is a rare case of a fish bone buried in the tongue muscle layer, and intraoperative CT was useful in identifying the positon of the foreign body.

Effects of interleukin-31 on MUC5AC gene expression in nasal allergic inflammation.

BACKGROUND: Interleukin-31 (IL-31) is a newly discovered T helper lymphocyte-derived cytokine that plays an important role in allergic inflammation. However, the effects of IL-31 on mucus production in nasal allergic inflammation are completely unknown. OBJECTIVE: To investigate the effects of IL-31 on mucin gene expression (MUC5AC) in patients with allergic rhinitis and in human airway epithelial cells. METHODS: Expression levels of IL-31 and IL-31 receptor A (IL-31RA) were evaluated in the inferior turbinate of patients with allergic rhinitis and non-allergic rhinitis with immunohistochemistry. IL-31-induced MUC5AC gene expression was measured with a MUC5AC luciferase reporter assay in human epithelial HM3-MUC5AC cells and quantified by quantitative real-time polymerase chain reaction in human airway epithelial A549 cells. RESULTS: IL-31RA was primarily localized in submucosal glands and upregulated in allergic rhinitis. IL-31 was detected in submucosal tissue and increased in allergic inflammation. MUC5AC gene expression was induced by IL-31 stimulation both in HM3-MUC5AC and A549 cells. Additionally, IL-31 cooperated with Th2 cytokines on MUC5AC gene expression in HM3-MUC5AC cells. CONCLUSION: IL-31 and IL-31RA are upregulated in patients with allergic rhinitis, and induce MUC5AC gene expression in human airway epithelial cells. These findings suggest that IL-31 plays an important role in mucus overproduction in nasal allergic inflammation.

Descending necrotizing mediastinitis from deep neck infection.

This study aims to identify predisposing characteristics of descending necrotizing mediastinitis (DNM) arising from deep neck infection (DNI) and to determine appropriate therapeutic intervention strategies. We retrospectively reviewed 54 patients (male, n = 34; female, n = 20; mean age, 64.5 years) who had been treated at Mie University Hospital for DNI between April 2001 and October 2011. Eight of nine patients who developed DNM confirmed by computed tomography of the neck and chest, underwent mediastinal drainage (video-assisted thoracic surgical drainage, n = 6; mediastinoscopy-assisted drainage, n = 2). A patient developed uncontrolled acute respiratory distress syndrome after aggressive surgery, resulting in a mortality rate of 12 %. High blood CRP values, and the pharynx and tonsils as origins of infection were factors involved in the development of DNM arising from DNI. In conclusion, DNM remains a destructive and fatal disease that requires aggressive treatment including mediastinal exploration.

[Case of papillary carcinoma of the thyroid gland with concurrent tuberculous lymphadenitis].

We report a case of papillary carcinoma of the thyroid gland and cervical lymph node metastases with concurrent tuberculous lymphadenitis that was diagnosed preoperatively. A 35-year-old woman presented with multiple lymph node swellings and an anterior neck mass. No findings suggesting the coexistence of pulmonary tuberculosis were present. The patient underwent a total thyroidectomy with bilateral neck dissection together with medication. Measures to prevent tuberculosis were undertaken during the perioperative period. The histopathological diagnosis was papillary carcinoma with both metastatic and tuberculous lymphadenitis of the lymph nodes in the neck. The possible coexistence of tuberculous lymphadenitis must be ruled out when lymph node swellings are observed in patients with head and neck cancer, including thyroid carcinoma.

The role of miR-21 as a predictive biomarker and a potential target to improve the effects of chemoradiotherapy against head and neck squamous cell carcinoma.

This study aimed to clarify whether circulating miR-21 represents a predictive biomarker in patients with head and neck squamous cell carcinoma (HNSCC) undergoing chemoradiotherapy, and to investigate the effect of miR-21 inhibitor for chemoradiation in human SCC cells. Plasma samples were obtained from 22 patients with HNSCC and 25 non-cancer volunteers. Plasma miR-21 expression was measured using real-time quantitative reverse transcription polymerase chain reaction. The effects of miR-21 inhibitor in human SCC cells were investigated by performing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometry and western blot analysis. As a result, plasma miR-21 expression was higher in HNSCC patients than in control patients (P < 0.001). Seven patients with recurrence showed significantly higher plasma miR-21 than the 15 patients without recurrence. And high miR-21 expression group showed poor overall survival. Moreover, miR-21 inhibition significantly enhanced cisplatin- or radiation-induced apoptosis. Western blot analysis suggested the programmed cell death 4 protein as a potential target of miR-21 in relation to apoptosis. In conclusion, this study provides new insights into the role of miR-21 as a predictive biomarker for HNSCC treated with chemoradiotherapy and suggests a potential target to improve the effects of chemoradiotherapy against HNSCC.

Intravenous Delivery of miR-21 Inhibitor in Mice With Head and Neck Squamous Cell Carcinoma.

BACKGROUND/AIM: Synthetic miRNA inhibitors have recently attracted considerable interest as potential therapeutic agents for head and neck squamous cell carcinoma. However, due to the lack of evidence, no attempts have been made to deliver these inhibitors intravenously for squamous cell carcinoma. MATERIALS AND METHODS: This study investigated whether intravenous administration of a miR-21 inhibitor with lipid nanoparticles could suppress HNSCC in xenograft mice. Head and neck squamous cell carcinoma xenograft mice were intravenously injected with Invivofectamine 3.0® containing either a miR-21 inhibitor or a control inhibitor, using a modified protocol for nucleic acid encapsulation. Quantitative PCR was used to measure the expression level of intratumoral miR-21. And TdT-mediated dUTP nick-end labeling (TUNEL) immunohistochemistry was used to assess cell death. RESULTS: Intravenous injection of miR-21 inhibitor significantly inhibited head and neck squamous cell carcinoma growth and miR-21 expression in tumor tissue compared to the control inhibitor. TUNEL assay showed significant apoptosis of tumor cells after intravenous administration of miR-21 inhibitor. CONCLUSION: Intravenous delivery of a miR-21 inhibitor with lipid nanoparticles is a promising approach for miRNA-targeted therapy of head and neck squamous cell carcinoma.

The role of transforming growth factor-α on mucin overproduction in eosinophilic chronic rhinosinusitis.

OBJECTIVES: Eosinophilic chronic rhinosinusitis (ECRS) is considered a refractory and intractable disease with thick mucus production, long-term nasal congestion, loss of sense of smell and intermittent acute exacerbations secondary to bacterial infections. In this study, we investigated which growth factor is deeply involved in the mucin overproduction in ECRS. METHOD: We employed fluorescence immunohistochemical analysis to evaluate whether or not TGF-α expression was upregulated in the nasal tissue of ECRS patients. We also examined MUC5AC transcription using a luciferase reporter plasmid in HM3-MUC5AC cells and A549 cells in order to assess the role of TGF-α in human epithelial cells. RESULTS: TGF-α immunoreactivity was found markedly increased in the submucosal tissue in the ECRS patient compared with that of a normal patient and with noneosinophilic CRS. TGF-α synergized with TNF-α to upregulate MUC5AC expression in human epithelial cells through the ERK signaling pathway. CONCLUSION: Our results demonstrated that TGF-α was highly expressed in the upper airway tract in ECRS patients and is deeply involved in mucus hypersecretion.

Effects of clarithromycin and dexamethasone on mucus production in isografted rat trachea.

OBJECTIVES: The purpose of this study was to develop an animal model for the study of mucus overproduction and to assess the effect of a 14-membered macrolide antibiotic and a glucocorticoid on lipopolysaccharide (LPS)-induced mucus production. METHODS: Tracheas from donor rats were homografted to recipient rats for 4 weeks, and the usefulness of this tracheal homograft model in the study of mucus production was examined. RESULTS: Oral administration of clarithromycin (CAM) to recipient rats for 4 weeks significantly reduced LPS-induced mucus production in the homografted trachea. Dexamethasone administered for 4 weeks also significantly reduced the mucus volume in LPS-treated homografted trachea compared with that in the control rats. The implanted trachea containing control medium was not histologically different from normal trachea. When the medium instilled into the implanted trachea contained 1 µg/ml LPS, the volume and spinability of mucus produced in the tracheal lumen were significantly increased compared to those in the trachea instilled with control medium. Goblet cell metaplasia was also observed in the implanted trachea containing LPS. CONCLUSIONS: The present study shows that LPS-administered homografted trachea is a good animal model of chronic hypersecretory diseases of the upper and lower airways. CAM and dexamethasone could be treatment choices in such hypersecretory diseases.

Effects of a novel nonantibiotic macrolide, EM900, on cytokine and mucin gene expression in a human airway epithelial cell line.

BACKGROUND/AIMS: Long-term macrolide therapy is an effective treatment for chronic sinusitis and diffuse panbronchiolitis. However, long-term use of macrolides may promote the growth of drug-resistant bacteria; therefore, development of macrolides with no antibacterial action is desirable. A new erythromycin (EM) derivative, (8R,9S)- 8,9-dihydro-6,9-epoxy-8,9-anhydropseudoerythromycin A (EM900), does not possess antibacterial action. METHODS: To determine whether EM900 induced a clinically relevant anti-inflammatory response and repressed mucin gene expression in cells derived from human airway epithelia, we assessed the effects of EM900 on IL-1ß-induced inflammatory cytokines in A549 cells and MUC5AC gene expression in HM3-MUC5AC cells. We also investigated the effects of EM900 on IL-1ß-induced NF-κB activation. We performed reporter gene assays and quantitative PCR in A549 and HM3-MUC5AC cells. RESULTS: Both EM and EM900 suppressed IL-1ß-induced IL-8 expression in A549 cells. EM900 also suppressed IL-1ß-induced IL-1ß and TNF-α expression in A549 cells. EM900 inhibited IL-1ß-induced MUC5AC expression in HM3-MUC5AC cells. Both EM and EM900 suppressed IL-1ß-induced NF-κB activation in A549 cells. CONCLUSION: This study demonstrated that EM900 suppressed the induction of inflammatory cytokines and MUC5AC gene expression in cells derived from human airway epithelia, and our findings indicate that these effects may be mediated by the suppression of NF-κB activation.

Synergistic induction of nuclear factor-kappaB by transforming growth factor-beta and tumour necrosis factor-alpha is mediated by protein kinase A-dependent RelA acetylation.

The TGF-beta (transforming growth factor-beta) pathway represents an important signalling pathway involved in regulating diverse biological processes, including cell proliferation, differentiation and inflammation. Despite the critical role for TGF-beta in inflammatory responses, its role in regulating NF-kappaB (nuclear factor-kappaB)-dependent inflammatory responses still remains unknown. In the present study we show that TGF-beta1 synergizes with proinflammatory cytokine TNF-alpha (tumour necrosis factor-alpha) to induce NF-kappaB activation and the resultant inflammatory response in vitro and in vivo. TGF-beta1 synergistically enhances TNF-alpha-induced NF-kappaB DNA binding activity via induction of RelA acetylation. Moreover, synergistic enhancement of TNF-alpha-induced RelA acetylation and DNA-binding activity by TGF-beta1 is mediated by PKA (protein kinase A). Thus the present study reveals a novel role for TGF-beta in inflammatory responses and provides new insight into the regulation of NF-kappaB by TGF-beta signalling.

Remodeling of nasal mucosa by allergen exposure in guinea pigs is suppressed by steroid and pranlukast.

BACKGROUND: It is unclear whether remodeling exists in allergic rhinitis in man. The aim of this study was to establish a guinea pig model of allergic rhinitis with remodeling and to examine the effects of dexamethasone and pranlukast on nasal mucosa remodeling. METHODS: In the first experiment, three groups of ovalbumin-sensitized Hartley guinea pigs received intranasal challenges with ovalbumin for 1, 8, 12 weeks, respectively. In the second experiment, to examine the effect of dexamethasone and pranlukast, the animals were divided into 4 groups: negative control group; ovalbumin-sensitized group; ovalbumin + dexamethasone group; and ovalbumin + pranlukast group. During 12 weeks of intranasal exposure to ovalbumin, the latter two groups received daily intraperitoneal injections of dexamethasone and pranlukast, respectively. RESULTS: In the first experiment, in contrast to the negative control group, the ovalbumin-sensitized group exhibited significant goblet cell hyperplasia, epithelial damage and deposition of extracellular matrix in the nasal septal mucosa and conchae. In the second experiment, these changes were significantly inhibited by dexamethasone and pranlukast, respectively. CONCLUSIONS: We have established a model of upper airway remodeling in guinea pigs. The tissue remodeling was inhibited by early intervention with the antiallergic-inflammatory agents dexamethasone and pranlukast.

Third Epidemiological Analysis of Nasopharyngeal Carcinoma in the Central Region of Japan from 2006 to 2015.

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 (2006-2015) 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.

Leukotriene D4 upregulates MUC2 gene transcription in human epithelial cells.

BACKGROUND/AIMS: Leukotriene (LT) D(4) has been shown to induce mucus secretion in the airways. Excessive mucus secretion characterizes airway inflammatory disease such as asthma, allergic rhinitis. However, little is known about the effect of LTD(4) on mucin gene expression. The aim of this study was to investigate the effect of LTD(4) on MUC2 gene expression in cultured epithelial cells (HM3-MUC2 cells). METHODS: HM3-MUC2 cells were treated with LTD(4) for 2 or 6 h. Reporter gene assay was mainly used for analysis.MUC2 protein levels were measured using an enzyme-linked immunosorbent assay. RESULTS: LTD(4) significantly increased MUC2 gene transcriptional activity in a dose-dependent manner. Pranlukast, which is a selective antagonist of CysLT(1) receptor, inhibited LTD(4)-induced MUC2 gene transcriptional activity in a dose-dependent manner. LTD(4)-induced MUC2 gene transcriptional activity was also suppressed by a G-protein inhibitor (pertussis toxin),a protein kinase C (PKC) inhibitor (bisindolylmaleimide), a mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitor (PD98059), an extracellular signal regulated kinase-2 (ERK-2) inhibitor (AG126) and a nuclear factor kappaB (NF-kappaB) inhibitor. In addition, pranlukast inhibited LTD(4)-induced NF-kappaB activity. CONCLUSION: These results suggest that LTD(4 )upregulates MUC2 gene transcription via a signaling pathway involving CysLT(1) receptor, G-protein, PKC, MEK, ERK and NF-kappaB.

A Case of Pyriform Sinus Fistula with Respiratory Distress in the Neonatal Period.

Pyriform sinus fistula (PSF) is an anomaly that can arise due to failure of involution of the third or fourth branchial cleft during embryogenesis. It can manifest clinically as sinuses, cysts, or abscesses in the neck and is common in childhood. Herein, we describe a neonate who presented with neck swelling and respiratory distress, which was secondary to a fourth branchial pouch sinus. Physical examination revealed swollen areas in the posterolateral pharyngeal wall and on the external left side of the neck. Computed tomography imaging showed a left-sided mass that was filled with air and fluid. Eventually, the pyriform sinus cyst and the entire fistulous tract were excised. The postoperative course was uneventful. Follow-up after 18 months showed no recurrence.