Neck metastasis in patients with T1-2 supraglottic cancer.

OBJECTIVES: Unlike glottic cancer, supraglottic cancer often presents with neck metastases. This different might be attributable to the location of the primary lesion. This study aimed to clarify the relationships between the sublocation of T1-2 supraglottic cancer, human papillomavirus (HPV) infection, neck metastasis, and prognosis of supraglottic cancer. METHODS: This retrospective clinical study investigated 55 Japanese patients with T1-2 supraglottic cancer treated between 1994 and 2015. RESULTS: Of 55 patients with T1-2 supraglottic cancer, neck metastasis was present at initial diagnosis in 14 patients (25.5%). Presence of neck metastasis was the only factor associated with worse prognosis of T1-2 supraglottic cancer (p=0.004). In multivariate analysis, age <70years (p=0.033) and sublocation of the primary lesion in the superior epilaryngeal portion (p=0.017) were significantly associated with presence of neck metastasis in multivariate analysis. Twelve (27.9%) of 43 patients showed positive results for human papillomavirus infection. However, human papillomavirus infection was not associated with prognosis, presence of neck metastasis, or primary lesion sublocation in T1-2 supraglottic cancer. CONCLUSION: Relatively young patients with supraglottic cancer at the superior epilaryngeal portion are more likely to show neck metastasis. Human papillomavirus infection was not associated with frequency of neck metastasis.

IL-22/IL-22R1 signaling regulates the pathophysiology of chronic rhinosinusitis with nasal polyps via alteration of MUC1 expression.

BACKGROUND: IL-22 is an IL-10-family cytokine that regulates chronic inflammation. We investigated the role of IL-22 and its receptor, IL-22R1, in the pathophysiology of chronic rhinosinusitis with nasal polyps (CRSwNP). METHODS: IL-22 and IL-22R1 protein and mRNA expression in NP and in uncinate tissues (UT) from CRS and non-CRS patients was examined using immunohistochemistry and real-time PCR, respectively. Dispersed NP and UT cells were cultured with the Staphylococcus aureus exotoxins, staphylococcal enterotoxin B and alpha-toxin, following which exotoxin-induced IL-22 levels and their association with clinicopathological factors were analyzed. Effects of IL-22 on MUC1 expression and cytokine release in NP cells were also determined. RESULTS: IL-22 and IL-22R1 in NP were mainly expressed in infiltrating inflammatory cells and in epithelial cells, respectively. IL-22 mRNA levels in NP were significantly higher than those in UTs from non-CRS patients whereas IL-22R1 levels were conversely lower in NPs. NP cells produced substantial amounts of IL-22 in response to exotoxins. Exotoxin-induced IL-22 production by NP cells significantly and negatively correlated with the degree of local eosinophilia and postoperative computed tomography (CT) score, whereas conversely it positively correlated with the forced expiratory volume in 1s (FEV1)/forced vital capacity (FVC) ratio. IL-22 significantly enhanced MUC1 mRNA expression in NP cells. IL-22-induced MUC1 mRNA levels were significantly and positively correlated with IL-22R1 mRNA levels in NPs. CONCLUSIONS: These data suggest that imbalance of IL-22/IL-22R1 signaling regulates the pathogenesis of CRSwNP, including local eosinophilia, via alteration of MUC1 expression.

Effect of intranasal corticosteroid on pre-onset activation of eosinophils and mast cells in experimental Japanese cedar pollinosis.

BACKGROUND: Minimal persistent inflammation (MPI) contributes to hyperreactivity in allergic rhinitis. However, little is known regarding whether pre-onset activation of eosinophils and mast cells is present or not in Japanese cedar pollinosis (JCP). Furthermore, a prophylactic effect of intranasal corticosteroids on such MPI in JCP has not been investigated. METHODS: We designed a double-blinded, randomized, placebo-controlled, crossover trial. Twenty patients with JCP were examined outside the pollen season (UMIN000008410). Nasal provocation with paper discs containing extracts of Japanese cedar pollen was performed once a day for 3 consecutive days. Onset of nasal symptoms was monitored over 15 min after each provocation. The levels of eosinophil cationic protein (ECP) and tryptase in nasal secretions were examined. Fluticasone furoate nasal spray or placebo treatment was started one day before the first provocation. RESULTS: In the placebo group, 25% of the patients showed onset of nasal symptoms following provocation on the first day. In addition, 75% and 68% of the patients showed symptom onset on the second and third day of provocation, respectively. After the first provocation, the levels of ECP and tryptase in nasal secretions were significantly increased. These increases were seen not only in symptomatic but also in asymptomatic subjects in response to provocation, and the levels were similar between these subjects. Prophylactic treatment with fluticasone significantly suppressed the increase in nasal ECP and tryptase associated with repeated provocations. CONCLUSIONS: These results suggest that pre-onset activation of eosinophils and mast cells is present in experimental JCP, and that prophylactic treatment with intranasal corticosteroids has the potential to control such activation.

Regulatory effect of TLR3 signaling on staphylococcal enterotoxin-induced IL-5, IL-13, IL-17A and IFN-γ production in chronic rhinosinusitis with nasal polyps.

BACKGROUND: Toll-like receptor 3 (TLR3) is expressed in upper airways, however, little is known regarding whether Toll-like receptor 3 (TLR3) signals exert a regulatory effect on the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP), especially on eosinophilic inflammation. We sought to investigate the effect of Poly(IC), the ligand for TLR3, on cytokine production by dispersed nasal polyp cells (DNPCs). METHODS: DNPCs were pretreated with or without Poly(IC), and were then cultured in the presence or absence of staphylococcal enterotoxin B (SEB), following which the levels of IL-5, IL-10, IL-13, IL-17A and interferon (IFN)-γ in the supernatant were measured. To determine the involvement of IL-10 and cyclooxygenase in Poly(IC)-mediated signaling, DNPCs were treated with anti-IL-10 monoclonal antibody and diclofenac, the cyclooxygenase inhibitor, respectively. Poly(IC)-induced prostaglandin E2 (PGE2) production was also determined. RESULTS: Exposure to Poly(IC) induced a significant production of IL-10, but not of IL-5, IL-13, IL-17A or IFN-γ by DNPCs. Pretreatment with Poly(IC) dose-dependently inhibited SEB-induced IL-5, IL-13 and IL-17A, but not IFN-γ production. Neutralization of IL-10 significantly abrogated the inhibitory effect of Poly(IC). Treatment with diclofenac also abrogated the inhibitory effect of Poly(IC) on SEB-induced IL-5 and IL-13 production. However, unlike exposure of diclofenac-treated DNPCs to lipopolysaccharide, the ligand for TLR4, exposure of these cells to Poly(IC) did not enhance IL-5 or IL-13 production. Poly(IC) did not significantly increase PGE2 production by DNPCs. CONCLUSIONS: These results suggest that TLR3 signaling regulates eosinophilia-associated cytokine production in CRSwNP, at least in part, via IL-10 production.

Pulmonary function in never-smoker patients with chronic rhinosinusitis.

BACKGROUND: A close relationship between upper and lower respiratory tract diseases has been reported. The purpose of this study was to evaluate lung function in patients with chronic rhinosinusitis (CRS) who have never smoked. METHODS: A total of 208 patients with CRS were enrolled in this study. Of these subjects, 96 patients were ever smokers and 112 patients were never smokers. CRS patients with lower pulmonary diseases including chronic obstructive pulmonary disease (COPD) and asthma were excluded from this study. Age-matched normal control subjects (n = 55) who were never smokers were also recruited. Pulmonary function testing was performed using spirometry. Lund-Mackay computed tomography (CT) score, peripheral blood eosinophil count, and immunoglobulin E (IgE) level in serum samples were examined. Nasal obstruction was evaluated by active anterior rhinomanometry. RESULTS: CRS patients who were ever smokers have decreased lung function. Never-smoking patients with CRS also showed significant obstructive lung function changes as compared with normal controls. No significant correlation was detected between the clinical parameters (CT score, eosinophil count, IgE level, and nasal resistance) and lung function. CONCLUSION: Asymptomatic obstructive lung function changes were observed in never-smoking patients with CRS. Our findings suggest that patients with CRS should be followed carefully in order to detect lung diseases.

How long should we continue S-1 as adjuvant chemotherapy for squamous cell carcinoma of the head and neck?

CONCLUSION: It appears that patients with SCCHN should be recommended to take S-1 for more than 1 year and, if possible, more than 2 years, as adjuvant chemotherapy for SCCHN. OBJECTIVES: There is no established consensus on the duration of administration of S-1 as adjuvant chemotherapy for squamous cell carcinoma of the head and neck (SCCHN). Since it might be difficult to undergo prospective randomized study to identify the optimal duration of the administration period of S-1 without a standard, the authors have undergone a retrospective clinical study to decide the tentative standard of therapeutic duration of S-1 as adjuvant chemotherapy for SCCHN. METHODS: The clinical records of 89 patients with SCCHN who underwent adjuvant chemotherapy with S-1 were investigated. RESULTS: The median duration of S-1 administration as adjuvant chemotherapy for SCCHN was 7 months (range = 0.1-58 months). Disease-free survivals (DFSs) were generally longer when S-1 administration periods were longer. After adjusting for prognostic factors, S-1 administration periods of 24 months or longer showed significantly lower hazard ratios (HRs) than 0-12 months.

Macrophage Migration Inhibitory Factor Deficiency Causes Prolonged Hearing Loss After Acoustic Overstimulation.

HYPOTHESIS: Macrophage migration inhibitory factor plays an important role in noise-induced hearing loss. BACKGROUND: Macrophage migration inhibitory factor is an essential factor in axis formation and neural development. Macrophage migration inhibitory factor is expressed in the inner ear, but its function remains to be elucidated. METHODS: Macrophage migration inhibitory factor-deficient mice (MIF(-/-) mice) were used in this study. Wild-type and MIF(-/-) mice received noise exposure composed of octave band noise. Auditory brainstem response thresholds were examined before (control) and at 0, 12, and 24 hours and 2 weeks after the intense noise exposure. Morphological findings of cochlear hair cells were investigated using scanning electron microscopy. Histopathological examination with hematoxylin and eosin staining and TUNEL assay were also performed. RESULTS: In both the wild-type and MIF(-/-) mice, acoustic overstimulation induced significant hearing loss compared with the control level. Two weeks after the intense noise exposure, the MIF(-/-) mice had an increased hearing threshold compared with the wild-type mice. Scanning electron microscopy demonstrated that the outer hair cells in the MIF(-/-) mice were affected 2 weeks after noise exposure compared with the wild-type mice. TUNEL-positive cells were identified in the organ of Corti of the MIF(-/-) mice. CONCLUSION: The MIF(-/-) mice had prolonged hearing loss and significant loss of cochlear hair cells after intense noise exposure. Macrophage migration inhibitory factor may play an important role in recovery from acoustic trauma. Management of macrophage migration inhibitory factor may be a novel therapeutic option for noise-induced hearing loss.

Staphylococcal protein A-formulated immune complexes suppress enterotoxin-induced cellular responses in nasal polyps.

BACKGROUND: Recent studies have revealed that Staphylococcus aureus and its components participate in the pathogenesis of eosinophilic airway diseases, such as chronic rhinosinusitis with nasal polyps. OBJECTIVE: We sought to determine whether staphylococcal protein A (SpA) from S aureus regulated cellular responses in nasal polyps, especially when coupled to immunoglobulins in immune complexes (ICs). METHODS: Dispersed nasal polyp cells (DNPCs) or peripheral blood monocytes were cultured in vitro with SpA in the presence or absence of IgG, and IL-5, IL-13, IFN-γ, IL-17A, and IL-10 levels were measured in the supernatants. The effect of SpA exposure on staphylococcal enterotoxin B-induced cytokine production by DNPCs in the presence and absence of IgG, IgA, and autologous serum was also examined. RESULTS: Exposure to SpA induced DNPCs to produce significantly higher IL-10, IL-13, and IL-17A levels than DNPCs without SpA, although the magnitude of the IL-17A increase was less than that of IL-10 and IL-13. SpA induced IL-10 production mainly from adherent DNPCs, and this was significantly enhanced in the presence of IgG; similar results were observed in peripheral blood monocytes. IC formation between SpA and IgG (SpA-IgG ICs) was confirmed by using native polyacrylamide gel electrophoresis. SpA-IgG ICs, but not SpA alone, almost completely suppressed staphylococcal enterotoxin B-induced IL-5, IL-13, IFN-γ, and IL-17A production by DNPCs; similar inhibition was observed in DNPCs treated with SpA in the presence of either IgA or autologous serum. CONCLUSIONS: Our results suggest that SpA can regulate the pathogenesis of enterotoxin-induced inflammation in patients with chronic rhinosinusitis with nasal polyps through coupling to immunoglobulins.

Chronic rhinosinusitis patients have decreased lung function.

BACKGROUND: The relationship between upper and lower airway diseases has been reported. However, the pulmonary function of patients with chronic rhinosinusitis (CRS) has not been fully examined. METHODS: Pulmonary function was measured in 273 patients with CRS and 100 age-matched normal control subjects. No patients with chronic obstructive pulmonary disease (COPD) were included in this study. The patients with CRS were divided into 8 subgroups based on the presence of asthma, sensitization to common inhaled antigens, and nasal polyposis. The relationships between pulmonary function and clinical parameters, including radiographic severity of CRS according to the Lund-Mackay computed tomography (CT) staging system, eosinophil count in the peripheral blood, and serum total immunoglobulin E (IgE) levels, were assessed. RESULTS: In pulmonary function testing, the CRS patients had affected pulmonary function. The CRS patients without asthma showed latent obstructive pulmonary function changes when compared to normal controls. No significant correlations were observed between pulmonary function and any clinical parameters (Lund-Mackay CT staging score, eosinophil count in the peripheral blood, and serum total IgE levels). CONCLUSION: CRS patients had significant obstructive lung function changes regardless of the presence of asthma. The patients with CRS who had not been clinically diagnosed as having lower respiratory tract diseases might have had subclinical lower airway diseases. Therefore, clinicians should be aware of pulmonary function and lower lung diseases in patients with CRS.

Cellular responses to Staphylococcus aureus alpha-toxin in chronic rhinosinusitis with nasal polyps.

BACKGROUND: In contrast to Staphylococcus aureus-derived superantigenic exotoxins, the role of non-superantigenic exotoxins in the pathogenesis of eosinophilic airway diseases remains obscure. We sought to characterize S. aureus alpha-toxin-induced cellular responses in chronic rhinosinusitis with nasal polyps (CRSwNP). METHODS: Dispersed nasal polyp cells and uncinate tissue cells were prepared from patients with CRS with and without nasal polyps, respectively. Cells were incubated with various concentrations of alpha-toxin or staphylococcal enterotoxin B and then the levels of IL-5, IL-13, IFN-γ, IL-17A, and IL-10 in the cell supernatants were determined. The pathophysiological significance of alpha-toxin-induced cytokine production was also determined including radiological severity of rhinosinusitis, tissue and blood eosinophilia, serum total IgE level, and 1-s forced expiratory volume/forced vital capacity ratio (FEV1/FVC). RESULTS: Nasal polyp cells produced substantial amounts of IL-5, IL-13, IFN-γ, IL-17A, and IL-10 in response to alpha-toxin. Cytokine production was higher in nasal polyp cells than in uncinate tissue cells. The potency of alpha-toxin in stimulating IL-5, IL-13, and IL-10 production was comparable to that of enterotoxin. Alpha-toxin-induced IFN-γ, IL-17A, and IL-10 production significantly and negatively correlated with the degree of eosinophil infiltration into nasal polyps. Conversely, alpha-toxin-induced IFN-γ and IL-10 production significantly and positively correlated with FEV1/FVC. IL-10 production was significantly lower in asthmatic patients compared to non-asthmatics CONCLUSIONS: S. aureus-derived alpha-toxin can provoke cellular responses in nasal polyps. These responses, especially failure to synthesize IL-10, may play a role in the pathophysiology of CRSwNP.

Cervical lymph node extirpation for the diagnosis of malignant lymphoma.

PURPOSE: Lymph node enlargement in the neck is a common presentation of malignant lymphoma (ML) and requires tissue sampling for accurate diagnosis. Although delayed diagnosis may be critical for some patients, unnecessary biopsy should be avoided wherever possible. This study examined the process for determining the necessity to perform a biopsy and evaluated the value of an open biopsy as a diagnostic tool to enable definite subclassification of the disease. METHODS: The subjects included 20 patients with suspected ML who underwent cervical lymph node extirpation at Okayama Saiseikai general hospital between 2007 and 2010. The decision to perform a biopsy was made based on the results of sonographic evaluation, fine needle aspiration cytology (FNAC), and serum levels of lactate dehydrase (LDH) and soluble interleukin-2 receptor (sIL-2r). RESULTS: The diagnosis was ML in 15 patients (75%), Castleman's disease in 1 (5%), and benign lymphadenopathy in 4 (20%). CONCLUSIONS: A lymph node biopsy remains the gold standard for the diagnostic evaluation of ML. Sonographic evaluation combined with serum levels of LDH and sIL-2r is useful in determining the need for biopsy. Many of the cases of ML where it was difficult to determine whether a biopsy should be performed were relatively low grade and critical conditions could be avoided by close observation of the patient.

Neuroendocrine carcinoma of the larynx presenting as a primary unknown carcinoma.

OBJECTIVE: The case of an 80-year-old man showing a metastatic cervical small cell neuroendocrine carcinoma is presented. RESULTS: The primary site could not be found at first; it took 8-10 months to detect the primary lesion in the larynx. CONCLUSION: (18)F-deoxyglucose positron emission tomography (FDG-PET) was useful to find the submucosal lesion. Despite surgical treatments and chemotherapy, the patient survived for only 21 months.

Orbital emphysema causing syncope.

Orbital emphysema is an abnormal condition in which air is present within the orbit. We report a rare case of a 19-year-old man who suffered syncopic attacks caused by sniffles following orbital emphysema as a result of trauma. Treating rhinitis is important in patients with orbital emphysema, and patients with cardiac disorders in addition to those with this condition must be warned about the risks of sniffles, sneezing, or nose blowing.