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Recently, JESREC score and mucosal eosinophil count have been used to diagnose eosinophilic chronic rhinosinusitis (ECRS) in Japan. However, it remains unknown whether the subtypes of CRS diagnosed by these criteria have different endotypes. In the present study, we investigated whether JESREC score and mucosal eosinophil count were appropriate for classification of CRS subgroups into endotypes.A cross-sectional study involving 71 consecutive patients with CRS with nasal polyps (CRSwNP) and 13 control patients was performed. Nasal polyp tissues from CRSwNP patients and uncinate process tissues from control patients were collected for analysis of inflammatory cells by immunohistochemistry and measurement of cytokines and chemokines by ELISA and quantitative real-time PCR. We compared the differences between subtypes according to JESREC score and mucosal eosinophil count and investigated the subgroups with different endotypes by cluster analysis and principal component analysis.In the 71 CRSwNP patients, 9 patients had JESREC score11 and mucosal eosinophil count70/HPF (Group A), 20 patients had JESREC score ≥11 and mucosal eosinophil count70/HPF (Group C), and 42 patients had JESREC score ≥11 and mucosal eosinophil count ≥70/high-power field (HPF) (Group D). Semiquantitative analysis of inflammatory cells showed that eosinophils, neutrophils, macrophages, mast cells, and basophils differed significantly between the subgroups. At the mRNA level, CLC, IL5, IL13, CCL11, CCL24, CCL26, POSTN, CSF3, and IL8 showed significant differences. At the protein level, eotaxin-2/CCL24, eotaxin-3/CCL26, and G-CSF had significant differences. Cluster analysis using gene expression levels in 55 CRS patients and 11 control patients revealed that the patients could be classified into five clusters. Cluster 1 (n=27) contained all patients with Group D. Cluster 2 (n=11) comprised all control patients. Cluster 3 (n=4) included mixed subtypes: one with Group A and three with Group D. Cluster 4 (n=7) and Cluster 5 (n=17) contained all patients with Groups A and C, respectively. Furthermore, the principal component analysis revealed that the subtypes had different characteristics.CRS subtypes based on JESREC score and mucosal eosinophil count showed different inflammatory patterns, and unsupervised statistical analyses supported the classification that can predict endotypes. From these results, we concluded that the classification based on JESREC score and mucosal eosinophil count was useful for predicting CRS endotypes.

Background Strong eosinophil infiltration in chronic rhinosinusitis with nasal polyp (CRSwNP) is highly associated with recalcitrance and higher nasal polyp recurrence rate after surgery. The prevalence of eosinophilic CRSwNP (ECRS) is increasing in Asian countries including Japan. Benralizumab is a humanized anti-IL-5R alpha monoclonal antibody that depletes eosinophils by antibody-dependent cell-mediated cytotoxicity. Objective To assess the efficacy and safety of benralizumab in patients with ECRS. Methods This phase II, randomized, double-blind, placebo-controlled study was conducted in Japan. Patients were randomized 1:2:2 to placebo, a single administration of benralizumab 30 mg, or benralizumab 30 mg every 4 weeks (q4w) for a total of three doses. The primary endpoint was the change in nasal polyp score from baseline at Week 12. Results Overall, 56 patients were enrolled (placebo, n = 11; benralizumab single dose, n = 22; benralizumab q4w, n = 23). Although the mean total nasal polyp score began to decrease after the initiation of benralizumab treatment, there were no statistically significant differences in change in nasal polyp score from baseline at Week 12 between benralizumab and placebo (placebo, −0.5 ± 0.8; benralizumab single, −0.3 ± 0.8; benralizumab q4w, −0.5 ± 1.5). Post-hoc analysis showed that the administration of benralizumab decreased nasal polyp scores ≥2 points in 42.2% of ECRS patients and that patients with high blood eosinophil levels had a greater tendency to respond to benralizumab treatment. The safety profile was similar to that in previous studies and no unexpected adverse events were noted. Conclusion Although benralizumab did not meet the primary efficacy endpoint, reductions of nasal polyp scores were seen in the benralizumab group compared with the placebo group over the whole study period, especially in patients with high levels of blood eosinophils.

Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is known to have 2 phenotypes in East Asia. Eosinophilic CRSwNP (ECRSwNP), defined as tissue eosinophilia and easily recurrent, is distinguished from other non-eosinophilic CRSwNP (NECRSwNP) types. However, the pathogenesis of each remains unclear. Methods Nasal polyp tissues from ECRS (ECRSwNP) and NECRS (NECRSwNP) patients were obtained, and their comprehensive gene expression profiles were investigated by microarray analysis. Bioinformatics approaches (eg, Ingenuity Pathway Analysis [IPA]) were used to interrogate the data sets. Results Hierarchical clustering and principal component analysis (PCA) collectively showed that ECRSwNP and NECRSwNP had distinct gene expression patterns. Of note, these genes could be divided into 8 distinctive clusters having different expression patterns and functions. Upstream Regulator Analysis revealed that not only T-helper 2 (Th2) and the eosinophilia-related molecules (interleukin 4 [IL4], IL5, and colony stimulating factor 2 [CSF2]) reported so far, but also cell cycle regulators (cyclin dependent kinase inhibitor 1A [CDKNA1] and cyclin D1 [CCND1]) and a tissue fibrosis-related molecule (transforming growth factor β [TGFβ]) were identified in ECRSwNP. On the other hand, mainly interferons (IFNs) and acute inflammatory cytokines (IL1 and IL6) were predicted as upstream regulators in NECRSwNP. Conclusion These results are useful for understanding the molecular basis of the mechanisms of CRSwNP and point to new targets for developing specific biomarkers and personalized therapeutic strategies for CRSwNP.

Reverse transcription–quantitative polymerase chain reaction is a valuable and reliable method for gene quantification. Target gene expression is usually quantified by normalization using reference genes (RGs), and accurate normalization is critical for producing reliable data. However, stable RGs in nasal polyps and sinonasal tissues from patients with chronic rhinosinusitis (CRS) have not been well investigated. Here, we used a two-stage study design to identify stable RGs. We assessed the stability of 15 commonly used candidate RGs using five programs—geNorm, NormFinder, BestKeeper, ΔCT, and RefFinder. Ribosomal protein lateral stalk subunit P1 (RPLP1) and ribosomal protein lateral stalk subunit P0 (RPLP0) were the two most stable RGs in the first stage of the study, and these results were validated in the second stage. The commonly used RGs β-actin (ACTB) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) were unstable according to all of the algorithms used. The findings were further validated via relative quantification of IL-5, CCL11, IFN-γ, and IL-17A using the stable and unstable RGs. The relative expression levels varied greatly according to normalization with the selected RGs. Appropriate selection of stable RGs will allow more accurate determination of target gene expression levels in patients with CRS.

Mechanotransduction plays an important role in cell-proliferative activities. Negative pressure in the middle ear is thought to be an important factor related to the etiology of acquired middle ear cholesteatoma. However, the correlation between negative pressure in the middle ear and the mechanism of middle ear cholesteatoma formation remains unclear. In this study, we investigated the expression of key molecules for mechanotransduction immunohistochemically.An immunohistochemical analysis was performed using anti-Wnt5a (a marker of alternative Wnt signaling), -Yes-associated protein (YAP) (a marker of mechanosensing) and -pYAP (phosphorylated YAP at Ser 127: inactivated YAP) antibody in the tympanic membrane (TM) under a negative pressure load and in human middle ear cholesteatoma tissues.The number of Wnt5a-positive cells had increased and YAP nuclear translocation was observed in epithelial and mesenchymal cells in the pars flaccida (PF) of the TM under a negative-pressure load and in human middle ear cholesteatoma tissues.We demonstrated that negative pressure in the middle ear might possibly induce cell proliferation PF of TM in response to mechanical force (mechanotransduction) through YAP nuclear translocation mediated by alternative Wnt signaling, thus affecting human middle ear cholesteatoma formation.

DNA methylation is an important epigenetic mechanism for cellular maintenance. However, the methylation pattern and the key molecule regulated epigenetically in oral mucosal regeneration is unclear. In this study, we generated a rat oral ulcer model and investigated the cell proliferative activities and DNA methylation patterns immunohistochemically. We also performed immunohistochemical analysis of a regulator of epithelial stem/progenitor cell differentiation in the rat model. We demonstrated immunohistochemistry using antibodies for the molecules as follows: Ki-67, a marker of cellular proliferation; 5-methylcytosine (5-mC), a marker of DNA methylation; 5-hydroxymethylcytosine (5-hmC), a marker of DNA demethylation; Dnmt1, a maintenance DNA methyltransferase; Dnmt3a and Dnmt3b, de novo DNA methyltransferases; and Wnt5a, a regulator of stem/progenitor cell differentiation. In this model, re-epithelialization was completed at Day 4 after ulceration. Regenerating mucosal hypertrophy reached a peak at Day 5 and appeared normal at Day 14. Ki-67-positive cells increased at Day 2 and returned to normal at Day 6 after ulceration. The ratio of the expression level of 5-mC to 5-hmC declined at Day 5 and returned to normal at Day 6. The expression level of Dnmt1 had not changed compared to the normal control at every time point. On the other hand, the expression levels of Dnmt3a and Dnmt3b had decreased significantly at Day 5 and returned to normal at Day 6. Moreover, Wnt5a-positive cells increased at Day 5. In conclusion, oral mucosal regeneration was strictly regulated by DNA methylation. Moreover, Wnt5a might play a critical role in oral mucosal regeneration.

Letter to the Editor

Background Chronic rhinosinusitis (CRS) can be classified into CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). CRSwNP displays more intense eosinophilic infiltration and the presence of Th2 cytokines. Mucosal eosinophilia is associated with more severe symptoms and often requires multiple surgeries because of recurrence; however, even in eosinophilic CRS (ECRS), clinical course is variable. In this study, we wanted to set objective clinical criteria for the diagnosis of refractory CRS. Methods This was a retrospective study conducted by 15 institutions participating in the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC). We evaluated patients with CRS treated with endoscopic sinus surgery (ESS), and risk of recurrence was estimated using Cox proportional hazard models. Multiple logistic regression models and receiver operating characteristics curves were constructed to create the diagnostic criterion for ECRS. Results We analyzed 1716 patients treated with ESS. To diagnose ECRS, the JESREC scoring system assessed unilateral or bilateral disease, the presence of nasal polyps, blood eosinophilia, and dominant shadow of ethmoid sinuses in computed tomography (CT) scans. The cutoff value of the score was 11 points (sensitivity: 83%, specificity: 66%). Blood eosinophilia (>5%), ethmoid sinus disease detected by CT scan, bronchial asthma, aspirin, and nonsteroidal anti-inflammatory drugs intolerance were associated significantly with recurrence. Conclusion We subdivided CRSwNP in non-ECRS, mild, moderate, and severe ECRS according to our algorithm. This classification was significantly correlated with prognosis. It is notable that this algorithm may give useful information to clinicians in the refractoriness of CRS before ESS or biopsy.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is known to have 2 phenotypes in East Asia. Eosinophilic CRSwNP (ECRSwNP), defined as tissue eosinophilia and easily recurrent, is distinguished from other non-eosinophilic CRSwNP (NECRSwNP) types. However, the pathogenesis of each remains unclear.Nasal polyp tissues from ECRS (ECRSwNP) and NECRS (NECRSwNP) patients were obtained, and their comprehensive gene expression profiles were investigated by microarray analysis. Bioinformatics approaches (eg, Ingenuity Pathway Analysis [IPA]) were used to interrogate the data sets.Hierarchical clustering and principal component analysis (PCA) collectively showed that ECRSwNP and NECRSwNP had distinct gene expression patterns. Of note, these genes could be divided into 8 distinctive clusters having different expression patterns and functions. Upstream Regulator Analysis revealed that not only T-helper 2 (Th2) and the eosinophilia-related molecules (interleukin 4 [IL4], IL5, and colony stimulating factor 2 [CSF2]) reported so far, but also cell cycle regulators (cyclin dependent kinase inhibitor 1A [CDKNA1] and cyclin D1 [CCND1]) and a tissue fibrosis-related molecule (transforming growth factor β [TGFβ]) were identified in ECRSwNP. On the other hand, mainly interferons (IFNs) and acute inflammatory cytokines (IL1 and IL6) were predicted as upstream regulators in NECRSwNP.These results are useful for understanding the molecular basis of the mechanisms of CRSwNP and point to new targets for developing specific biomarkers and personalized therapeutic strategies for CRSwNP.

Objective The Lund–Mackay system (L–M system) is widely used for computed tomography (CT) evaluation of chronic rhinosinusitis (CRS). However, a major drawback of the L–M system is its insufficiency of gradation. To avoid this deficiency, a new staging system proposed by American societies and the Zinreich system were reported as modifications of the L–M system. The aim of this study was to investigate the efficiency of gradation and the accuracy of the visual quantification of these modified staging systems. Methods Preoperative CT scanning was performed on 20 adult patients with CRS. A computer workstation was used to measure the volume of each sinus and the volume of inflammatory disease in each sinus. Then the soft tissue density rate (STDR) and objective scores, which were adapted to each system, were calculated. Visual evaluation of the CT images was performed using these systems. The visual score with each staging system and STDR value were evaluated for a correlation, and the rate of agreement was determined between the visual and objective scores obtained with each staging system. Results The correlation between the visual scores and the STDR values was shown with all staging system including L–M system. The coefficients of correlation between the visual scores and the STDR values with these modified systems were higher than with the L–M system. While the agreement rates with these modified systems were significantly lower than with the L–M system, differences of 2 or greater between the subjective and objective scores were rare. Conclusion We cannot conclude that one of these three staging systems is superior to the other. With this study, the simple grading system such L–M staging score was considered easy and accurate method to use the clinical level. The modified staging systems showed more efficient ability to gradate in evaluating rhinosinusitis inflammation compared with the L–M system and also showed acceptable accuracy.

Background Endoscopic medial maxillectomy (EMM) is a safe and effective procedure for treatment of inverted papilloma (IP) originating from the maxillary sinus. However, EMM usually removes the inferior turbinate and nasolacrimal duct. The inferior turbinate has a critical function in conditioning of the nasal airflow, and resection of the nasolacrimal ducts has a risk of epiphora. We developed a newly derived surgical technique, endoscopic modified medial maxillectomy (EMMM), which enables preservation of the inferior turbinate and nasolacrimal duct. Methods A retrospective case series of six patients with IP and nine patients with mucoceles of the maxillary sinus after a Caldwell-Luc operation, who underwent surgery using the EMMM technique, were reviewed. Results In patients with IP, there were no recurrences for a mean follow-up of 16.7 months. Eight of nine patients with mucoceles of the maxillary sinus showed patency. All patients showed preservation of the inferior turbinate. One patient with mucocele was referred for dacryocystorhinostomy because of epiphora. Conclusion EMMM produces access to the maxillary sinus identically to conventional EMM, despite preservation of the inferior turbinate and nasolacrimal duct.

Background The pathophysiology of chronic rhinosinusitis (CRS) is not fully understood. In Europe and the United States, major subsets of CRS classification are based on the presence or absence of polyps. Although nasal polyps (NPs) are a critical factor, many other factors also contribute to the pathogenesis of CRS. The aim of this study was to investigate diverse CRS phenotypes using cluster analysis. Methods This was a multicenter study examining clinical data from CRS patients treated at five hospitals. The study design was a retrospective analysis of prospectively collected data. Complete data were available for 425/496 patients. Data were subjected to k-means cluster analysis in an attempt to identify the different phenotypes involved in CRS. Results CRS was divided into four clusters. Cluster 1 (n = 180) and cluster 2 (n = 129) comprised patients with low peripheral eosinophil and mucosal eosinophil counts. However, polyp scores in cluster 2 were higher than cluster 1. Cluster 3 (n = 50) comprised patients with very high mucosal eosinophil counts but low polyp and symptom scores. Finally, subjects in cluster 4 (n = 66) showed severe polyposis. Polyp score and mucosal eosinophil count were the strongest predictors of clustering by discriminant analysis. Conclusion The results of this study identified distinct clinical CRS phenotypes. CRS was classified into four phenotypes based on NPs and mucosal eosinophil counts. Cutoff points for these factors were identified by tree analysis. Additional studies are needed to establish clinical significance of the phenotypes.

Current knowledge on the prevalence and clinical features of antrochoanal polyps (ACPs), benign lesions arising in the maxillary sinus and extending into the choana, is very limited in Japan. We prospectively evaluated prevalence and clinical features in 15 subjects with ACPs from among 728 undergoing endoscopic endonasal sinus surgery between April 2007 and March 2008, and prospectively enrolled in this study. The 15 subjects, who accounted for 2.1% of the total, had nasal obstruction, rhinorrhea, and postnasal drip. Symptoms significantly reduced postoperatively. Maxillary-sinus-origin ACP distribution was 40% from the maxillary sinus floor to the posterior wall, 26.7% from maxillary sinus floor, and 20% from the maxillary sinus floor to the internal wall. Postoperative recurrence was 13.3%. Endoscopic endonasal sinus surgery for ACPs was most effective for polyp is originating in the maxillary sinus determined carefully and excised as completely as possible, followed by appropriate postoperative treatment.

Background: Interleukin (IL)-33, which is a member of the IL-1 family of cytokines, is now recognized as an important contributor to Th2-type immune responses. We examined whether the levels of IL-33 in sera and nasal secretions are upregulated in allergic rhinitis (AR) patients, and we tested for correlations between the IL-33 level and the parameters of atopy and the nasal symptom score. Methods: The study included 24 Japanese cedar pollinosis patients (12 male and 12 female patients with a mean age of 47.7 years) with a history of moderate-to-severe AR, 14 house-dust-mite-sensitized patients with AR (9 male and 5 female patients with a mean age of 42 years) and 8 normal controls. We used Japan Rhinoconjunctivitis Quality-of-Life Questionnaire sheets to evaluate the nasal symptoms. We collected sera and nasal secretions to examine the level of IL-33 protein by ELISA. Results: IL-33 protein was not detected in the serum of any of the subjects. However, the IL-33 level in nasal secretions was significantly elevated in patients with Japanese cedar pollinosis at peak season and in patients with perennial AR compared to Japanese cedar pollinosis patients at preseason and the normal controls. Furthermore, IL-33 in nasal secretions correlated significantly with the total nasal symptom score. Conclusions: Our results suggest that IL-33 in nasal secretions may be related to exacerbation of AR, including that of Japanese cedar pollinosis cases.

Background: Eosinophils accumulate in tissues during various allergic inflammatory processes. Selective eosinophil recruitment is the result of orchestrated events involving cell adhesion molecules and chemoattractants. However, the exact mechanism of the regulation of integrin avidity during interstitial migration is poorly understood. Objective: The purpose of this study was to investigate whether extracellular matrix proteins might activate human eosinophil chemotaxis and, if so, to clarify the mechanism in terms of integrin avidity. Method: Eosinophils were purified from the peripheral blood of healthy donors. Eosinophil migration was measured using Boyden chambers with filter membranes coated with fibronectin (Fn), vitronectin (Vn), laminin (Ln), hyaluronic acid, collagen type IV, or bovine serum albumin (BSA) overnight. Platelet-activating factor (PAF) was introduced into the lower chamber of each well. Eosinophils were placed in the upper chamber after incubation with IL-5 for 15 min. The number of eosinophils that transmigrated into the lower chamber was calculated by measuring the eosinophil peroxidase activity. Results: Fn, Ln and BSA enhanced PAF-induced chemotaxis of eosinophils. Inhibition experiments using blocking monoclonal antibodies showed that in the early phase of chemotaxis, Fn and Ln facilitated eosinophil chemotaxis that was mediated by α4 and α6 integrins, respectively. In the late phase of chemotaxis, BSA, but not other matrix proteins, facilitated both chemokinesis and chemotaxis that was mediated by β2 integrin. Conclusion: Our data strongly suggest that during chemotaxis, matrix proteins might activate eosinophils via binding with integrins to facilitate PAF-induced chemotaxis, and that such a mechanism might participate in allergic inflammatory processes.

The relationship between eosinophil and chronic sinusitis was investigated by measuring the concentration of eosinophil cationic protein (ECP). In addition to the blood, a cytological brush was inserted into middle meatus to scrape the nasal membrane, and the concentration of ECP in the collected specimen was measured. There was a moderate degree of correlation between the blood eosinophil count and the ECP concentration in the blood (r = 0.543, p < 0.01). On the other hand, there was high degree of correlation between the number of EG2-positive cells and ECP of the nasal membrane in the middle meatus (r = 0.805, p < 0.001), reflecting the amount of ECP in the nasal mucous membrane. The ECP in 10 control group subjects and 14 patients with severe chronic sinusitis and nasal polyps was significantly lower than that in 14 patients with severe chronic sinusitis and asthma (p < 0.01). The ECP concentration of the nasal membrane in the middle meatus was significantly lower in patients showing a good postoperative course compared with patients showing a poor postoperative course following Endoscopic Sinus Surgery (p < 0.01). These findings suggest that eosinophils are closely related to the pathology and clinical course of chronic sinusitis, and that the ECP concentration of the nasal membrane in the middle meatus reflects the pathology of chronic sinusitis. The ECP concentration thus has potential as a prognostic indicator for chronic sinusitis.

Background Chronic rhinosinusitis (CRS) is characterized by local inflammation of the sinonasal tissues. CRS patients with nasal polyps and asthma often develop acute exacerbation of sinonasal symptoms after upper respiratory tract infections. However, the influence of concomitant asthma on the nasal immune response to viral infection remains unclear. Methods Specimens of nasal polyp and mucosal tissues were obtained from 3 groups of CRS patients ( n = 14 per group): 1) patients without asthma (CRS group), 2) patients with aspirin-tolerant asthma (ATA group), and 3) patients with aspirin-intolerant asthma (AIA group). Nasal fibroblasts isolated from the specimens were stimulated with poly I:C. CXCL10 expression was analyzed by the quantitative real-time polymerase chain reaction and enzyme-linked immunoadsorbent assay. Biopsy specimens from CRS patients without asthma were subjected to immunohistochemistry for detection of T-bet and GATA-3 expression in CD3+ T cells by double labeling. Results Nasal fibroblasts from the ATA and AIA groups showed significantly enhanced expression of CXCL 10 mRNA and protein after poly I:C stimulation compared with cells from the CRS group and the control group (normal nasal mucosa). In addition to T helper (Th)2 cells, there was more abundant infiltration of Th1 cells into tissues from the AIA and ATA groups. Conclusions Our findings suggest that CRS associated with asthma may become intractable through the over-production of CXCL10 in response to viral infection.

To investigate whether keratinocytes proliferate in response to epiregulin produced by subepithelial fibroblasts derived from middle ear cholesteatoma. Tissue samples were obtained from patients undergoing tympanoplasty. The quantitative polymerase chain reaction and immunohistochemistry were performed to examine epiregulin expression and localization in cholesteatoma tissues and retroauricular skin tissues. Fibroblasts were cultured from cholesteatoma tissues and from normal retroauricular skin. These fibroblasts were used as feeder cells for culture with a human keratinocyte cell line (PHK16-0b). To investigate the role of epiregulin in colony formation by PHK16-0b cells, epiregulin mRNA expression was knocked down in fibroblasts by using short interfering RNA and epiregulin protein was blocked with a neutralizing antibody. Epiregulin mRNA expression was significantly elevated in cholesteatoma tissues compared with that in normal retroauricular skin. Staining for epiregulin was more intense in the epithelial cells and subepithelial fibroblasts of cholesteatoma tissues than in retroauricular skin. When PHK16-0b cells were cultured with cholesteatoma fibroblasts, their colony-forming efficiency was 50% higher than when these cells were cultured with normal skin fibroblasts. Also, knockdown of epiregulin mRNA in cholesteatoma fibroblasts led to greater suppression of colony formation than knockdown in skin fibroblasts. Furthermore, the colony-forming efficiency of PHK16-0b cells was significantly reduced after treatment with an epiregulin neutralizing antibody in co-culture with cholesteatoma fibroblasts, but not in co-culture with skin fibroblasts. These results suggest that keratinocyte hyperproliferation in cholesteatoma is promoted through overexpression of epiregulin by subepithelial fibroblasts via epithelial–mesenchymal interactions, which may play a crucial role in the pathogenesis of middle ear cholesteatoma.

It is still controversial how old patients we should define the young in the colorectal cancer. First we studied the survival rates by age groups and the patients group under 30 years of age had significantly poorer prognosis than those in other age groups. So we defined the patients group under 30-year-old as young patients and the clinicopathological feature in 25 young patients were compared to other parients over 30-year-old. No significant differences were noted in the location of cancer, family history and histological type. Young patients suffered from symptoms for long time and 40% of them had Dukes D disease, and 48% of them underwent palliative operation. However, the prognosis of patients under 30 undergoing curative operation was good. It is likely that the prognosis of young patients with colorectal cancer was poor because of the late diagnosis of cancer rather than because of its aggressiveness in biologic behaivior.

Background Chronic ocular allergic diseases such as vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC) are accompanied by serious comorbidities; however, the underlying pathogenesis remains obscure. Furthermore, diagnosing conjunctival lesions in patients with atopic dermatitis and estimating the severity in AKC are important for the treatment of ocular allergic diseases. Objective We addressed whether periostin, a novel mediator and biomarker in allergic inflammation, is involved in the pathogenesis of ocular allergic diseases and whether periostin can be a biomarker for these diseases. Methods We investigated tear periostin in patients with seasonal allergic conjunctivitis (SAC), VKC, and AKC and allergic patients without conjunctivitis and compared it with tear IL-13 and serum periostin. Furthermore, in patients with AKC, we measured tear periostin before and after topical treatment with tacrolimus. Results Tears from patients with ocular allergic disease showed significantly high periostin levels than did tears from allergic patients without conjunctivitis and from patients with AKC, VKC, and SAC in descending order. Tear periostin was associated with serious comorbidities such as large papilla formation and corneal damage in AKC, although both tear IL-13 and serum periostin had little to no such abilities. Furthermore, after topical tacrolimus treatment, tear periostin tended to decrease in most patients with AKC along with their clinical improvement. Conclusions Periostin produced in conjunctival tissues stimulated by IL-13 may contribute to the pathogenesis of ocular allergic diseases. Furthermore, tear periostin can be potentially applied as a biomarker to diagnose conjunctivitis in allergic patients and to evaluate disease severity as well as the efficacy of treatments in AKC.

OBJECTIVE Our objective was to determine the rate of complications in endoscopic sinus surgery (ESS) and associated risk factors. METHODS We prospectively studied 1,382 subjects undergoing ESS for rhinosinusitis and cystic sinus disease at 16 hospitals during 2007 and 2008. Surgeons provided information on peri-and postoperative complication occurrence. RESULT Results of complications were seen in 80 subjects (5.8%), the most frequent was perioperative lamina papyracea injury. Analysis showed the complication rate to be linked to gender, and anesthesia type, but not the grade of surgeon. CONCLUSIONS While care should be taken to avoid them, complications should be identified and treated in a timely and accurate manner.

Background Patients undergoing endoscopic sinus surgery (ESS) are at risk of complications because of the close proximity of the sinuses to the orbit and anterior skull base. The aim of this study was to evaluate the complications of ESS and to identify patient characteristics that were risk factors for the complications. Methods We conducted a prospective study of 706 patients who underwent ESS for chronic rhinosinusitis. Patients completed preoperative examinations that included computed tomography, endoscopic observation for nasal polyps, and tests for comorbidities including asthma and vascular disease. Perioperative complications were evaluated based on information provided by the surgeons. Multivariate analysis was performed to identify patient characteristics that were risk factors for complications. Results Overall, perioperative complications occurred in 41 patients (5.8%). A major complication, cerebrospinal fluid leakage, occurred in one patient (0.1%). Minor complications occurred in 40 patients (5.7%), with the most common being intraoperative hemorrhage (n = 18). Multivariate analysis indicated that presence of asthma and the total polyp score correlated significantly with the occurrence of complications. Conclusion The risk factors for perioperative complications were asthma and the polyp score. We conclude that the surgeon should confirm whether the patient has lower airway disease, especially asthma, before operating. The surgeon should also determine the grade of nasal polyps.

Background: Eosinophils and nasal polyps are believed to affect the surgical outcome of chronic rhinosinusitis (CRS). CRS is classified based on the presence of nasal polyps in western countries. The majority of patients with CRS with nasal polyps (CRS with NP) are characterized by predominantly eosinophilic inflammation. However, Asian patients with CRS with NP show characteristics indicative of neutrophilic inflammation. Therefore, are eosinophils or nasal polyps more important for the classification of CRS? Methods: A prospective cohort study conducted from April 2007 to March 2008 classified patients with CRS based on the presence of nasal polyps and mucosal eosinophilia. The recurrence rate of nasal polyps was compared between the groups. Recurrence rate was analysed as a time-dependent variable by the Kaplan-Meier method. Results: Eosinophilic inflammation was found in 59.6% of patients with CRS with NP. Patients with mucosal eosinophilia had higher polyp recurrence rate than patients without mucosal eosinophilia, whereas patients with nasal polyps did not have higher polyp recurrence rate than patients without nasal polyps. Conclusions: Presence of mucosal eosinophilia is a more important factor than nasal polyps for classifying CRS in terms of the surgical outcome.

Objective: The pathogenesis of chronic rhinosinusitis is still unclear. A variety of factors are thought to be involved in the pathogenesis of chronic paranasal sinusitis. We sought to identify the phenotypes of chronic paranasal sinusitis patients by means of a cluster analysis.Method: We conducted a retrospective analysis of prospectively collected data from April 2007 to March 2008 in a multicenter study involving 5 hospitals.Results: The cluster analysis yielded 6 phenotypes: Cluster 1(n = 102), low blood and tissue eosinophil counts; Cluster 2 (n = 118), slightly increased blood and tissue eosinophil counts, but higher CT polyp score than in Cluster 1; Cluster 3 (n = 84), moderately elevated IgE level and high blood eosinophil counts, but mild increase in tissue eosinophil counts, and common aspirin-tolerant asthma as comorbidity; Cluster 4 (n = 69), extremely high tissue eosinophil counts, but mild blood eosinophil increase; Cluster 5 (n = 20), hyperimmunoglobulinemia E and specific IgE antibodies t...

Objective Nasal packing after septoplasty is uncomfortable and painful for patients. The aim of this study was to determine the efficacy of nasal splinting using silicone plates to prevent complications and decrease the pain after septoplasty compared with the conventional gauze packing. Materials and methods Thirty-five adult patients who had undergone septoplasty were included in this study. The patients were allocated into two groups: Group S, silicone plates were used (13 males, 2 females); and Group G, gauze packing smeared with an antibiotic ointment was used (19 males, 1 female). We evaluated and compared the postoperative pain, pain due to postoperative cleaning, nasal bleeding, postnasal drip, body temperature, effect on stay in the hospital, effect on food intake and sleep disturbance using visual analogue scale (VAS) scores. Results The postoperative pain score in Group S was significantly lower than in Group G on days 1 and 2 after the septoplasty. And the pain due to postoperative cleaning score was significantly lower than in Group G on days 2 and 3 after operation. No statistically significant differences were found between the two groups in regard to nasal bleeding, postnasal drip, body temperature, effect on stay in the hospital, effect on food intake or sleep disturbance. Objective evaluation performed at 4 weeks postoperatively revealed that nasal crusting occurred at a significantly higher incidence in Group G compared with Group S. Conclusion The use of silicone plates in lieu of conventional gauze packing decreased post-septoplasty nasal pain and pain due to postoperative cleaning of the nasal cavity. We conclude that nasal splinting using silicone plates after septoplasty is an effective method for managing pain and preventing complications.

Objective: Nasal packing is used to control postoperative bleeding and wound healing, and it also exerts a very strong influence on the comfort of the patient. Sorbsan 1 (calcium alginate) is an absorbent packing that shows a potent hemostatic effect and is able to maintain wound surfaces in a moist environment by absorbing and gelling the wound exudate. The aim of this study was to evaluate the early symptoms and QOL with Sorbsan 1 versus Beschitin-F 1 (chitin-coated gauze) for middle meatus packing after endoscopic sinus surgery (ESS). Methods: We performed a cohort study of 40 patients who underwent ESS. Following ESS, the patients were randomly allocated into two groups of 20 patients each who underwent insertion of either Sorbsan 1 or Beschitin-F 1 into the middle meatus. A daily diary was used to record the symptoms and QOL, measured using visual analogue scales, before the ESS and on each day thereafter. Postoperative bleeding and local infection were also recorded. Results: The scores for each of the symptoms of nasal pain, headache, nasal bleeding and postnasal drip were statistically significantly lower in the Sorbsan 1 group. The scores for each of the QOL parameters, including the effect on their stay in the hospital and sleep disturbance, were also significantly lower in the Sorbsan 1 group. There were no findings of postoperative hemorrhage or local infection in either group. Conclusion: Sorbsan 1 packing did not cause any major complications and has the potential to reduce nasal pain and suffering in post ESS patients compared with gauze packing. # 2011 Elsevier Ireland Ltd. All rights reserved.

Suppressor of cytokine signaling (SOCS) 1 is an essential physiologic regulator of the IFN-gamma signaling that is crucial to lead appropriate immune responses, and impaired IFN-gamma production is considered a hallmark of atopic diseases. Recent study has shown that SOCS1 is also crucial in attenuating type 1 IFN signaling and in limiting the host response to viral infection. Clinical and experimental evidence suggest an important role for respiratory viral infections in the development of asthma. To assess genetic functional variants of SOCS1 related to susceptibility and clinical phenotypes in adult asthma in a Japanese population, we conducted association and haplotype analyses of 462 subjects with adult asthma and 639 control subjects. After screening for polymorphisms, we identified a total of 13 variants and characterized the linkage disequilibrium (LD) mapping of the gene. Three variants were selected for genotyping with regard to the LD pattern, and we found a significant association between an SOCS1 promoter polymorphism -1478CAdel and adult asthma (P = 0.0063). The three-locus haplotype of SOCS1 using these three polymorphisms also showed a positive association with a haplotype T-C-del (-5388T, -3969C, and -1478 del; P = 0.0097). Furthermore, reporter gene analysis revealed that related promoter variant -1478 del enhanced the transcriptional level of SOCS1 in human lung epithelial cells, and induced higher levels of protein expression of SOCS1 and lower phosphorylation of STAT1 stimulated with IFN-beta. These findings suggest that the SOCS1 gene might be involved in the development of adult asthma through functional genetic polymorphism.

Respiratory epithelial cells play important roles not only in host defense mechanisms, but also in inflammatory responses. Inhaled corticosteroids are widely used for the treatment of patients with inflammatory lung disorders, including asthma, chronic obstructive pulmonary disease, and sarcoidosis. Corticosteroids effectively reduce the production of inflammatory mediators, such as cytokines and chemokines. Although these molecules are also essential for host defense responses, there is no convincing evidence that inhaled corticosteroids increase susceptibility to lower respiratory tract infections. To test the involvement of Toll-like receptor (TLR) family molecules in this phenomenon, we examined the effects of various cytokines and corticosteroid on the expression of TLRs in human respiratory epithelial cells. Among the TLRs tested, TLR2 expression was significantly enhanced after stimulation with a combination of tumor necrosis factor-alpha and interferon-gamma. Dexamethasone synergistically enhanced TLR2 expression in combination with tumor necrosis factor-alpha and interferon-gamma in terms of both mRNA and protein levels. Furthermore, increased cell-surface TLR2 was functional, judging from the remarkable induction of interleukin-6, interleukin-8, and beta-defensin-2 after stimulation with peptidoglycan. These results provide evidence for a novel function of corticosteroids in airway inflammatory disorders, and indicate that the use of inhaled corticosteroids in such disorders may have a beneficial role in host defense mechanisms.

Rodent mast cells (MCs) are common experimental tools but are somewhat different from their human counterparts in their responses to certain cytokines and drugs. We examined the expression of more than 10 000 distinct genes in human and mouse cultured MCs using high-density oligonucleotide probe arrays to find molecules similarly regulated and expressed by the 2 MC types. After stimulation via high-affinity Fcepsilon receptor I (FcepsilonRI), the transcriptional levels of several CC chemokines were markedly increased, and I-309 (CCL1), macrophage inflammatory protein-1alpha (MIP-1alpha) (CCL3) and MIP-1beta (CCL4) were found among the 10 most increased human and mouse transcripts from approximately 12 000 genes (including some expressed sequence tags). In addition, a costimulatory molecule that was originally found on the membrane of activated T cells, 4-1BB (CD137), was found among the 10 most increased transcripts. The FcepsilonRI-induced expression of CC chemokines and 4-1BB was also detected at the protein level in both MC types. The conservation of these responses suggests that MCs play a crucial role in recruitment of various CCR-expressing cells into the tissue in a manner dependent on immunoglobin E, and that FcepsilonRI-mediated induction of several CC chemokines and 4-1BB is highly conserved between human and mouse. Interspecies comparison studies at the whole genome expression level should be useful for the interpretation of experimental data obtained in animal models of human pathobiology.

Background Nitric oxide (NO) has various roles in airway physiology and pathophysiology. Monitoring exhaled NO levels is increasingly common to measure airways inflammation and inhaled NO studied for its therapeutic value in premature infants and adult respiratory distress syndrome. NO is produced by 3 isoforms of NO synthase (NOS1, 2, 3), and each can play distinct and perhaps overlapping roles in the airways. However, the distribution, regulation, and functions of NOS in various cells in the upper airways, particularly in leukocytes, are incompletely understood. Objective To characterize the expression of NOS isoforms in leukocytes in normal middle turbinate tissues (MT) and in inflammatory nasal tissue (nasal polyps, NP). Methods Normal MT tissue was collected from surgical specimens that were to be discarded. The NP samples were from surgical tissue archives of 15 patients with chronic rhinosinusitis. Isoforms of NOS in cells were identified by double immunostaining using NOS isoform-specific and leukocyte-specific (mast cell, eosinophil, macrophage, neutrophil, or T cell) antibodies. Results The proportion of total cells below the epithelium that were positive for each isoform of NOS was higher in NP than in MT. Each isoform of NOS was found in all leukocyte populations studied, and there were significant differences in the percentage of leukocytes expressing NOS isoforms between MT and NP. Conclusion All isoforms of NOS are expressed in leukocytes in MT and NP, and their expression varies among leukocyte types. Our data provide a basis to investigate the regulation, cell distribution, and distinct functions of NOS isoforms in normal and inflamed nasal tissues.