Global expert views on the diagnosis, classification and pharmacotherapy of allergic rhinitis in clinical practice using a modified Delphi panel technique.

Background: Diagnosis, classification, and treatment of allergic rhinitis (AR) varies considerably despite the availability of treatment guidelines. Objectives: We aimed to carry out a two-part modified Delphi panel study to elucidate global expert management of AR in real life. Methods: The modified Delphi panel study was composed of two ten-minute online questionnaires sent to global AR experts, aiming to identify areas of consensus (defined as >75% respondent agreement) on aspects of their real-world daily practice related to AR diagnosis, classification, and pharmacotherapy. A workshop discussion with respondents held after the first-round questionnaire informed the development of the second-round questionnaire. Results: Eighteen experts (from 7 countries across 3 continents) completed both questionnaires in September-October 2021 and January 2022, respectively. The majority of respondents agreed that diagnosis of AR is best confirmed using a mixture of observation and testing (n = 15) and collaborating with colleagues across other specialties (n = 14). Experts agreed that severity (n = 18), upper/lower respiratory tract involvement (n = 15) and symptom frequency (n = 14) are important factors when classifying AR, however consensus was not reached on which classification tool should be used. Although there were mixed opinions on the preferred pharmacotherapy treatment in the presented case studies, respondents largely agreed on which treatments require less monitoring (intranasal corticosteroid therapies [INCS]) and when treatments should be stepped down (≤3 months). Although opinions varied across respondents, some respondents considered as-needed INCS treatment and surgery to be viable treatment options. Conclusion: We identified clear differences between real-world practice and treatment guidelines related to the management of AR. Furthermore, we recognized differences among physicians concerning their clinical practice in the pharmacological treatment of AR. These findings highlight the need for greater research into the management of AR and further indicate there is still a major gap between treatment guidelines and daily practice, even among specialists, suggesting a need for local guideline adaptation and implementation plans.

Differences in the expression of multidrug resistance proteins in chronic rhinosinusitis according to endotype.

BACKGROUND: Chronic rhinosinusitis is a common disease of the nasal cavity and is classified into two major endotypes, which are neutrophilic and eosinophilic. Some patients with neutrophilic and eosinophilic chronic rhinosinusitis are refractory to treatment, and the mechanism of drug resistance is not completely understood. METHODS: Nasal polyp samples were collected from patients with non-eosinophilic chronic rhinosinusitis (nECRS) and eosinophilic chronic rhinosinusitis (ECRS). Transcriptomic and proteomic analyses were performed simultaneously. Gene Ontology (GO) analysis was conducted to extract genes involved in drug resistance. Then, GO analysis results were validated via real-time polymerase chain reaction and immunohistochemistry analysis. RESULTS: The nasal polyps of patients with ECRS were enriched with 110 factors in the genes and 112 in the proteins, unlike in those of patients with nECRS. GO analysis on the combined results of both showed that the factors involved in extracellular transportation were enriched. Our analysis focused on multidrug resistance protein 1-5 (MRP1-5). Real-time polymerase chain reaction revealed that the MRP4 expression was significantly upregulated in ECRS polyps. Immunohistochemical staining showed that the MRP3 and MRP4 expressions significantly increased in nECRS and ECRS, respectively. MRP3 and MRP4 expressions were positively correlated with the number of neutrophil and eosinophil infiltrates in polyps and associated with the tendency to relapse in patients with ECRS. CONCLUSIONS: MRP is associated with treatment resistance and is expressed in nasal polyps. The expression pattern had different features based on chronic rhinosinusitis endotype. Therefore, drug resistance factors can be associated with therapeutic outcomes.

Reflux-related Extraesophageal Symptoms Until Proven Otherwise: A Direct Measurement of Abnormal Proximal Exposure Based on Hypopharyngeal Multichannel Intraluminal Impedance as a Reliable Indicator for Successful Treatment Outcomes.

BACKGROUND/AIMS: The Lyon Consensus defined parameters based on upper endoscopy and 24-hour combined multichannel intraluminal impedance-pH (MII-pH), that conclusively establish the presence of gastroesophageal reflux disease (GERD). However, the true role of upper endoscopy and MII-pH to evaluate patients with extraesophageal symptoms (EES) has not been well established. Hypopharyngeal MII (HMII), which directly measures laryngopharyngeal reflux (LPR) events, has been utilized to evaluate patients with EES suggestive of LPR. METHODS: This was a retrospective study involving patients with EES for > 12 weeks despite proton pump inhibitor therapy, and had no endoscopic confirmatory evidence for GERD and negative MII-pH. All patients were subsequently referred for further evaluation of EES with "unknown" etiology and underwent laryngoscopy and HMII. Based on HMII, abnormal proximal exposure (APE) was defined as LPR ≥ 1/day and/or full column reflux (reflux 2 cm distal to the upper esophageal sphincter) > 4/day. Patients with APE were offered antireflux surgery (ARS) and the outcome of ARS was objectively assessed using Reflux Symptom Index. RESULTS: Of 21 patients with EES which was thought to be GERD-unrelated based on endoscopy and MII-pH, 17 patients (81%) had APE. Eight patients with APE who had undergone ARS had significant symptomatic improvement in the Reflux Symptom Index score (19.6 ± 4.9 pre-ARS to 5.8 ± 1.4 post-ARS, P = 0.008). CONCLUSIONS: A conventional diagnostic approach using endoscopy and MII-pH may not be sufficient to evaluate patients with EES suggestive of LPR. HMII is essential to evaluate patients with EES, and APE could be a reliable indicator for successful treatment outcomes.

A Phase II, Multicenter, Randomized, Placebo-Controlled Study of Benralizumab, a Humanized Anti-IL-5R Alpha Monoclonal Antibody, in Patients With Eosinophilic Chronic Rhinosinusitis.

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.

DNA Methylation and HPV-Associated Head and Neck Cancer.

Head and neck squamous cell carcinoma (HNSCC), especially oropharyngeal squamous cell carcinoma (OPSCC), has recently been found to be significantly associated with human papillomavirus (HPV) infection. The incidence of OPSCC has been increasing and surpassed the number of cervical cancer cases in the United States. Although HPV-associated OPSCC has a relatively better prognosis than HPV-negative cancer, approximately 20% of HPV-associated HNSCC patients show a poor prognosis or therapeutic response, and the molecular mechanism behind this outcome in the intermediate-risk group is yet to be elucidated. These biological differences between HPV-associated HNSCC and HPV-negative HNSCC are partly explained by the differences in mutation patterns. However, recent reports have revealed that epigenetic dysregulation, such as dysregulated DNA methylation, is a strikingly common pathological feature of human malignancy. Notably, viral infections can induce aberrant DNA methylation, leading to carcinogenesis, and HPV-associated HNSCC cases tend to harbor a higher amount of aberrantly methylated DNA than HPV-negative HNSCC cases. Furthermore, recent comprehensive genome-wide DNA-methylation analyses with large cohorts have revealed that a sub-group of HPV-associated HNSCC correlates with increased DNA methylation. Accordingly, in this review, we provide an overview of the relationship between DNA methylation and HPV-associated HNSCC.

"Gas" laryngopharyngeal reflux cause unexplained chronic cough.

Hypopharyngeal multichannel intraluminal impedance (HMII) that can measure laryngopharyngeal reflux (LPR) events has supported the causal relationship between chronic cough (CC) and LPR containing liquid. However the role of "gas" LPR associated with CC has been poorly understood. We present two cases of patients with CC who had negative LPR containing liquid but had multiple episodes of "gas" LPR on HMII. The majority of "gas" LPR events had a minor pH drop at hypopharynx. Since any etiology of CC was excluded and medical therapy failed, both patients underwent laparoscopic antireflux surgery (LARS). Both of the patients had complete resolution of cough postoperatively. The present cases demonstrated successful outcome of LARS to treat the patients with CC who had documented "gas" LPR on HMII, thus suggesting the causal relationship between CC and "gas" LPR. The number of "gas" LPR events may need to be considered as an important diagnostic parameter.

The influence of tonsillectomy on allergic diseases in pediatric patients.

BACKGROUND: The influence of tonsillectomy on allergic airway diseases is not well known. OBJECTIVES: In the present study, the influence of tonsillectomy on perennial allergic rhinitis (PAR) and bronchial asthma (BA) among pediatric subjects was prospectively investigated. METHODS: The tonsillectomy (surgery group) and the age-matched non-surgical subjects (control group) were examined and followed prospectively. In addition, immunological analysis was conducted. RESULTS: After in vitro allergen stimulation, the production of a small number of allergen-specific Th2 cells was induced in the tonsillar cells, even in sensitized subjects. Flow cytometry analysis detected more effector regulatory T cells (Tregs) in the tonsils than in peripheral blood. Clinically, after surgery, the PAR and BA symptoms improved in the surgery group but not in the control group. The total IgE in the surgery group was significantly lower than in the control group; after surgery, IgE levels slightly increased but remained lower. The postoperative Dermatophagoides farina (Der f)-specific IgE level increased in the sensitized subjects but not in the non-sensitized subjects. CONCLUSION: Tonsillectomy did not improve the underlying mechanisms of the allergy, however the decreased risk of infection and upper airway obstruction could lead to improved symptoms of allergic airway diseases.

Japanese guidelines for allergic rhinitis 2020.

Like asthma and atopic dermatitis, allergic rhinitis is an allergic disease, but of the three, it is the only type I allergic disease. Allergic rhinitis includes pollinosis, which is intractable and reduces quality of life (QOL) when it becomes severe. A guideline is needed to understand allergic rhinitis and to use this knowledge to develop a treatment plan. In Japan, the first guideline was prepared after a symposium held by the Japanese Society of Allergology in 1993. The current 8th edition was published in 2016, and is widely used today. To incorporate evidence based medicine (EBM) introduced from abroad, the most recent collection of evidence/literature was supplemented to the Practical Guideline for the Management of Allergic Rhinitis in Japan 2016. The revised guideline includes assessment of diagnosis/treatment and prescriptions for children and pregnant women, for broad clinical applications. An evidence-based step-by-step strategy for treatment is also described. In addition, the QOL concept and cost benefit analyses are also addressed. Along with Allergic Rhinitis and its Impact of Asthma (ARIA), this guideline is widely used for various clinical purposes, such as measures for patients with sinusitis, childhood allergic rhinitis, oral allergy syndrome, and anaphylaxis and for pregnant women. A Q&A section regarding allergic rhinitis in Japan was added to the end of this guideline.

Establishment of epigenetic markers to predict irradiation efficacy against oropharyngeal cancer.

Irradiation, or chemoradiotherapy, is a curative treatment for oropharyngeal squamous cell carcinoma (OPSCC). Its invasiveness, however, can often negate its efficacy. Therefore, developing methods to predict which patients would benefit from irradiation is urgent. Promoter DNA hypermethylation was recently reported to correlate with favorable OPSCC prognosis. It is still unclear, however, whether there is an association between promoter DNA methylation and response to irradiation. In this study, we analyzed DNA methylation in the specimens from 40 OPSCC patients who had undergone irradiation, using the Infinium assay. Our results showed significant correlation between high levels of promoter DNA methylation and better response to treatment (P < 0.01). We used the 10 most differentially-methylated genes between responders and non-responders to develop a panel of predictive markers for efficacy. Our panel had high sensitivity, specificity and accuracy (92%, 93% and 93%, respectively). We conducted pyrosequencing to quantitatively validate the methylation levels of 8 of the 10 marker genes (ROBO1, ULK4P3, MYOD1, LBX1, CACNA1A, IRX4, DPYSL3 and ELAVL2) obtained by Infinium. The validation by pyrosequencing showed that these 8 genes had a high prediction performance for the training set of 40 specimens and for a validation set of 35 OPSCC specimens, showing 96% sensitivity, 89% specificity and 94% accuracy. Methylation of these markers correlated significantly with better progression-free and overall survival rates, regardless of human papillomavirus status. These results indicate that increased DNA methylation is associated with better responses to irradiation therapy and that DNA methylation can help establish efficacy prediction markers in OPSCC.

Stratification of HPV-associated and HPV-negative oropharyngeal squamous cell carcinomas based on DNA methylation epigenotypes.

While the incidence of oropharyngeal squamous cell carcinoma (OPSCC) has been increasing in these two decades, primarily due to human papillomavirus (HPV), stratification of OPSCC into molecular subgroups showing different clinicopathological features has not been fully investigated. We performed DNA methylome analysis using Infinium 450k for 170 OPSCC cases, including 89 cases in our cohort and 81 cases reported by The Cancer Genome Atlas, together with targeted exon sequencing analysis. We stratified OPSCC by hierarchical clustering analysis using methylome data. Methylation levels of classifier markers were validated quantitatively using pyrosequencing, and area under the curve (AUC) values of receiver operating characteristics (ROC) curves were calculated. OPSCC was stratified into four epigenotypes: HPV(+) high-methylation (OP1), HPV(+) intermediate-methylation (OP2), HPV(-) intermediate-methylation (OP3) and HPV(-) low-methylation (OP4). Ten methylation marker genes were generated: five to classify HPV(+) cases into OP1 and OP2, and five to classify HPV(-) cases into OP3 and OP4. AUC values of ROC curves were 0.969 and 0.952 for the two marker panels, respectively. While significantly higher TP53 mutation and CCND1 copy number gains were observed in HPV(-) than in HPV(+) groups (p < 0.01), no significant difference of genomic aberrations was observed between OP1 and OP2, or OP3 and OP4. The four epigenotypes showed significantly different prognosis (p = 0.0006), distinguishing the most favorable OPSCC subgroup (OP1) among generally favorable HPV(+) cases, and the most unfavorable OPSCC subgroup (OP3) among generally unfavorable HPV(-) cases. HPV(+) and HPV(-) OPSCC are further divided into distinct DNA methylation epigenotypes, showing significantly different prognosis.

Regulatory T cells induce CD4- NKT cell anergy and suppress NKT cell cytotoxic function.

BACKGROUND: Due to the strong tumoricidal activities of activated natural killer T (NKT) cells, invariant NKT cell-based immunotherapy has shown promising clinical efficacy. However, suppressive factors, such as regulatory T cells (Tregs), may be obstacles in the use of NKT cell-based cancer immunotherapy for advanced cancer patients. Here, we investigated the suppressive effects of Tregs on NKT cells and the underlying mechanisms with the aim to improve the antitumor activities of NKT cells. METHODS: Peripheral blood samples were obtained from healthy donors, patients with benign tumors, and patients with head and neck squamous cell carcinoma (HNSCC). NKT cells, induced with α-galactosylceramide (α-GalCer), and monocyte-derived dendritic cells (DCs) were co-cultured with naïve CD4+ T cell-derived Tregs to investigate the mechanism of the Treg suppressive effect on NKT cell cytotoxic function. The functions and phenotypes of NKT cells were evaluated with flow cytometry and cytometric bead array. RESULTS: Treg suppression on NKT cell function required cell-to-cell contact and was mediated via impaired DC maturation. NKT cells cultured under Treg-enriched conditions showed a decrease in CD4- NKT cell frequency, which exert strong tumoricidal responsiveness upon α-GalCer stimulation. The same results were observed in HNSCC patients with significantly increased effector Tregs. CONCLUSION: Tregs exert suppressive effects on NKT cell tumoricidal function by inducing more CD4- NKT cell anergy and less CD4+ NKT cell anergy. Both Treg depletion and NKT cell recovery from the anergy state may be important for improving the clinical efficacy of NKT cell-based immunotherapy in patients with advanced cancers.

Activated iNKT cells enhance the anti-tumor effect of antigen specific CD8 T cells on mesothelin-expressing salivary gland cancer.

BACKGROUND: Salivary gland cancers are not sensitive to conventional radiotherapy or chemotherapy regimens. Therefore, the development of a new treatment strategy is of critical importance for improving the prognosis. We examined the expression of mesothelin molecules in salivary gland cancers and the efficacy of adoptive cell therapy based on mesothelin-specific chimeric antigen receptor transduced T cells. METHODS: The expression of mesothelin molecule was studied in salivary gland cancer samples obtained from 16 patients as well as a salivary gland cancer cell line (A-253) and five other cell lines. The activation of mesothelin-specific chimeric antigen receptor-expressing CD8 T cells after stimulation with mesothelin and the effects of invariant natural killer T cells on this activation were evaluated. RESULTS: Mesothelin was detected in the A-253 cells and the surgical specimens except for the case of squamous cell carcinoma to various degrees. Following stimulation with mesothelin expressing cancer cells, chimeric antigen receptor T cells were dose-dependently activated; this activation was enhanced by co-culture with invariant natural killer T cells and subsequently abrogated by treatment with anti-interferon-γ antibodies. Furthermore, the cytotoxicity of chimeric antigen receptor T cells against various cancer cells was further augmented by invariant natural killer T cells. CONCLUSIONS: The use of adoptive transfer with mesothelin-specific chimeric antigen receptor-expressing CD8 T cells against salivary gland cancers is an effective therapy and invariant natural killer T cells are expected to be used in adjuvant treatment for T cell-based immunotherapy.

Crucial role of CD69 in anti-tumor immunity through regulating the exhaustion of tumor-infiltrating T cells.

The introduction of immune checkpoint inhibitors in cancer treatment highlights the negative regulation of anti-tumor immunity, such as effector T-cell exhaustion in the tumor microenvironment. However, the mechanisms underlying the induction and prevention of T-cell exhaustion remain largely unknown. We found that CD69, a type II glycoprotein known to regulate inflammation through T-cell migration and retention in tissues, plays an important role in inducing the exhaustion of tumor-infiltrating T cells. Cd69-/- mice showed reduced tumor growth and metastasis in a 4T1-luc2 murine breast cancer model, in which increased numbers of tumor-infiltrating lymphocytes, relatively little T-cell exhaustion, and enhanced IFNγ production were observed. Anti-CD69 monoclonal antibody treatment attenuated the T-cell exhaustion and tumor progression in tumor-bearing mice. These findings highlight a novel role of CD69 in controlling the tumor immune escape mediated by T-cell exhaustion and indicate that CD69 is a novel target for cancer immunotherapy.

Immunosuppressive property of submandibular lymph nodes in patients with head and neck tumors: differential distribution of regulatory T cells.

OBJECTIVE: Different sensitizations and immune responses are thought to be induced in response to antigens at different mucosal sites between the oral floor and nose. The aim of this study was to investigate differences in the distributions of lymphocyte subsets in the submandibular (SM) and upper jugular (UJ) lymph nodes (LNs), which are supposed to be regional LNs of the oral floor and nasal mucosa, respectively. SMLNs and UJLNs were collected from patients with head and neck tumors who underwent surgical resection. The populations of T cells, Natural Killer (NK) cells, Natural Killer T (NKT) cells, regulatory T cells (Tregs) and dendritic cells (DCs) in LNs without metastasis were analyzed by flow cytometry. The high-affinity IgE receptor (FcεRI) expression of LN cells were also evaluated. RESULTS: The proportions of CD4+CD25+Foxp3+ Tregs, CD4+CD45RA-Foxp3high effector Tregs and FcεRIα+CD33+CD11c+ DCs were significantly larger in SMLNs compared with UJLNs, while those of CD3+ T cells, CD3-CD56+ NK cells, CD3+Vα24+Vß11+ NKT cells, and CD123+CD303+ DCs did not show any significant differences between SMLNs and UJLNs. The differential distributions of CD4+CD25+Foxp3+ Tregs were observed regardless of tumor region, LN metastasis and clinical staging. These data indicate that SMLNs may have immunosuppressive properties compared with UJLNs.

Amphiregulin-Producing Pathogenic Memory T Helper 2 Cells Instruct Eosinophils to Secrete Osteopontin and Facilitate Airway Fibrosis.

Memory T cells provide long-lasting protective immunity, and distinct subpopulations of memory T cells drive chronic inflammatory diseases such as asthma. Asthma is a chronic allergic inflammatory disease with airway remodeling including fibrotic changes. The immunological mechanisms that induce airway fibrotic changes remain unknown. We found that interleukin-33 (IL-33) enhanced amphiregulin production by the IL-33 receptor, ST2hi memory T helper 2 (Th2) cells. Amphiregulin-epidermal growth factor receptor (EGFR)-mediated signaling directly reprogramed eosinophils to an inflammatory state with enhanced production of osteopontin, a key profibrotic immunomodulatory protein. IL-5-producing memory Th2 cells and amphiregulin-producing memory Th2 cells appeared to cooperate to establish lung fibrosis. The analysis of polyps from patients with eosinophilic chronic rhinosinusitis revealed fibrosis with accumulation of amphiregulin-producing CRTH2hiCD161hiCD45RO+CD4+ Th2 cells and osteopontin-producing eosinophils. Thus, the IL-33-amphiregulin-osteopontin axis directs fibrotic responses in eosinophilic airway inflammation and is a potential target for the treatment of fibrosis induced by chronic allergic disorders.

Inhibition of integrin ß1-mediated oncogenic signalling by the antitumor microRNA-29 family in head and neck squamous cell carcinoma.

Due to their aggressive behavior, local recurrence and distant metastasis, survival rate of advanced stage of the patients with head and neck squamous cell carcinoma (HNSCC) is very poor. Currently available epidermal growth factor receptor (EGFR)-targeted therapies are not considered curative for HNSCC. Therefore, novel approaches for identification of therapeutic targets in HNSCC are needed. All members of the miRNA-29 family (miR-29a, miR-29b, and miR-29c) were downregulated in HNSCC tissues by analysis of RNA-sequencing based microRNA (miRNA) expression signature. Ectopic expression of mature miRNAs demonstrated that the miR-29 family inhibited cancer cell migration and invasion by HNSCC cell lines. Comprehensive gene expression studies and in silico database analyses were revealed that integrin ß1 (ITGB1) was regulated by the miR-29 family in HNSCC cells. Overexpression of ITGB1 was confirmed in HNSCC specimens, and high expression of ITGB1 significantly predicted poor survival in patients with HNSCC (p = 0.00463). Knockdown of ITGB1 significantly inhibited cancer cell migration and invasion through regulating downstream of ITGB1-mediated oncogenic signalling. In conclusion, regulation of the antitumor miR-29 family affected integrin-mediated oncogenic signalling to modulate HNSCC pathogenesis; these molecules may be novel therapeutic targets for HNSCC.

Endoscopic contralateral transmaxillary approach for pterygoid process osteotomy in total maxillectomy: A technical case report.

An approach for total maxillectomy with endoscopic transection of the pterygoid process via the contralateral maxillary sinus is described. In total maxillectomy, the resection of the pterygoid process of the sphenoid is a key step for successful resection. However, a conventional craniofacial approach requires extensive incision in the face, elevation of the lateral cheek flap. Even after elevation of the lateral cheek flap, visualization of this region is not good. An endoscopic approach through the contralateral maxillary sinus improved visualization of the pterygoid process, and osteotomy using a diamond-drilling bar was successfully performed. This technique has the potential to widen the indication for total maxillectomy in malignant neoplasms of the maxillary sinus.

Hypopharyngeal multichannel intraluminal impedance leads to the promising outcome of antireflux surgery in Japanese population with laryngopharyngeal reflux symptoms.

BACKGROUND: Clinical characteristics of laryngopharyngeal reflux (LPR) in Japanese population remain unclear, and its treatment outcome is suboptimal. The objectives of this study were to evaluate Japanese patients with LPR symptoms using hypopharyngeal multichannel intraluminal impedance (HMII) and to assess the outcome of antireflux surgery (ARS). METHODS: Subjects included patients who had LPR symptoms for > 12 weeks or laryngoscopic findings suggestive of LPR and underwent laryngoscopy and esophageal testing including HMII. Abnormal proximal exposure (APE) was defined as LPR ≥ 1/day and/or full column reflux (FCR) (reflux 2 cm distal to the upper esophageal sphincter) ≥ 5/day on HMII. Patients with APE were offered ARS and the outcome of ARS was objectively assessed using Reflux Symptom Index (RSI). RESULTS: From July 2015 to September 2016, 52 patients with LPR symptoms (28 men, 24 women, median BMI 22.3) underwent HMII, and 38 patients (73%) had APE. Of them, 29 (76%) patients were not obese (BMI < 25) and 19 (50%) patients had a negative DeMeester score. Approximately one-third of LPR and FCR events were non-acid in the distal esophagus. A positive symptom-association probability was seen only in 18 patients (35%). Mild esophagitis and hiatal hernia were found in 5 (10%) and 23 (48%) patients, respectively. All 12 patients (100%) who had undergone ARS were able to discontinue PPI and had a significant improvement in the RSI scores postoperatively (22.9 ± 10.0 vs. 6.8 ± 6.8, p < .001). CONCLUSIONS: APE was frequently observed in Japanese patients with LPR symptoms. Obesity and esophagitis were uncommon in this population. Since a large number of patients with APE had negative DeMeester score and proximal reflux events were often non-acid, a conventional pH monitoring is insufficient. HMII is crucial to evaluate patients with LPR symptoms as the documentation of APE is a key for successful outcome of ARS.

Passenger strand of miR-145-3p acts as a tumor-suppressor by targeting MYO1B in head and neck squamous cell carcinoma.

Analysis of the microRNA (miRNA) expression signature of head and neck squamous cell carcinoma (HNSCC) based on RNA sequencing showed that dual strands of pre­miR­145 (miR­145­5p, guide strand; and miR­145­3p, passenger strand) were significantly reduced in cancer tissues. In miRNA biogenesis, passenger strands of miRNAs are degraded and have no biological activities in cells. The aims of this study were to investigate the functional significance of the passenger strand of miR­145 and to identify miR­145­3p­regulated oncogenic genes in HNSCC cells. Expression levels of miR­145­5p and miR­145­3p were significantly downregulated in HNSCC tissues and cell lines (SAS and HSC3 cells). Ectopic expression of miR­145­3p inhibited cancer cell proliferation, migration and invasion, similar to miR­145­5p, in HNSCC cells. Myosin 1B (MYO1B) was directly regulated by miR­145­3p, and knockdown of MYO1B by siRNA inhibited cancer cell aggressiveness. Overexpression of MYO1B was confirmed in HNSCC clinical specimens by analysis of protein and mRNA levels. Interestingly, high expression of MYO1B was associated with poor prognosis in patients with HNSCC by analysis of The Cancer Genome Atlas database (p=0.00452). Our data demonstrated that the passenger strand of miR­145 acted as an antitumor miRNA through targeting MYO1B in HNSCC cells. The involvement of dual strands of pre­miR­145 (miR­145­5p and miR­145­3p) in the regulation of HNSCC pathogenesis is a novel concept in present RNA research.

Unexpected prominent tension pneumosella five years after endoscopic endonasal transsphenoidal surgery.

Tension pneumosella (TP) is a rare entity reported as the invagination of the sphenoid sinus mucosa into the skull base after endonasal transsphenoidal surgery. Few studies have reported on TP, and in these studies, invagination is confined to either the intrasellar or suprasellar area. We encountered a case of unexpected prominent TP toward the intracranial space 5 years after endoscopic endonasal transsphenoidal surgery (EETS) for a nonfunctioning pituitary adenoma. In addition, we present a hypothesis of the underlying mechanism by a pressure gradient change between the extracranial and intracranial space in TP formation. For repair, a pedicled nasal septal flap was fabricated from the remaining part of the septal mucosa, and a pedicled inferior turbinate flap was created. Moreover, the nasal septal cartilage was used as a rigid support for reconstruction, which was useful for preventing TP recurrence. This is the first report of an unexpected prominent TP after EETS. It is important for otorhinolaryngologists and neurosurgeons to be aware of the possibility of TP following EETS. Laryngoscope, 1798-1801, 2018.