Role of induction chemotherapy in advanced-stage olfactory neuroblastoma.

OBJECTIVES: To evaluate the treatment outcomes in patients with advanced-stage olfactory neuroblastoma (ONB) who received induction chemotherapy (IC). MATERIALS AND METHODS: The clinical data of 38 patients with advanced-stage ONB who received initial IC were retrospectively analyzed. The response was defined using the Response Evaluation Criteria in Solid Tumors version 1.1. Patients with complete remission or partial remission were defined as responders. RESULTS: Seventeen (44.7%) patients responded to IC. The response rate was higher in patients with high Hyams grade tumor (III/IV) compared to those with low-grade tumors (I/II) (60% vs. 22.2%, p = 0.038). Overall, the 5-year cancer-specific survival (CSS) rate was 76.0%. Among nonresponders to IC, a significant difference in 5-year CSS rates was observed between surgery with adjuvant radiotherapy (RT) (100%) versus definitive RT or chemoradiotherapy (CRT) (68.6%) (log-rank p = 0.006). However, for responders, there was no significant difference in 5-year CSS rates between surgery with adjuvant therapy (75%) and definitive RT or CRT (51.1%) (log-rank p = 0.536). When only high-grade tumors were considered among responders, the 5-year CSS rate was significantly higher in patients who received RT or CRT (51.4%) compared to those who underwent surgery with adjuvant therapy (0%) (log-rank p = 0.008). CONCLUSION: In advanced-stage ONB, RT or CRT may be preferable for high-grade tumor responding to IC. Higher response rate and a potential role for induction IC in determining the optimal definitive treatment modality suggest a positive role for advanced-stage high-grade ONB.

The Search for an Ideal Definitive Treatment of Sinonasal Squamous Cell Carcinoma With Orbit Invasion.

OBJECTIVES: Sinonasal squamous cell carcinoma (SqCC) often invades the orbit. The treatment approach for sinonasal cancer that has spread to the orbit varies across medical centers and depends on the extent of the invasion. The decision to preserve the orbit in the treatment strategy is made on a case-by-case basis and. RESULTS: in varying outcomes. Currently, a multimodal treatment regimen, which may include surgery, chemotherapy, radiotherapy (RT), or concurrent chemoradiotherapy (CCRT), is commonly adopted for managing sinonasal cancers. This study aims to assess the prognosis of sinonasal SqCC with orbital invasion from various perspectives. METHODS: We conducted a retrospective review of patients with primary sinonasal SqCC invading the orbit who were treated at Seoul National University Hospital and Seoul National University Bundang Hospital between 2009 and 2018. The extent of the tumor, orbital invasion, treatment strategies, recurrence rates, and survival rates were analyzed. RESULTS: Overall survival and disease-free survival (DFS) rates showed no significant differences based on the grade of orbital invasion. When tumor resection with orbit preservation was employed as the definitive treatment, DFS was significantly extended compared to cases where surgery was not the definitive treatment (RT or CCRT). Additionally, there was no significant difference in DFS between patients who underwent orbit exenteration and those who underwent tumor resection with orbit preservation as the definitive treatment. CONCLUSION: Tumor resection with orbit preservation as the definitive treatment appears to be the preferred approach, prolonging DFS and increasing the likelihood of longer-term survival in cases of SqCC with orbital invasion.

Treatment outcome and prognostic factors of inverted papilloma involving the frontal sinus.

Objectives: This study aimed to evaluate the characteristics and treatment outcomes of inverted papillomas involving the frontal sinus. Methods: Patients treated for inverted papilloma involving the frontal sinus between 2003 and 2020 were reviewed. Tumors were classified based on their extent (Extent 1: partially encroaching on the frontal sinus; Extent 2: completely filling the frontal sinus; Extent 3: eroding bony borders beyond the frontal sinus) and site of origin (Origin 1: originating outside the frontal sinus and prolapsing into the frontal sinus; Origin 2: originating from the frontal sinus walls medial to the vertical plane of the lamina papyracea; Origin 3: originating from the frontal sinus walls lateral to the vertical plane of the lamina papyracea). Treatment outcomes including tumor recurrence and patency of the frontal recess were analyzed according to tumor characteristics and surgical treatment modalities. Results: A total of 49 surgical cases were analyzed. Extent 1 were the most common type (n = 27), followed by Extent 2 (n = 15), and Extent 3 (n = 7). The most common sites of origin were Origin 1 (n = 23), followed by Origin 2 (n = 15), and Origin 3 (n = 11). Overall, there were nine recurrences (18.4%). Recurrence was not associated with tumor extent, whereas tumor origin, particularly Origin 3 was associated with higher recurrence; 1/23 (4.3%) for Origin 1, 3/15 (20.0%) for Origin 2, and 5/11 (45.5%) for Origin 3 (Log-rank p < .001). Draf III frontal sinusotomy was associated with in the highest patency rate (84.6%) during the follow-up. Conclusion: The recurrence rate of frontal sinus inverted papilloma depends on tumor origin rather than the extent of the tumor. In particular, lesions originating from the frontal sinus lateral to the lamina papyracea recur frequently. Draf III frontal sinusotomy can achieve patent frontal recess allowing active surveillance. Level of Evidence: IV.

The clinical influence of nasal surgery on PAP compliance and optimal application among OSA subjects uncomfortable with PAP device wear.

This study aimed to evaluate the alteration of PAP compliance after nasal surgery and to determine the optimal indications of nasal surgery in obstructive sleep apnea (OSA) subjects. Among OSA subjects using PAP devices, 29 subjects who underwent septoturbinoplasty due to nasal obstruction were included and their pre- and postoperative medical and PAP records were reviewed retrospectively. Postoperative autoPAP usage data was further assessed by grouping the compliance (the percentage of days with usage ≥ 4 h) data (group 1: the good compliance group; group 2: the poor compliance group). The data showed that 56% of subjects in group 1 complained of nasal obstruction as the only barrier to using a PAP device and about 89% reported experiencing the efficacy of PAP usage. Both the mean and peak average PAP pressures were significantly reduced in group 1 following nasal surgery. Group 2 had multiple subjective problems that interfered with wearing a PAP device and reported a lack of experiencing the efficacy of PAP usage. Preoperative nasal cavity volume values were smaller and absolute blood eosinophil counts were significantly lower in group 1. The current data demonstrate that nasal surgery might increase the compliance of PAP device wear in OSA subjects who complained of only nasal obstruction as a barrier to wearing PAP and who had small nasal cavity volumes combined with allergic inflammation.

Optimal application of soft-palate webbing flap pharyngoplasty combined with nasal surgery for surgical treatment of primary snoring and obstructive sleep apnea.

BACKGROUND: Excessive collapse of the soft palate and lateral pharyngeal wall narrowing are established causes of loud snoring and sleep apnea in subjects with obstructive sleep apnea (OSA). Therefore, delicate surgical techniques are needed to reshape the soft palate and create sufficient tension in the lateral pharyngeal wall. This study aimed to determine the therapeutic outcome and favorable indications of soft-palate webbing flap pharyngoplasty in subjects with OSA and primary snoring. METHODS: A total of 174 subjects who underwent soft-palate webbing flap pharyngoplasty combined with uvulopalatal flap and septoturbinoplasty from August 2015 to February 2020 were included in this study. Medical records, including pre- and postoperative sleep parameters, were retrospectively reviewed. The primary outcome measure was the degree of improvement in AHI after surgery. Other outcomes were differences in surgical response rates, subjective visual analog score (VAS) for snoring, sleep quality, and complications. RESULTS: Polysomnographic results showed that apnea-hypopnea index (AHI) scores were significantly reduced from 39.6 ± 6.1 to 22.9 ± 3.6 following soft-palate webbing flap pharyngoplasty in 59 subjects, and overall success and response rates of this technique were analyzed with 71%. We found that the successful outcomes were observed in 50% of mild (n = 12) and 56% of moderate (n = 16) subjects with OSA subjects due to lateral pharyngeal wall collapse. The success rate of soft-palate webbing flap pharyngoplasty was relatively higher in subjects with mild and moderate OSA than those with severe OSA. Additionally, the mean VAS snoring scale was 4.7 and subjects' primary snoring intensity significantly improved to 2.9 after soft-palate webbing flap pharyngoplasty. Subjective symptoms such as daytime sleepiness and sleep quality also showed improvement. Most complications were found to be minimal and improved by 1 month after the operation. CONCLUSION: Our data demonstrate that soft-palate webbing flap pharyngoplasty is an effective treatment for OSA and primary snoring and may be a promising technique to reduce lateral pharyngeal wall collapse.

DEP-induced ZEB2 promotes nasal polyp formation via epithelial-to-mesenchymal transition.

BACKGROUND: Diesel exhaust particles (DEPs) are associated with the prevalence and exacerbation of allergic respiratory diseases, including allergic rhinitis and allergic asthma. However, DEP-induced mechanistic pathways promoting upper airway disease and their clinical implications remain unclear. OBJECTIVE: We sought to investigate the mechanisms by which DEP exposure contributes to nasal polyposis using human-derived epithelial cells and a murine nasal polyp (NP) model. METHODS: Gene set enrichment and weighted gene coexpression network analyses were performed. Cytotoxicity, epithelial-to-mesenchymal transition (EMT) markers, and nasal polyposis were assessed. Effects of DEP exposure on EMT were determined using epithelial cells from normal people or patients with chronic rhinosinusitis with or without NPs. BALB/c mice were exposed to DEP through either a nose-only exposure system or nasal instillation, with or without house dust mite, followed by zinc finger E-box-binding homeobox (ZEB)2 small hairpin RNA delivery. RESULTS: Bioinformatics analyses revealed that DEP exposure triggered EMT features in airway epithelial cells. Similarly, DEP-exposed human nasal epithelial cells exhibited EMT characteristics, which were dependent on ZEB2 expression. Human nasal epithelial cells derived from patients with chronic rhinosinusitis presented more prominent EMT features after DEP treatment, when compared with those from control subjects and patients with NPs. Coexposure to DEP and house dust mite synergistically increased the number of NPs, epithelial disruptions, and ZEB2 expression. Most importantly, ZEB2 inhibition prevented DEP-induced EMT, thereby alleviating NP formation in mice. CONCLUSIONS: Our data show that DEP facilitated NP formation, possibly via the promotion of ZEB2-induced EMT. ZEB2 may be a therapeutic target for DEP-induced epithelial damage and related airway diseases, including NPs.

Machine learning-based preoperative datamining can predict the therapeutic outcome of sleep surgery in OSA subjects.

Increasing recognition of anatomical obstruction has resulted in a large variety of sleep surgeries to improve anatomic collapse of obstructive sleep apnea (OSA) and the prediction of whether sleep surgery will have successful outcome is very important. The aim of this study is to assess a machine learning-based clinical model that predict the success rate of sleep surgery in OSA subjects. The predicted success rate from machine learning and the predicted subjective surgical outcome from the physician were compared with the actual success rate in 163 male dominated-OSA subjects. Predicted success rate of sleep surgery from machine learning models based on sleep parameters and endoscopic findings of upper airway demonstrated higher accuracy than subjective predicted value of sleep surgeon. The gradient boosting model showed the best performance to predict the surgical success that is evaluated by pre- and post-operative polysomnography or home sleep apnea testing among the logistic regression and three machine learning models, and the accuracy of gradient boosting model (0.708) was significantly higher than logistic regression model (0.542). Our data demonstrate that the data mining-driven prediction such as gradient boosting exhibited higher accuracy for prediction of surgical outcome and we can provide accurate information on surgical outcomes before surgery to OSA subjects using machine learning models.

Symbiotic microbiome Staphylococcus aureus from human nasal mucus modulates IL-33-mediated type 2 immune responses in allergic nasal mucosa.

BACKGROUND: The host-microbial commensalism can shape the innate immune responses in respiratory mucosa and nasal microbiome also modulates front-line immune mechanism in the nasal mucosa. Inhaled allergens encounter the host immune system first in the nasal mucosa, and microbial characteristics of nasal mucus directly impact the mechanisms of initial allergic responses in nasal epithelium. However, the roles of the nasal microbiome in allergic nasal mucosa remain uncertain. We sought to determine the distribution of nasal microbiomes in allergic nasal mucosa and elucidate the interplay between nasal microbiome Staphylococcus species and Th2 cytokines in allergic rhinitis (AR) models. RESULTS: Staphylococcus aureus (AR-SA) and S. epidermidis (AR-SE) were isolated from the nasal mucosa of patients with AR. The influence of nasal microbiome Staphylococcus species on allergic nasal mucosa was also tested with in vitro and in vivo AR models. Pyrosequencing data showed that colonization by S. epidermidis and S. aureus was more dominant in nasal mucus of AR subjects. The mRNA and protein levels of IL-33 and TSLP were significantly higher in AR nasal epithelial (ARNE) cells which were cultured from nasal mucosa of AR subjects, and exposure of ARNE cells to AR-SA reduced IL-33 mRNA and secreted protein levels. Particularly, ovalbumin-driven AR mice inoculated with AR-SA by intranasal delivery exhibited significantly reduced IL-33 in their nasal mucosa. In the context of these results, allergic symptoms and Th2 cytokine levels were significantly downregulated after intranasal inoculation of AR-SA in vivo AR mice. CONCLUSION: Colonization by Staphylococcus species was more dominant in allergic nasal mucosa, and nasal commensal S. aureus from subjects with AR mediates anti-allergic effects by modulating IL-33-dependent Th2 inflammation. The results demonstrate the role of host-bacterial commensalism in shaping human allergic inflammation.

The influence of interferon-lambda on restricting Middle East Respiratory Syndrome Coronavirus replication in the respiratory epithelium.

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) causes severe respiratory in human with high mortality and it has been a challenge to determine optimum treatment for MERS-CoV-induced respiratory infection. Here, we observed the distribution of MERS-CoV receptors using human respiratory mucosa and also evaluated the contribution of interferon-lambdas (IFN-λs) in response to MERS-CoV infection using in vitro normal human nasal epithelial (NHNE) and bronchial epithelial (NHBE) cells. We found that the gene and protein expression of DPPIV, MERS-CoV receptor, were more dominantly located in nasal and bronchial epithelium although human nasal mucosa exhibited relatively lower DPPIV expression than lung parenchymal tissues. The quantitative mRNA level of the MERS-CoV envelope (upE) gene was significantly induced in MERS-CoV-infected cultured NHNE and NHBE cells until 3 days after infection. The induction of IFNs was identified in NHNE and NHBE cells after MERS-CoV infection and IFN-λs were predominantly increased in MERS-CoV-infected respiratory epithelial cells. Inoculation of IFN-λs to NHNE and NHBE cells suppressed MERS-CoV replication and in particular, IFN-λ4 showed a strong therapeutic effect in reducing MERS-CoV infection with higher induction of IFN-stimulated genes. Thus, IFN-λ has a decisive function in the respiratory epithelium that greatly limits MERS-CoV replication, and may be a key cytokine for better therapeutic outcomes against MERS-CoV infection in respiratory tract.

The clinical efficacy of relocation pharyngoplasty to improve retropalatal circumferential narrowing in obstructive sleep apnea patients.

Lateral pharyngeal wall appears to be a critical culprit of obstructive sleep apnea (OSA) subjects and relocation pharyngoplasty has been expected to be a promising surgical option to correct retropalatal circumferential narrowing in OSA patients. The purpose of our study is to evaluate the therapeutic outcomes of relocation pharyngoplasty and its clinical effectiveness in OSA patients with retropalatal circumferential narrowing. We performed relocation pharyngoplasty combined with nasal surgery in 133 OSA patients with the following characteristics: apnea-hypopnea index (AHI) over 10, retropalatal circumferential narrowing greater than grade I when awake, and redundant soft tissue around the lateral pharyngeal wall. The analysis of surgical success rate was performed with the data of 68 subjects who underwent pre and postoperative polysomnography. The objective success rate of relocation pharyngoplasty was 52.9%, and significant reduction of mean AHI with improvement of lowest SpO2 was seen in 69% of patients 3 months after the surgery. The median AHI was decreased from preoperative 37.3 to postoperative 21.4. Median lowest SpO2 changed from 78.4 to 84.1%. Total sleep time, daytime sleepiness, and visual analogue scale for snoring showed improvement as well. Postoperative complications including pain or bleeding were minimal in 133 subjects and a few patients complained of subtle taste loss. Our data demonstrate that relocation pharyngoplasty can be a favorable surgical option fighting against retropalatal circumferential narrowing.

IL-17C Protects Nasal Epithelium from Pseudomonas aeruginosa Infection.

IL-17 family cytokines are directly involved in host immune responses and the critical mediators for host defense against infection or inflammation. IL-17C is highly expressed in respiratory epithelium and is induced after acute bacterial lung infection. However, the definite function of IL-17C induced by Pseudomonas aeruginosa (PAO1 strain) is not fully understood, and our study was designed to demonstrate IL-17C-induced immune response against PAO1 infection in nasal epithelium. Passage-2 normal human nasal epithelial (NHNE) cells were infected with PAO1 and the relationship between IL-17C-related immune responses and the iron absorption of PAO1, depending on inoculation of recombinant human IL-17C (rhIL-17C), was assessed by measuring the siderophore activity of PAO1. Microarray data showed that IL-17C expression increased 34.7 times at 8 hours postinfection (hpi) in NHNE cells, and IL-17C mRNA levels increased until 48 hpi. The PAO1 colonies significantly increased from 8 hpi in NHNE cells, and siderophore activity of PAO1 was enhanced in the supernatants of PAO1-infected NHNE cells. Interestingly, PAO1 colonies were reduced in PAO1-infected NHNE cells treated with rhIL-17C, and supernatants from NHNE cells treated with rhIL-17C also exhibited decreased PAO1 colonies. We found that the siderophore activity of PAO1 was significantly reduced in the supernatants of NHNE cells treated with rhIL-17C where LCN2 expression was highly elevated. Our findings indicate that IL-17C mediates an antibacterial effect against PAO1 by inhibiting siderophore activity in nasal epithelium. We propose that IL-17C might be an efficient mediator to suppress PAO1 infection through disturbing iron absorption of PAO1 in nasal epithelium.

Superior immune responses induced by intranasal immunization with recombinant adenovirus-based vaccine expressing full-length Spike protein of Middle East respiratory syndrome coronavirus.

Middle East respiratory syndrome coronavirus (MERS-CoV) causes an acute and severe lower respiratory illness as well as vomiting, diarrhea, and renal failure. Because no licensed MERS-CoV vaccines are currently available, preventive and therapeutic measures are urgently needed. The surface spike (S) glycoprotein of MERS-CoV, which binds to the cellular receptor dipeptidyl peptidase 4 (DPP4), is considered as a major target for MERS-CoV vaccine development. Here, we designed recombinant replication-deficient adenovirus-based vaccines expressing the N-terminal domain (rAd/NTD) and receptor-binding domain (rAd/RBD) of the MERS-CoV S1 subunit and full-length Spike protein (rAd/Spike). We found that immunization with candidate vaccines via intranasal route induced S1-specific IgG antibodies and neutralizing antibodies against MERS spike pseudotyped virus. Especially, rAd/Spike induced the highest neutralizing antibody titer and the strongest cytokine-induced T cell responses among the three candidate vaccines. To compare the immune responses induced by different administration routes, rAd/Spike was administered via intranasal, sublingual, or intramuscular route. All these administration routes exhibited neutralizing effects in the serum. MERS-CoV-specific neutralizing IgA antibodies in the bronchoalveolar lavage fluid were only induced by intranasal and sublingual administration but not by intramuscular administration. Intranasal administration with rAd/Spike also created resident memory CD8 T cells in the airway and lung parenchyma. Taken together, our results showed that both the humoral and cellular immune responses are highly induced by rAd/Spike administration, suggesting that rAd/Spike may confer protection against MERS-CoV infection.

Inhaled delivery of Interferon-lambda restricts epithelial-derived Th2 inflammation in allergic asthma.

The possibility has been suggested that interferon (IFN)-λs can be induced rapidly for restricting respiratory viral infection in asthmatic mice and may modulate Th2-related immune responses that underlie the pathogenesis of asthma. We sought to determine the in vivo contribution of IFN-λs on decrease of Th2 cytokines in the respiratory tract of in vivo asthma. Lungs of asthmatic mice were severely inflamed, with extensive inflammatory cell infiltration and increased goblet cell metaplasia with higher total lung resistance. The mean protein levels of TSLP and IL-33 from BAL fluid of asthmatic mice were significantly higher until 7 days. Following the collection of lung tissue of 20 asthmatic mice, TSLP and IL-33 gene expressions inversely correlated with mRNA levels of IFN-λ2/3. Asthmatic mice were administered recombinant IFN-λ2/3 via the intranasal route and the mRNA levels of IFN-stimulated genes were elevated to an even greater extent in the lung tissue of the mice without intranasal IFN-λ2/3. Asthma-related histopathologic lung inflammation was significantly improved and total lung resistance was maintained within normal range in IFN-λ2/3-treated asthmatic mice. Moreover, IFN-λ2/3-treated asthmatic mice exhibited significant decrease of secreted protein levels of TSLP and IL-33 in the BAL fluid until 7 days after IFN administration. The current data provide compelling evidence that the compensation of IFN-λs can restrict the secretion of epithelial-derived Th2 cytokines, accompanied with reduced asthmatic immunopathology and IFN-λs are critical for limiting Th2-mediated allergic responses in allergic asthma.

Indications for and Outcomes of Expansion Sphincter Pharyngoplasty to Treat Lateral Pharyngeal Collapse in Patients With Obstructive Sleep Apnea.

IMPORTANCE: The lateral pharyngeal wall is recognized as an important site of upper airway collapse during sleep in patients with obstructive sleep apnea (OSA), and expansion sphincter pharyngoplasty (ESP) may have promising clinical utility in patients with OSA and lateral pharyngeal wall collapse. OBJECTIVES: To evaluate the therapeutic outcomes of ESP in conjunction with other surgical procedures and to investigate indications for ESP in patients with OSA. DESIGN, SETTING, AND PARTICIPANTS: Cohort study of 63 patients with OSA diagnosed with lateral pharyngeal collapse under drug-induced sleep endoscopy who underwent ESP combined with tonsillectomy, uvuloplasty, or nasal surgery at Seoul National University Hospital in Seoul, Korea, between March 1, 2015, and December 1, 2016. MAIN OUTCOMES AND MEASURES: The primary outcome measure was the change in the apnea-hypopnea index (AHI) after surgery (AHI represents the number of apnea-hypopnea events per hour). Other outcome measures were differences in the surgical response rates, lowest oxygen saturation, subjective visual analog scale scores for snoring and apnea, and Epworth Sleepiness Scale score. RESULTS: Fifty of the 63 patients (79%) were male; the mean age was 42.1 (range, 20-54) years, and the mean body mass index (calculated as weight in kilograms divided by height in meters squared) was 27.6 (range, 19.0-32.1). Expansion sphincter pharyngoplasty was performed in patients with OSA with an AHI greater than 15 events per hour, more than 75% retropalatal circumferential narrowing when awake, and narrowed oropharynx due to bulky soft tissue around the lateral pharyngeal wall. In 42 of the 63 patients (67%), ESP was objectively successful in correcting lateral pharyngeal collapse; there was a significant reduction in mean AHI from 35.5 to 17.3 (mean difference, 18.1; 95% CI, 16.3-20.0) and improvement of the lowest mean (SD) oxygen saturation measurement from 78.2% (21.3%) to 86.4% (10.6%) (mean difference, 8.60%; 95% CI, 6.60%-10.60%) 6 months after the operation. The rate of postoperative complications, including pain and bleeding, was minimal after ESP, and a few patients reported an abnormal sensation around the soft palate and swallowing difficulty after ESP. CONCLUSIONS AND RELEVANCE: Expansion sphincter pharyngoplasty appears to be a promising surgical technique to reduce lateral pharyngeal collapse in patients with moderate or severe OSA. Clinical data suggest that both severe palatal circumferential narrowing and bulky lateral pharyngeal tissue are favorable surgical indications for ESP in patients with OSA.

The IFN-γ-p38, ERK kinase axis exacerbates neutrophilic chronic rhinosinusitis by inducing the epithelial-to-mesenchymal transition.

Chronic rhinosinusitis (CRS) is a heterogeneous and multifactorial inflammatory disease characterized by involvement of diverse types of inflammatory cells. Asian CRS patients frequently show infiltration of neutrophils and an elevated level of interferon (IFN)-γ; by contrast, western patients exhibit eosinophil infiltration and enhanced levels of Th2-related cytokines. Neutrophilia in tissues decreases sensitivity to corticosteroids, but the mechanisms underlying the progression of neutrophilic CRS are unclear. In this study, we investigated the role of IFN-γ in CRS patients with marked neutrophil infiltration. We report that the IFN-γ level is upregulated in the tissues of these patients, particularly those with non-eosinophilic nasal polyps. The level of IFN-γ was significantly correlated with markers of the epithelial-to-mesenchymal transition (EMT). We further demonstrated that IFN-γ induced the EMT via the p38 and extracellular signal-regulated kinase (ERK) pathways in a manner distinct from the hypoxia-inducible factor (HIF)-1α, SMAD, and NF-κB signaling pathways. In a murine nasal polyp (NP) model, blocking the p38 and ERK signaling pathways prevented NP formation and chemotactic cytokine secretion by neutrophils but not eosinophils. Taken together, our results suggest that IFN-γ can induce the EMT in nasal epithelial cells, and thus blocking the p38 and ERK pathways could be an effective therapeutic strategy against neutrophil-dominant CRS.

Clinicopathological and Preclinical Findings of NUT Carcinoma: A Multicenter Study.

BACKGROUND: NUT carcinoma is a rare aggressive disease caused by BRD4/3-NUT fusion, and C-MYC upregulation plays a key role in the pathogenesis. Here, we report on the clinicopathological characteristics of Korean patients with NUT carcinoma and the in vitro efficacy of MYC-targeting agents against patient-derived NUT carcinoma cell lines. MATERIALS AND METHODS: Thirteen patients with NUT carcinoma were evaluated for p53, C-MYC, epidermal growth factor receptor (EGFR), HER2, and programmed cell death ligand 1 (PD-L1) by immunohistochemistry. The half maximal inhibitory concentration (IC50) values of NUT carcinoma cell lines (SNU-2972-1, SNU-3178S, HCC2429, and Ty-82) were determined using MYC-targeting agents, including bromodomain and extraterminal (BET) inhibitors (I-BET, OTX-015, AZD5153) and histone deacetylase (HDAC) inhibitors (vorinostat, romidepsin, panobinostat, CUDC-907). RESULTS: Primary tumor sites included head and neck (n = 9) and lung (n = 4). The patient age ranged from 8 to 73 years with the male/female ratio of 1.2:1. Nine patients died at 3-23.6 months (median, 10.6) after diagnosis. Eight patients had been misdiagnosed initially with other diseases. One patient with metastatic NUT carcinoma who received mass excision plus metastasectomy followed by chemoradiotherapy was a long-term survivor (>27 months). Although expressions of C-MYC (8/12, 73%) and p53 (12/12, 100%) were commonly observed, EGFR, HER2, and PD-L1 expressions were observed in 2 of 7 (29%), 2 of 8 (25%), and 1 of 12 (8.3%) patients, respectively. BET and HDAC inhibitors showed variable but limited in vitro efficacy. However, a dual HDAC/PI3K inhibitor, CUDC-907, was most potent against NUT carcinoma cells, with an IC50 of 5.5-9.0 pmol/L. Consistent with these findings, kinome short interfering RNA screening showed a positive hit for PI3KCA in NUT carcinoma cells. Panobinostat (IC50, 0.4-1.3 nmol/L) and a bivalent BET inhibitor, AZD5153 (IC50, 3.7-8.2 nmol/L), also showed remarkable efficacies. CONCLUSION: East Asian patients with NUT carcinoma showed dismal survival outcomes like Western patients, and CUDC-907 might be promising in NUT carcinoma treatment. IMPLICATIONS FOR PRACTICE: NUT carcinoma (NC) is a disease caused by BRD-NUT fusion leading to C-MYC upregulation. NC is often misdiagnosed and very aggressive, requiring development of effective therapeutic strategy. This article presents the clinicopathological features of the largest series of NCs in East Asians and preclinical sensitivities to MYC-targeting agents in NC cell lines. Patients with NC had grave outcomes and poor response to treatment. Among MYC-targeting agents, including BET and HDAC inhibitors, CUDC-907 (a dual PI3K/HDAC inhibitor) was most effective against NC cells, followed by panobinostat (an HDAC inhibitor) and AZD5153 (a bivalent BET inhibitor). CUDC-907 might be promising in NC treatment.

Robot-assisted Tongue Base Resection ensures favorable therapeutic outcome to Obstructive Sleep Apnea patients with Lingual tonsil hypertrophy.

Tongue base (TB) narrowing is recognized as a significant site of upper airway collapse during sleep in obstructive sleep apnea (OSA) patients and robot technology is expected to have promising clinical utility in OSA patients with TB narrowing. The purpose of our study is to demonstrate the better therapeutic conditions and favorable indications of robot-assisted TB resection (TBR) in OSA. We performed robot-assisted TBR combined with nasal and palatal surgery in 16 OSA patients with any of the following characteristics: severe TB narrowing (over grade II) and moderate or severe OSA. The preoperative median AHI was 48.8/hr and the median lowest SaO2 was 82.0%. The median AHI decreased to 18.7/hr and ten patients (62.5%) were included in the responder group following robot-assisted TBR combined with nasal and palatal surgery. The lowest SaO2 improved to 90.5% and the posterior airway space (PAS) was significantly increased following robot-assisted TBR. Cephalometric results showed that wider PAS were observed in responders compared to non-responders prior to robot-assisted TBR. Interestingly, there was greater improvement in the objective parameters including PAS in the OSA patients with lingual tonsilar hypertrophy than they were in those without and all patients with lingual tonsillar hypertrophy (n = 6) responded to robot-assisted TBR. Robot-assisted TBR exhibited minimal morbidity and postoperative complications in OSA patients. Robot-assisted TBR can be considered a promising and innovative surgical option to reduce TB volume and improve sleep parameters in OSA patients with TB narrowing. OSA patient with TB narrowing due to lingual tonsil hypertrophy shows greater therapeutic outcome and lingual tonsil hypertrophy appears to be most favorable surgical indications of robot-assisted TBR.

Immunologic modification in mono- and poly-sensitized patients after sublingual immunotherapy.

OBJECTIVES/HYPOTHESIS: To compare immunologic modification and treatment outcomes after 2 years of sublingual immunotherapy (SLIT) with house dust mite extracts (HDM) between monosensitized and polysensitized patients with allergic rhinitis. STUDY DESIGN: Retrospective cohort study. METHODS: Among the patients who were prospectively enrolled in the SLIT cohort study, patients with allergic rhinitis who were sensitized to HDM and treated with SLIT for at least 2 years were studied. All participants underwent serologic tests at baseline and after SLIT to evaluate changes in immunologic parameters. The total nasal symptom score (TNSS) was measured before and after SLIT, and effective and less effective responder groups were categorized depending on whether patients had a TNSS reduction of 50%, as compared with baseline. RESULTS: The increase in Dermatophagoides pteronyssinus and Dermatophagoides farinae specific immunoglobulin G4 levels was significantly higher in monosensitized patients than in polysensitized patients (P = .020 and P = .005, respectively). The TNSS significantly improved after SLIT in both the monosensitized and polysensitized groups (P < .001 in both groups). However, the difference in the changes in TNSS from baseline was not significant between the two groups (P = .374). CONCLUSIONS: This study demonstrated different immunologic modifications after SLIT between monosensitized and polysensitized patients. However, patients in the polysensitized group who were treated with single-allergen SLIT experienced clinical improvement in TNSS that was comparable with that in the monosensitized group despite demonstrating different immunologic changes. LEVEL OF EVIDENCE: 2b Laryngoscope, 129:E170-E177, 2019.

Principal Clinical Factors Predicting Therapeutic Outcomes After Surgical Drainage of Postoperative Cheek Cysts: Experience From a Single Center.

OBJECTIVES: Postoperative cheek cyst (POCC) is a late postoperative complication of radical maxillary sinus surgery including the Caldwell-Luc (C-L) operation. The present study aimed to evaluate the therapeutic outcomes of surgical treatment for POCC and to assess the clinical factors correlated to these outcomes. METHODS: This study included 57 patients (67 nostrils) diagnosed with POCC who underwent surgical drainage. The medical records of the patients were retrospectively reviewed for radiological findings, treatment modalities, residual symptoms, and recurrences. RESULTS: In total, 30 patients were male and 27 patients were female with a mean age of 55 years, and the patients were usually diagnosed with POCC 28.2 years after radical surgery. Endonasal endoscopic marsupialization was performed via inferior meatal antrostomy, and if possible, middle meatal antrostomy was performed at the same time. In patients with cysts that were difficult to reach using an endonasal endoscopic approach, additional open C-L approaches were performed. The median follow-up period was 19.4 months. Overall, adequate drainage and symptomatic relief were achieved in 91% (61/67) of the patients. The recurrence rate was significantly higher in patients who had anterolateral POCC. Failure to achieve symptomatic relief was correlated to a smaller cyst and the use of the open C-L approach for drainage. CONCLUSION: The location and size of the cyst as well as the use of the open surgical approach were important factors in predicting the therapeutic outcome of POCC. The time point of treatment and surgical approaches should be based on the above-mentioned findings.