S100A8 enhances IL-1ß production from nasal epithelial cells in eosinophilic chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis is classified into eosinophilic chronic rhinosinusitis (ECRS) and non-eosinophilic chronic rhinosinusitis (NECRS). ECRS is a refractory allergic disease involving a variety of immune and epithelial cells. S100A8 is a damage-associated molecular pattern that is closely related to allergic inflammation. However, the pathological implications of S100A8 in ECRS have not been clarified. METHODS: We evaluated the role of S100A8 in the pathogenesis of ECRS. Gene expression profiles of nasal polyps obtained from patients with ECRS or NECRS were evaluated using RNA sequencing. RESULTS: S100A8 was identified as a significantly upregulated gene in nasal polyps associated with ECRS. Immunohistochemistry consistently revealed intense S100A8 staining in nasal polyps from patients with ECRS. Human nasal epithelial cells expressed the receptor for advanced glycation end products and Toll-like receptor 4. Recombinant S100A8 protein induced interleukin-1ß secretion in human nasal epithelial cells. CONCLUSIONS: Our data demonstrate that S100A8 results in production of interleukin-1ß in the nasal epithelium, which may be involved in the pathogenesis of ECRS.

Pathological and therapeutic implications of eosinophil-derived semaphorin 4D in eosinophilic chronic rhinosinusitis.

BACKGROUND: Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis. Clinical markers for ECRS disease activity and treatment strategies have not been sufficiently established. Although semaphorins are originally identified as neuronal guidance factors, it is becoming clear that they play key roles in immune regulation and inflammatory diseases. OBJECTIVE: We sought to investigate the pathological functions and therapeutic potential of semaphorin 4D (SEMA4D) in ECRS. METHODS: Serum soluble SEMA4D levels in patients with paranasal sinus diseases were measured by ELISA. The expression of SEMA4D in blood cells and nasal polyp tissues was assessed by flow cytometry and immunohistochemistry, respectively. Generation of soluble SEMA4D was evaluated in matrix metalloproteinase-treated eosinophils. Endothelial cells were stimulated with recombinant SEMA4D, followed by eosinophil transendothelial migration assays. Allergic chronic rhinosinusitis was induced in mice using Aspergillus protease with ovalbumin. The efficacy of treatment with anti-SEMA4D antibody was evaluated histologically and by nasal lavage fluid analysis. RESULTS: Serum soluble SEMA4D levels were elevated in patients with ECRS and positively correlated with disease severity. Tissue-infiltrated eosinophils in nasal polyps from patients with ECRS stained strongly with anti-SEMA4D antibody. Cell surface expression of SEMA4D on eosinophils from patients with ECRS was reduced, which was due to matrix metalloproteinase-9-mediated cleavage of membrane SEMA4D. Soluble SEMA4D induced eosinophil transendothelial migration. Treatment with anti-SEMA4D antibody ameliorated eosinophilic infiltration in sinus tissues and nasal lavage fluid in the ECRS animal model. CONCLUSIONS: Eosinophil-derived SEMA4D aggravates ECRS. Levels of serum SEMA4D reflect disease severity, and anti-SEMA4D antibody has therapeutic potential as a treatment for ECRS.

Eosinophil-derived neurotoxin enhances airway remodeling in eosinophilic chronic rhinosinusitis and correlates with disease severity.

Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis (CRS) that is characterized by intractable nasal polyp formation. Eosinophil-derived neurotoxin (EDN) is an eosinophil granule protein that is closely related to allergic inflammation, but the pathological implications of EDN in ECRS remain unknown. In this study, we evaluated the function of EDN in ECRS pathogenesis and assessed its potential as a disease activity marker. Serum EDN levels were significantly higher in patients with ECRS than in those with other nasal and paranasal diseases, and were positively correlated with clinical disease activity. Production of EDN from isolated human eosinophils was induced by stimulation with IL-5 in vitro. Human nasal epithelial cells were stimulated with EDN, and the resultant changes in gene expression were detected by RNA sequencing. Pathway analysis revealed that the major canonical pathway affected by EDN stimulation was 'regulation of the epithelial-mesenchymal transition pathway'; the only gene in this pathway to be up-regulated was matrix metalloproteinase 9 (MMP-9). Consistent with this, immunostaining analysis revealed intense staining of both EDN and MMP-9 in nasal polyps from patients with ECRS. In conclusion, our data demonstrate that serum EDN level is a useful marker for the evaluation of ECRS severity. Furthermore, EDN induces production of MMP-9 from the nasal epithelium, which may be involved in the pathogenesis of ECRS.

Allergic conversion of protective mucosal immunity against nasal bacteria in patients with chronic rhinosinusitis with nasal polyposis.

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is characterized by eosinophilic inflammation and polyposis at the nose and paranasal sinus and a high concentration of IgE in nasal polyps (NPs). The causative antigen and pathogenesis of CRSwNP remain unknown. OBJECTIVE: We aimed to identify reactive allergens of IgE antibodies produced locally in NPs of patients with CRSwNP. We also attempted to unravel the differentiation pathway of IgE-producing B cells in NPs. METHODS: IgE reactivity of patients with CRSwNP was investigated by characterizing single cell-derived mAbs. T-cell response against identified allergens was investigated in vitro. NP-infiltrating lymphocytes were characterized by using flow cytometry. Immunoglobulins expressed in NPs were analyzed by using high-throughput DNA sequencing for immunoglobulin. RESULTS: About 20% of isolated IgE antibodies derived from NP-residing plasmablasts specifically recognized surface determinants of nasal bacteria, such as Staphylococcus aureus, Streptococcus pyogenes, and Haemophilus influenzae. A TH2 response against S pyogenes was observed in patients with CRSwNP. Flow cytometric analysis revealed sizable germinal center B-like cell and plasmablast subsets expressing IgE on the cell surface in NPs. High-throughput DNA sequencing immunoglobulin analysis highlighted the clonal connectivity of IgE with IgG and IgA1. The Iε-Cα1 circle transcript was detected in NPs. CONCLUSIONS: In patients with CRSwNP, nasal bacteria-reactive B cells differentiate into IgE-producing B cells through IgG/IgA1-IgE class switching, suggesting that allergic conversion of the mucosal response against nasal bacteria underlies disease pathogenesis.

[Two Cases of Venous Malformation of the Orbit Treated by Endoscopic Endonasal Surgery].

Venous malformation of the orbit(VMO), previously called orbital cavernous hemangioma, has been classified as a vascular malformation according to the International Society for the Study of Vascular Anomalies. Among various surgical approaches for VMO, endoscopic endonasal surgery(EES)has recently been developed, especially for those in the inferomedial quadrant of the orbit. Two 67-year-old and 69-year-old women presented with decreased visual acuity and visual field deficit, respectively. Their CT and MRI scans revealed retrobulbar masses, suggestive of the inferomedial type of VMO. The first case was diagnosed as an intraconal VMO, and subtotal removal was achieved through binostril EES using a two-surgeon four-handed technique after palliative partial resection through a prior frontal craniotomy. In the second case, diagnosed as an extraconal VMO, total en bloc removal was achieved using the same surgical technique as above. In both cases, the visual functions improved after the procedures, with uneventful postoperative courses. Although the inferomedial VMO is an uncommon type, EES is well indicated for this condition. The international consensus of surgical techniques and staging from a surgical point of view should be established in the near future.

[Significant factors for surgical site infection: analysis of 203 head and neck surgeries].

Surgical site infection (SSI) is a common complication in head and neck surgeries. The aim of this study was to assess the rate of, and risk factors for SSI following surgical procedures of the head and neck. The study population comprised 206 patients who underwent surgery of head and neck region in NTT West Osaka Hospital between 2009 and 2011. The incidence rate and risk factors were estimated by the chi-square test and a logistic regression analysis. SSI occurred in 22 cases (10.8%) of 203 patients. A broad range of putative risk factors was recorded in each patient and statistically analyzed to elucidate SSI related factors. Univariate analysis indicated that low BMI, diabetes mellitus, anemia, hypoalbuminemia, surgical wound classification, duration of operation, blood loss, left implants and preoperative radiotherapy were risk factors associated with SSI. Multivariate statistics revealed four independent risk factors: surgical wound classification (odds ratio (OR) 5.88, p = 0.02), hypoalbuminemia (OR 11.48, p < 0.01), duration of operation (OR 18.66, p < 0.01) and left implants (OR 20.24, p < 0.01). Thus, to achieve a reduction in SSI, we need to take care of not only the factors related with surgical technique such as the duration of the operation or left implants, but the preoperative nutrition status.

Understanding hereditary hemorrhagic telangiectasia: From genetic anomalies to systemic manifestations, quality of life, and epistaxis management-Exploring the otolaryngologist's integral role.

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Rendu-Weber syndrome, is a rare autosomal dominant disorder characterized by vascular malformations. This comprehensive review aimed to provide an overview and summarize various aspects of HHT, including the genetic abnormalities, complications associated with visceral arteriovenous malformations (AVMs), prognosis of HHT, quality of life (QOL), and treatment of epistaxis. In addition, this review highlights the challenges in diagnosing HHT and emphasizes the critical role of otolaryngologists in the early detection of HHT. Otolaryngologists can refer patients with refractory epistaxis for AVM screening to expedite intervention. Mutation of the genes involved in the transforming growth factor-ß signaling pathway leads to the incidence of HHT, resulting in the formation of abnormal blood vessel formation. These vascular malformations commonly manifest as telangiectasia on the skin and mucous membranes; however, epistaxis remains the hallmark symptom of HHT. The impact of HHT goes beyond the visible symptoms and often includes the formation of life-threatening visceral AVMs in the lungs, liver, and brain. The prognosis of patients with HHT is closely related to the development of these complications, necessitating timely diagnosis and intervention. Refractory epistaxis diminishes the QOL of patients with HHT. The management of epistaxis ranges from conservative measures to advanced interventions such as prevention, conservative treatments, ablation, surgical procedures, and the administration of anti-angiogenic agents. However, effective management requires a multidisciplinary approach. The diagnosis of HHT remains challenging due to its variable presentation and lack of awareness among physicians. This review highlights the importance of reducing the duration between symptom onset and diagnosis. Otolaryngologists who are experienced in the management of refractory epistaxis can aid in identifying potential cases of HHT. They can facilitate the initiation of screening for visceral AVMs via prompt recognition of the signs and symptoms of HHT, contributing to improved patient outcomes. Early detection and intervention through screening can extend the life expectancy of patients with HHT to levels comparable with that of the general population. In conclusion, this review provides insight into various aspects of HHT and emphasizes the importance of timely diagnosis and intervention in the mitigation of the potentially life-threatening complications associated with this disorder. Otolaryngologists play a critical role in this process, serving as gatekeepers to the identification of cases of HHT and implementation of appropriate screening and management pathways, thereby improving the life expectancy and QOL of patients.

Efficacy of tokishakuyakusan and mecobalamin on post-infectious olfactory dysfunction: A prospective multicenter study.

OBJECTIVE: To determine if tokishakuyakusan (TSS) is effective for treating post-infectious olfactory dysfunction (PIOD) compared with vitamin B12 (mecobalamin). METHODS: We conducted a randomized, nonblinded clinical trial. Patients with PIOD enrolled in 17 hospitals and clinics from 2016 to 2020 were randomly divided into two groups, and we administered TSS or mecobalamin for 24 weeks. Their olfactory function was examined using interviews and T&T olfactometry. The improvement of olfactory dysfunction was assessed following the criteria of the Japanese Rhinologic Society. RESULTS: Overall, 82 patients with PIOD were enrolled in this study. In the TSS and mecobalamin groups, 39 patients completed the medication regimen. In the TSS and mecobalamin groups, olfactory dysfunction was significantly improved based on self-reports and olfactory test results. The improvement rate of olfactory dysfunction was 56% in the TSS group and 59% in the mecobalamin group. Early intervention within 3 months produced a better prognosis than the treatment initiated after 4 months. Furthermore, age and sex differences were not observed. Both medications produced no severe adverse events. CONCLUSION: The present study showed that TSS and mecobalamin might be useful for treating PIOD.

Buccal Abscess Caused by Toothbrush Trauma: A Case Report of a Two-Year-Old.

Children often experience impalement trauma when they fall while holding objects in their mouths. While most cases heal without complications, here we report a case of buccal abscess formation after toothbrush trauma. A two-year-old boy fell while running with a toothbrush in his mouth, which punctured his right buccal mucosa. The following day, he presented to a pediatrician with a fever and buccal swelling and was treated with oral antibiotics. However, the buccal swelling did not improve, and the patient was referred to our department. Four days after the visit, the buccal swelling and fever worsened, requiring hospitalization, intravenous antibiotics, and drainage. The inflammation quickly disappeared following treatment, with no recurrence. Prophylactic antibiotic administration for oral impalement trauma is controversial. Our results suggest that prophylactic antibiotics covering both anaerobic and aerobic bacteria are necessary in cases of toothbrush-related oral trauma, where multiple bacterial infections may occur.

Paranasal Schwannomas: A Comprehensive Study of 2 Cases.

Paranasal sinus tumors are a heterogeneous group of neoplasms (with paranasal schwannomas being a rare subtype) that are often present with non-specific symptoms, such as nasal obstruction and epistaxis. Thus, early diagnosis is crucial for optimal management. This study presents 2 cases of paranasal schwannomas, detailing their clinical presentation, diagnostic methods, and treatment approaches. Both patients underwent endoscopic sinus surgery with successful tumor excision and had no significant complications or recurrences during follow-up. Diagnosis was based on a combination of clinical examination, radiological imaging (computed tomography and magnetic resonance imaging), and histopathological confirmation with immunohistochemical staining. Treatment consisted primarily of endonasal resection, with consideration of frontal craniotomy if necessary. This study aims to contribute to the understanding of paranasal schwannomas and emphasizes the importance of early detection and treatment to improve patient outcomes.

Percutaneous Transluminal Angioplasty and Stenting for Progressive Intracranial Carotid Artery Stenosis Secondary to Invasive Sphenoid Sinus Aspergillosis: A Case Report.

We report a case of invasive sphenoid sinus aspergillosis with progressive internal carotid artery (ICA) stenosis and contralateral carotid occlusion that was successfully treated with percutaneous transluminal angioplasty and stenting (PTAS). A 70-year-old man presented with right-sided visual disturbance, ptosis, and left hemiparesis. Magnetic resonance imaging of the head revealed a space-occupying lesion within the sphenoid sinus with infiltration of the bilateral cavernous sinuses, right ICA occlusion, and multiple watershed cerebral infarcts involving the right cerebral hemisphere. The patient was diagnosed with invasive sinus aspergillosis based on transnasal biopsy findings. Despite intensive antifungal therapy using voriconazole, rapidly progressive aspergillosis led to a new stenotic lesion in the left ICA, which increased the risk of bilateral cerebral hypoperfusion. We performed successful PTAS to prevent critical ischemic events. Finally, aspergillosis was controlled with voriconazole treatment, and the patient was discharged. He showed a favorable outcome, with a patent left ICA observed at a 3-year follow-up. PTAS may be feasible in patients with ICA stenosis and invasive sinus aspergillosis.

Pseudo-malignant paranasal invasive aspergillosis showing bone destruction and FDG uptake on PET/CT: A case report.

RATIONALE: Aspergillosis is a rare disease that often occurs in patients with diabetes mellitus or compromised hosts. This study describes a 60-years-old woman with unusual pseudo-malignant paranasal invasive aspergillosis with 18F-fluorodeoxyglucose (18F-FDG) uptake treated by endoscopic sinus surgery. To the best of our knowledge, there are few reported cases of paranasal fungal infection with 18F-FDG uptake. PATIENTS CONCERNS: A 60-years-old woman was presented with headache and nasal obstruction. DIAGNOSES: Computed tomography (CT) showed a shadow with bone destruction in the sinus cavity and accumulation of 18F-FDG uptake. The patient was diagnosed with a malignant tumor or pseudo-malignant paranasal invasive aspergillosis. INTERVENTIONS: The patient underwent endoscopic sinus surgery; no neoplastic lesions were detected in the areas with CT shadows. All the observed fungal mass reservoirs were removed. OUTCOMES: The patient remained hospitalized for 1 week after the surgery with no significant postoperative abnormalities. There was no recurrence of the disease for 6 months, and the patient's symptoms resolved, indicating a good course of follow-up. LESSONS: Invasive aspergillosis should be considered a differential disease when positron emission tomography (PET)/CT scans show FDG uptake, CT shows bone destruction, and T2-weighted MRI scans show a low signal.

Organized Hematoma after Intra-Arterial Chemoradiotherapy for Maxillary Sinus Cancer: A Case Report.

An organized hematoma (OH) is a relatively rare benign lesion of the paranasal sinuses. Traditionally, it has been reported to occur following trauma, surgery, and sinus hemorrhagic lesions and in various bleeding predispositions. OHs are sometimes difficult to differentiate from malignancy because of the similar clinical symptoms and bone destruction. It is especially difficult when OHs occur in the same location as the primary tumor after treatment of a malignant tumor. In this paper, we report two cases of OH that occurred after intra-arterial chemoradiotherapy (IACRT) for maxillary sinus cancer. In one case, FDG accumulation was found in PET/CT and suspected to be a cancer recurrence. However, the postoperative pathology showed no malignant findings. This suggests that OH may show accumulation on 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET). In both cases, bleeding from the maxillary sinus continued after surgery. In one case, recurrence was observed, and in the other, nasal irrigation prevented the pooling of blood in the maxillary sinus, and no recurrence was observed. These cases suggest that OH after IACRT may easily recur because the bleeding continues even after surgery. In such cases, nasal irrigation or preoperative embolization may be helpful to avoid recurrence.

A Case of Endonasal Endoscopic Surgery for Intraorbital Metastasis of Gastric Ring Cell Carcinoma.

Gastric signet ring cell carcinoma has well-known metastatic features, including peritoneal dissemination and carcinomatous lymphangitis of the lung, but no intraorbital metastases were reported previously. A woman in her 60s developed left eye pain, sudden vision loss, and headache 12 years after gastric cancer treatment. Symptoms did not improve despite steroid pulses. Craniotomy showed no malignant findings. The patient was referred to our department for symptomatic relief and biopsy due to the lack of a definitive diagnosis and no improvement in her ocular pain. Endonasal endoscopic surgery was performed for diagnostic purposes and to relieve symptoms through orbital decompression. Preoperative computed tomography examination revealed a tumor at the left medial orbit, extending to the orbital apex. Orbital decompression through the open left medial orbital wall was performed with biopsy of the intraorbital tumor. Pathological findings were consistent with metastatic signet ring cell carcinoma. Pain and subjective improvement of visual acuity were noted the day after surgery. Twelve months postoperatively, diplopia remains, but there has been no worsening of symptoms.

Co-Treatment with Steroid and Dupilumab for Eosinophilic Chronic Rhinosinusitis after Eosinophilic Pneumonitis Caused by Dupilumab.

Eosinophilic chronic rhinosinusitis (ECRS) is a Type 2 inflammatory disease that manifests as chronic inflammation of the paranasal sinus. IL-4/IL-13 receptor monoclonal antibodies (dupilumab) to suppress Type 2 inflammation have become a good treatment option for patients who are refractory to surgery. Most patients respond normally, although significant side effects such as eosinophilic pneumonia may occur, requiring discontinuation of dupilumab. Here, we present a case in which dupilumab administration caused a side-effect of eosinophilic pneumonia. A 65-year-old woman presented with nasal obstruction and olfactory dysfunction due to a nasal polyp. Her symptoms temporarily improved with dupilumab; however, dupilumab was discontinued due to eosinophilic pneumonia. Discontinuation of dupilumab resulted in the rapid resolution of eosinophilic pneumonia and reappearance of nasal polyps. We, therefore, resumed dupilumab treatment in combination with low-dose steroids; eosinophilic pneumonia did not flare up, and the nasal polyps shrank steadily. There is no established treatment strategy in cases where a side effect of eosinophilic pneumonia arises while treating ECRS with dupilumab. Based on the described case, we recommend that a combination of a low-dose steroids and dupilumab be considered as a treatment option to counter the side-effect of eosinophilic pneumonia induced by dupilumab alone.

Skull Base Metastasis of Breast Cancer With Oculomotor and Trochlear Nerve Palsy.

Skull base metastatic tumors are rare. Breast cancer in particular can cause bone metastases after a long period of time. A 70-year-old woman presented with multiple cranial nerve palsy. Magnetic resonance imaging revealed a lesion that extended from the orbit to the base of the skull, and the patient was referred to our department. Ophthalmological evaluation showed left visual acuity impairment, left oculomotor nerve palsy, and left trochlear nerve palsy. Endoscopic biopsy performed 5 years after the completion of breast cancer treatment revealed skull base metastases. In unilateral multiple cranial nerve palsy, the possibility of skull base metastases should be considered.

Validation of epistaxis severity score for hereditary hemorrhagic telangiectasia in Japan.

OBJECTIVE: This study aimed to assess the health-related QoL (HR-QoL) of patients with hereditary hemorrhagic telangiectasia (HHT), with emphasis on the role/social aspects, and validate the Japanese version of the epistaxis severity score (ESS) in these patients. METHODS: The Japanese version of the ESS was created through forward and reverse translation, and consultation with the original author. A validation analysis was performed by comparing ESS severity with the invasiveness of previous treatments for epistaxis and assessing the correlation between the ESS and HR-QoL. Medical history forms, ESS questionnaires, and the Medical Outcomes Study Short Form 36 (SF-36) were distributed to participants with HHT in August 2020. The relation between the ESS and summary scores of SF-36 was assessed by performing analysis of variance and Spearman's correlation. RESULTS: In total, 73 participants were included in this study. The average ESS was 5.02; there were mild (32.9%), moderate (45.2%), and severe (21.9%) epistaxis groups. Patients with higher ESS received a significantly more invasive treatment (Fisher's exact test, p < 0.05). The ESS was also negatively correlated with the physical component score (PCS) (r = -0.489, p < 0.001). Comorbid liver and gastrointestinal arteriovenous malformations significantly reduced the PCS (p < 0.05). Multiple regression analysis revealed that the ESS was a significant variable (p < 0.01). The role/social component score was significantly lower in the severe ESS group than in the mild or moderate group. CONCLUSION: The Japanese version of the ESS was considered valid and may be useful as an outcome measure of future HHT-associated epistaxis trials in Japan.