Endoscopy-assisted transoral resection of a parapharyngeal space schwannoma without mandibular dissection.

Of the schwannomas that arise from the parapharyngeal space, those in the high cervical region are particularly invasive, requiring mandibular dissection. Because these tumors are benign, however, excessive surgical invasion and postoperative neurological complications should be avoided. Postoperative dropout symptoms may be avoided by intracapsular extraction, including nerve integrity monitoring (NIM) and narrow-band imaging (NBI). Video laryngoscopy surgery is reported to be useful for transoral resection of pharyngeal and laryngeal tumors. This report describes the transoral removal of a giant schwannoma located in the high cervical region from a 74-years-old man using a surgical support device without mandibular dissection. The tumor was located on the right lateral pharyngeal wall and extended from the upper oropharynx to the hypopharynx while compressing the epiglottis to the skull base. No separation was observed between the internal jugular vein and the internal carotid artery. The tumor was diagnosed as a schwannoma with no malignancy on the basis of the histology of a core needle biopsy (CNB), and was completely and safely removed endoscopically using NIM and NBI, with no need for an external incision or mandibular dissection. This case illustrates that even a huge sympathetic schwannoma located in the parapharyngeal space at a high cervical position can be excised transorally using video-laryngoscopic surgery (TOVS) without mandibular dissection.

Induction of airway progenitor cells via p63 and KLF11 by Rho-kinase inhibitor Y27632 in hTERT-human nasal epithelial cells.

Rho-kinase inhibitor Y27632, which is a factor in conditional reprogramming culture, induces airway progenitor clone formation. To investigate whether Y27632 enhances airway progenitor cells in nasal epithelium, primary cultures of HNECs transfected with human telomerase reverse transcriptase (hTERT-HNECs) were treated with Y27632. In TERT-HNECs treated with Y27632 for 5 days, upregulation of p63, gap junction molecules Cx26, Cx30, Cx43, cytochrome P450 enzymes CYP2C9, CYP2C18, CYP39A1, CYP4B1, CYP2G1P, CYP4Z1, and KLF families KLF10 and KLF11 were observed compared to the control. Downregulation of tight junction molecules claudin-4, -7, and -23 was observed. Circumfential submembrane F-actin was also induced. The functions of gap junctional intercellular communication (GJIC) and the epithelial barrier were upregulated. Knockdown of p63 by siRNAs of TAp63 or ΔNp63 inhibited Cx26, Cx43 and CYP2C18, and induced claudin-1, and -4. Knockdown of KLF11 prevented p63 expression and enhancement of the epithelial barrier function by Y27632. In nasal mucosal tissues from patients with allergic rhinitis (AR), localized alteration of p63, KLF11, RhoA, Cx30 and claudin-4 was observed. Treatment with Y27632 in long-term culture induced airway progenitor cells via KLF11 in p63-positive human nasal epithelium. Airway progenitor cells of nasal epithelium induced by Y27632 is important in understanding upper airway disease-specific characteristics.

Mechanism of fibrogenesis in submandibular glands in patients with IgG4-RD.

The aim of this study was to investigate the mechanisms driving fibrosis in the submandibular glands (SMG) of patients with IgG4-related disease (IgG4-RD). Immunohistochemistry showed that many fibroblast-like cells expressing IL-6, IL-18, TSLP, IL-33, and MMP1 were present in SMG from the affected patients. SMG fibroblasts were derived from patients with or without IgG4-RD and were cultured in vitro. Expression of IL-6, IL-18, TSLP, IL-33 and MMP1, the secretion of IL-6 and G2/M phase were upregulated in the fibroblasts from the affected patients. By treatment with inflammatory cytokines IL-1ß, TNFα or TGF-ß after treatment with or without the NF-κB inhibitor curcumin, curucumin blocked the production and secretion of IL-6 upregulated by IL-1ß, TNFα, or TNFα/TGF-ß in all fibroblasts. Wnt1-inducible signaling protein 1 (WISP1), which can enhance fibroblasts proliferation, was also more abundantly expressed in affected fibroblasts, while treatment with IL-6 induced WISP1, treatment with WISP1 increased the G2/M phase, and curucumin inhibited WISP1 induced by TNFα/TGF-ß in unaffected fibroblasts. IL-33 in affected fibroblasts was induced by IL-1ß, TNFα, or TNFα/TGF-ß, while the effect of IL-1ß or TNFα/TGF-ß was blocked by curcumin. These results suggest fibrosis in the SMG of affected patients is closely linked to the proliferation of fibroblasts following induction of IL-6 and WISP1 by inflammatory cytokines. The Th2 cytokines TSLP and IL-33 are also upregulated in affected SMG, and thus may cause chronic inflammation and IgG4 accumulation.

Guanylate binding protein-1-mediated epithelial barrier in human salivary gland duct epithelium.

Guanylate-binding protein-1 (GBP-1) is an interferon-inducible large GTPase involved in the epithelial barrier at tight junctions. To investigate the role of GBP-1 in the epithelial barrier, primary human salivary gland duct epithelial cells were treated with the the proinflammatory cytokines IFNγ, IL-1ß, TNFα and the growth factor TGF-ß. Treatment with IFNγ, IL-1ß, or TNFα markedly enhanced GBP-1 and the epithelial barrier function, and induced not only CLDN-7 but also the tricellular tight junction molecule lipolysis-stimulated lipoprotein receptor (LSR). Knockdown of GBP-1 by its siRNA induced endocytosis of tight junction molecules, and prevented the increases of CLDN-7 and LSR with the upregulation of the epithelial barrier function induced by treatment with IFNγ or TNFα. Treatment with a PKCα inhibitor induced expression of GBP-1, CLDN-7 and LSR and enhanced the epithelial barrier function. In almost intact salivary gland ducts from patients with IgG4-related disease (IgG4-RD) indicated significant infiltration of IgG-positive plasma cells, expression of GBP-1, CLDN-7 and LSR was increased. These findings indicated that GBP-1 might play a crucial role in barrier function of normal human salivary gland duct epithelium and perform a preventive role in the duct epithelium of IgG4-RD disease.

Clinical utility of 18 F-fluorodeoxyglucose/positron emission tomography in diagnosis of immunoglobulin G4-related sclerosing sialadenitis.

OBJECTIVES/HYPOTHESIS: The aim of this study was to evaluate the utility of 18 F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for accurately diagnosing immunoglobulin G4-related sclerosing sialadenitis (IgG4-SS). STUDY DESIGN: Retrospective cohort study. METHODS: We reviewed the records of 64 patients with IgG4-SS (35 male and 29 female patients) and 10 patients with clinically suspected IgG4-SS. Pathological diagnoses of patients clinically suspected with IgG4-SS included four cases of malignant lymphoma, one case of multicentric Castleman disease, one case of Sjögren's syndrome, and four cases of sialadenitis. All patients underwent submandibular gland (SMG) biopsies and baseline FDG-PET/CT evaluation. Clinical, serological, pathological, and PET/CT findings were analyzed. We also investigated maximum standardized uptake values (SUVmax) in the salivary glands of 15 patients with malignant disease of the salivary glands during the same period. RESULTS: Increased FDG uptake in the SMG and parotid gland was found in 63 (98%) and 23 (35%) patients with IgG4-SS, respectively. FDG uptake of the bilateral SMG and unilateral SMG was recorded in 57 patients (89%) and six patients (9%), respectively. Mean SUVmax in patients with malignant disease of the salivary glands was significantly higher than that in patients with IgG4-SS (P = .035). We defined a positive test for IgG4-SS diagnosis as high SMG FDG uptake and serum IgG4 level ≥135 mg/dL, resulting in a sensitivity, specificity, and accuracy of 96.9%, 90.0%, and 86.4%, respectively. CONCLUSIONS: FDG-PET/CT findings in combination with serological and clinical findings may have the capacity to diagnose IgG4-SS and lead to less-invasive biopsy procedures. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1120-1125, 2018.

The role of transcriptional factor p63 in regulation of epithelial barrier and ciliogenesis of human nasal epithelial cells.

Disruption of nasal epithelial tight junctions (TJs) and ciliary dysfunction are found in patients with chronic rhinosinusitis (CRS) and nasal polyps (NPs), along with an increase of p63-positive basal cells and histone deacetylase (HDAC) activity. To investigate these mechanisms, primary cultures of HNECs transfected with human telomerase reverse transcriptase (hTERT-HNECs) were transfected with siRNAs of TAp63 and ΔNp63, treated with the NF-kB inhibitor curucumin and inhibitors of HDACs, and infected with respiratory syncytial virus (RSV). In TERT-HNECs, knockdown of p63 by siRNAs of TAp63 and ΔNp63, induced claudin-1 and -4 with Sp1 activity and enhanced barrier and fence functions. The knockdown of p63 enhanced the number of microvilli with the presence of cilia-like structures. Treatment with curcumin and inhibitors of HDACs, or infection with RSV prevented expression of p63 with an increase of claudin-4 and the number of microvilli. The knockdown or downregulation of p63 inhibited phospho-p38MAPK, and the p38MAPK inhibitor downregulated p63 and upregulated the barrier function. Thus, epithelial barrier and ciliogenesis of nasal epithelium are regulated in a p63-negative manner in normal and upper airway diseases. Understanding of the regulation of p63/p38 MAPK/NF-κB may be important in the therapy for airway allergy and its drug delivery system.

Diagnosis and Treatment of Obstructive Sleep Apnea Syndrome in Children.

Sleep is important for children pertaining to their physical and mental growth. Obstructive sleep apnea syndrome (OSAS) in children has been shown to have different effects as compared to OSAS in adults, including deficits in cognition and neuropsychological functions, hyperactivity, ADHD, behavior problems, aggressive behavior, learning problems and nocturnal enuresis. Hypertrophy of the adenoids and tonsils is a major cause of OSAS in children; therefore, adenotonsillectomy may decrease the effects of OSAS pertaining to physical and mental growth. It is important to accurately diagnose and appropriately treat OSAS in children to prevent OSAS in their adulthood.

A Novel Drug Delivery System for the Human Nasal Epithelium.

The epithelium of upper respiratory tissues such as the human nasal mucosa forms a continuous barrier via tight junctions (TJs). The development of a drug delivery system for use across the nasal mucosa is being reconsidered. In intranasal administration across the nasal mucosa, the paracellular pathway regulated by TJs is extremely important. It is known that the C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) binds the TJ protein claudin and disrupts the tight junctional barrier without inducing a cytotoxic effect. We investigated the effects of C-CPE mutants on the function of TJs of human nasal epithelial cells (HNECs) and on the permeability of human recombinant insulin across HNECs treated with C-CPE 194 and C-CPE m19. We recently reported that C-CPE mutants 194 and m19 can regulate the permeability of insulin across HNECs via the MAPK pathway and may play a crucial role in therapy for various diseases via direct intranasal insulin administration. On the other hand, microRNAs (miRNAs) are known to regulate the expression of TJs as direct or indirect targets in genes to maintain barrier function. We investigated the effects of miRNAs on the epithelial barrier of HNECs and found that miRNA-146a plays crucial roles in the maintenance of the TJ barrier and innate immune response against invading pathogens. This chapter reviews a novel drug delivery system across the nasal mucosa from the point of view of the epithelial barrier function.

Clinical Evaluation of Sinonasal Lesions in Patients With Immunoglobulin G4-Related Disease.

OBJECTIVES: Immunoglobulin G4-related disease (IgG4-RD) is a systemic disease entity characterized by elevated serum IgG4 and extensive IgG4-positive plasma cell infiltration of various organs. Patients with IgG4-RD show nasal manifestations with chronic rhinosinusitis. The objective of this study was to evaluate the clinical characteristics of sinonasal lesions in patients with IgG4-RD. METHODS: We evaluated radiological findings of sinonasal lesions in 79 patients with IgG4-RD who were divided into 3 groups according to severity. We also compared serological findings, including serum IgG4 and IgE levels, and eosinophil counts. RESULTS: Rhinosinusitis was found in 41 patients (51.9%). Although there were no significant differences in the serum IgG4 and IgE levels of the groups, there was a significant increase in eosinophil counts (445 ± 311.9/mm³) in Group C. Furthermore, 14 of the 41 patients with rhinosinusitis (34.1%) showed improvement after prednisolone administration. Patients with IgG4-RD and serum eosinophilia tend to also have sinonasal lesions. CONCLUSIONS: Rhinosinusitis is common in patients with IgG4-RD, and its pathogenesis can be similar to eosinophilic chronic rhinosinusitis.

[A middle to long-term clinical study on pars flaccida and pars tensa cholesteatoma using survival analysis].

The current clinical study was performed on 311 cases of pars flaccida and 89 cases of pars tensa cholesteatoma which were treated with canal wall reconstructed tympanoplasty between 1991 and 2012. The average follow-up time of these patients was 5.3 years. Since follow-up periods were different in each case and some censored patients were involved, we used survival analysis on this study to discuss the cumulative rates of disease-free successful cases and the rates of recurrent cholesteatoma throughout the postoperative course. The disease-free successful cases were defined as those cases in which patients were both out of re-operation with recurrent and residual cholesteatoma and out of revision operation with another problem, furthermore, maintained good hearing outcome. Based on the criteria set by the Japan Otological Society (2010), the cases that satisfied the following were evaluated as good hearing results; (a) a successful case in which preoperative bone conduction was used, and (b) a case in which the postoperative air-bone gap was within 20dB after tympanoplasty for chronic otitis media. The analysis results were shown for each of (a) and (b). 1. In pars flaccida cholesteatoma, the 5-year survival rate of successful case was (a) 76.1% and (b) 83.9%, the 10-year survival rate was (a) 58.9% and (b) 73.0%. In pars tensa cholesteatoma, the 5-year survival rate of successful cases was (a) 57.7% and (b) 63.5%, the 10-year rate was (a) 42.1% and (b) 56.9%. A significant difference was seen between pars flaccida and pars tensa cholesteatoma (p < 0.001). 2. In pars flaccida cholesteatoma, the 5-year recurrence rate was 7.6% and the 10-year rate was 15.3%, and the recurrence rate increased gradually throughout the follow-up period. On the other hand, in pars tensa cholesteatoma, the increase in the recurrence rate reached a peak 15.8% at 5.5 years after the surgery. A long-term follow-up is necessary when evaluating the clinical results after tympanoplasty.

A study of infraorbital nerve swelling associated with immunoglobulin G4 Mikulicz's disease.

OBJECTIVES: Recent studies revealed that Mikulicz's disease (MD) should be considered as an immunoglobulin (Ig) G4-related disease with aspects of systemic disorders involving the orbit. This study aimed to analyze the relationship between Immunoglobulin G4 (IgG4)-related MD and infraorbital nerve thickness. METHODS: We measured infraorbital nerve thickness in 68 patients diagnosed as IgG4-related MD at our hospital and performed computed tomography scans of the head and neck region before treatment and compared these scans with those of the control group. RESULTS: The mean infraorbital nerve diameter (± standard deviation) was 3.2 ± 1.2 mm in patients with IgG4-related MD, and 2.6 ± 0.3 mm in the control group. Infraorbital nerves were significantly thicker in patients with IgG4-related MD. Nerve swelling was found in 20 of 68 patients (29.4%) with a cutoff value of 3.3 mm because this value was obtained from diameter of nerves in the control group + 2 standard deviation mm. No patients in the control group showed nerve swelling. In addition, we found significant correlations between infraorbital nerve swelling and serum IgG4 levels as well as the existence of multiple organ lesions. CONCLUSIONS: We found that significant infraorbital nerve swelling occurred in patients with IgG4-related MD and was thought to be a part of IgG4-related disease.