Efficacy of the Endoscopic Triportal Transmaxillary Approach for Treating Lateral Middle Skull Base Tumors: A Technical Note and Retrospective Case Series.

BACKGROUND: The endoscopic approach, chiefly via the maxillary sinus, has growing applications for the lateral skull base, and can be classified into the use of "endonasal" or "sublabial" entry. Although the endonasal transmaxillary approach has been well accepted, it has a limitation with respect to the lateral exposure. A possible solution is the use of the sublabial transmaxillary approach via the canine fossa, which assures lateral accessibility. In clinical practice, we have taken advantage of the concomitant use of the endonasal and sublabial transmaxillary approach for selected patients harboring lateral skull base lesions. In addition to binostril pathways, canine fossa trephination was constructed to facilitate this combined approach, termed the endoscopic triportal transmaxillary approach (ETTA). METHODS: The efficacy of the ETTA was evaluated within a case series. A single-institution retrospective analysis was performed in patients with lateral middle skull base tumors treated via ETTA. RESULTS: In clinical practice, 4 patients were eligible for the study, including 1 receiving a combined endoscopic and transcranial approach. No major complications occurred in patients included in this series. The ETTA facilitated the dynamic manipulation of instruments, which led to rapid hemostasis and the satisfactory surgical resection of tumors. Furthermore, it reduced intraoperative postural stress experienced by the surgeons who performed the procedures. CONCLUSIONS: The concomitant use of the trans-canine fossa approach effectively ameliorated significant technical challenges that tend to occur when using a purely endonasal approach. The ETTA can be an attractive option for treating lateral and middle skull base lesions.

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.

Minimal Change Nephrotic Syndrome Which Was Most Likely Caused by Chronic Sinusitis.

A 33-year-old Japanese man was admitted with severe edema, and a renal biopsy confirmed minimal change nephrotic syndrome (MCNS). CT revealed his severe chronic sinusitis, and he first received antimicrobial therapy, which resulted in decreased proteinuria. The surgical operation for sinusitis resulted in the complete disappearance of proteinuria without corticosteroid or immunosuppressant therapy within one week. MCNS may be triggered by infection, but there are no previously reported cases of MCNS that is completely remitted by infection control alone. Therefore, we herein report the first case of MCNS that attained complete remission following therapy for chronic sinusitis alone, which suggests a strong etiology of chronic sinusitis for MCNS.

Endoscopic Transseptal Approach to Frontal Sinus Disease.

This paper describes an endoscopic transseptal approach to identify and access the frontal sinus and reviews the clinical cases. Between May 2004 and July 2010, endoscopic modified Lothrop procedure (EMLP) with transseptal approach was performed on sixteen patients. The indications for EMLP were complicated frontal sinusitis or cyst, revision surgery for failed frontal sinusotomy or Lynch procedure, or trauma cases. The first step of this procedure was to open a window in the bilateral anterior portion of the middle turbinates and nasal septum. The nasal septum, which could be observed through the window, should be the landmark of the midline during the surgery. A drill bur was raised up just behind the nasal bone along the midline of the nose. After the bilateral frontal sinuses and their posterior walls were confirmed, the interfrontal septum was removed superiorly. We reviewed the clinical records of patients who underwent the EMLP with transseptal approach. We have managed sixteen patients in this fashion. Neither intracranial nor orbital complications were encountered during or after surgery. Endoscopic transseptal frontal sinus surgery is simple to perform, and does not cause severe complications.

Thyroid-stimulating hormone-secreting ectopic pituitary adenoma of the nasopharynx.

Thyroid-stimulating hormone-secreting ectopic pituitary adenoma of the nasopharynx is highly unusual, with only three reported cases in the world literature. We describe the clinical presentation and radiologic findings in one patient with such rare lesions. A 46-year-old male with typical symptoms of Grave's disease was found to have a mass on magnetic resonance imaging. An otolaryngologic examination revealed a nasopharyngeal mass lesion, which was endoscopically resected. The results of immunohistochemical staining for thyroid-stimulating hormone were positive. After the resection, the patient's TSH was within normal limits. The clinical significance of the case and a brief literature review are presented.

[Endoscopic sinus surgery for a paranasal sinuses mucocele with light guide and dacryoendoscopy].

It is hard to cure dacryocystitis caused by a paranasal sinus mucocele with treatment which only targets the mucocele. Also, it is difficult to identify the lacrimal sac and the nasolacrimal duct preoperatively and intraoperatively when the lacrimal passage is markedly changed by the mucocele or previous surgery. We experienced four cases of mucocele complicated by lacrimal stenosis or obstruction. We performed marsupialization of the mucocele and direct silicon intubation or endoscopic dacryocystorhinostomy simultaneously with the use of a fiberoptic illuminator or dacryoendoscopy. Assisted by those devices, lacrimal procedures can now be done quickly and safely regardless of the surgeon's experience. In addition, performing surgeries both for the lacrimal passage and for the mucocele at the same time can minimize the burden on patients.

[Juvenile nasopharyngeal angiofibroma--evaluation of the invasion of the pterygoid canal].

We operated on three patients with juvenile nasopharyngeal angiofibroma in the past 3 years. The endoscopic transnasal approach was utilized in all the cases, and in one case it was accompanied with a Caldwell-Luc procedure. All the tumors were located around the sphenopalatine foramen, but also had involved and enlarged the pterygoid canal. All the cases underwent preoperative selective embolization, but it was difficult to embolize the branch of the internal carotid artery. A partial resection of the middle turbinate facilitated the manipulation of the sphenopalatine foramen and the pterygoid canal. Endoscopic management of juvenile nasopharyngeal angiofibroma should be considered as a first-choice option for tumors at the early stage.

Bimodal regulation of T cell-mediated immune responses by TIM-4.

T cell Ig and mucin domain (TIM)-4 is preferentially expressed on antigen-presenting cells, and its counter-ligand, TIM-1, is thought to deliver co-stimulating signals to T cells. However, the physiological functions of TIM-4 remain unclear. Here, we demonstrate that TIM-4 inhibits naive T cell activation through a ligand other than TIM-1. The inhibitory effect of TIM-4 was specific to naive T cells which do not express TIM-1, and the effect disappeared in pre-activated T cells. Conversely, antibody-mediated blockade of TIM-4 in vivo substantially suppressed T cell-mediated inflammatory responses despite enhanced generation of antigen-specific T cells. Furthermore, treatment with anti-TIM-4 reduced the inflammatory responses developed in mice that were adoptively transferred with antigen-primed T cells. These results suggest that TIM-4 exerts bimodal functions depending on the activation status of T cells.

Requirement for CD100-CD72 interactions in fine-tuning of B-cell antigen receptor signaling and homeostatic maintenance of the B-cell compartment.

Co-receptors on the B-cell surface regulate B-cell antigen receptor (BCR) signaling; however, it remains unclear how BCR signals are coordinated to maintain immune homeostasis. CD72, a negative regulator of B-cell responses, has immunoreceptor tyrosine-based inhibitory motifs within its cytoplasmic region, and the tyrosine phosphatase SHP-1 binds these sites. The natural ligand of CD72, CD100/Sema4D, belongs to the semaphorin family and induces the dissociation of SHP-1 from CD72, thereby switching off the negative signals of CD72. In the absence of CD100, BCR signals are significantly suppressed due to the constitutive association of SHP-1 with CD72, resulting in B-cell hyporesponsiveness. Here we show that CD100 regulates the sensitivity of the BCR by preventing the association of the CD72 with BCR, and this interaction is required for proper B-cell homeostasis. Consequently, as CD100-deficient mice age, they accumulate marginal zone B cells and develop high auto-antibody levels and autoimmunity. Collectively, our findings indicate that the strength of BCR signals is strictly tuned by the interaction of CD100 with CD72, and this interaction is essential for maintaining immunological homeostasis as well as generating a proper immune response.

IgA class switch occurs in the organized nasopharynx- and gut-associated lymphoid tissue, but not in the diffuse lamina propria of airways and gut.

Secretory IgA plays a crucial role in the host immune response as a first line of defense. A recent demonstration of in situ IgA class switching in intestinal lamina propria provided an opportunity to reconsider the model for the homing of IgA-committed B cells characterized by distinctive trafficking patterns to effector sites. Those effector sites depend on the organized mucosa-associated lymphoid tissues as their site of induction. In this report we show the preferential presence of IgM(+)B220(+) and IgA(+)B220(+) cells belonging to pre- and post-IgA isotype class-switched cells in the organized mucosa-associated lymphoid tissues, such as nasopharynx-associated lymphoid tissues, isolated lymphoid follicles, and Peyer's patches, and the defect of those populations in the diffuse effector tissues, such as the nasal passage and intestinal lamina propria. Consistent with these findings, the expressions of a series of IgA isotype class switch recombination-related molecules, including activation-induced cytidine deaminase, Ialpha-C micro circle transcripts, and Ialpha-C micro circle transcripts, were selectively detected in these organized mucosa-associated lymphoid structures, but not in the diffuse mucosal effector sites. Taken together, these findings suggest that IgA isotype class switching occurs only in the organized mucosa-associated lymphoid organs (e.g., nasopharynx-associated lymphoid tissues, isolated lymphoid follicles, and Peyer's patches), but not in the diffuse effector tissues of the upper respiratory and gastrointestinal tracts.

Modulation of T-cell functions by laser surgery in patients with allergic rhinitis.

OBJECTIVE: Potassium-titanyl-phosphate (KTP) laser turbinectomy is an established treatment for hypertrophied inferior turbinates that do not respond to other medical treatments. KTP laser surgery is usually performed with the aim of reducing the size of hypertrophied inferior turbinates. We hypothesized that laser vaporation may also inhibit the allergic reaction in the nasal mucosa of inferior turbinates. MATERIAL AND METHODS: We examined the effect of KTP laser therapy on T-cell responses using peripheral blood mononuclear cells (PBMCs). RESULTS: Levels of T-cell proliferation after stimulation with Staphylococcus enterotoxin B (SEB) were higher in post- than pre-surgery patients. Levels of interferon-gamma and IL-2 produced by PBMCs after stimulation with SEB appeared to be higher in post- than pre-surgery patients. Serum levels of house dust-specific IgE were lower in post- than pre-surgery patients. These results indicate that KTP laser therapy modulates T-cell responses and probably tilts the Th1/Th2 balance towards the Th1-dominant state. CONCLUSION: KTP laser surgery eases or cures allergic rhinitis not only by reducing the volume of the inferior turbinates but also by modulating T-cell functions.

The alteration of odor-induced c-Fos immunoreactivity in the rat olfactory bulb after olfactory nerve transection.

We used the rats in which one olfactory nerve had been transected and observed the odor (Propionic acid) -induced c-Fos immunoreactivity in the bulb at different times (2, 4, 8 weeks) after nerve transection. The exposure to odor produced a strong cluster of c-Fos positive cells in the mediodorsal region of the intact bulb. On the other hand, the transected bulb showed much less reactivity 2 weeks after neurectomy; however, a large number of positive cells were observed in the whole of the bulb from 4 weeks after neurectomy. Furthermore, we measured the levels of mRNA for tyrosine hydroxylase (TH), which was the marker of odor-induced olfactory nerve activity in the bulb, by using real-time PCR. The level of TH mRNA decreased on the transected side at 2 weeks but recovered to the level of the contralateral side at 4 weeks after neurectomy. We firstly demonstrated that projection mapping of odor receptors was altered after olfactory nerve transection by using an immunohistochemical method.

Initiation of NALT organogenesis is independent of the IL-7R, LTbetaR, and NIK signaling pathways but requires the Id2 gene and CD3(-)CD4(+)CD45(+) cells.

Initiation of nasopharyngeal-associated lymphoid tissue (NALT) development is independent of the programmed cytokine cascade necessary for the formation of Peyer's patches (PP) and peripheral lymph nodes (PLN), a cytokine cascade which consists of IL-7R, LTalpha1beta2/LTbetaR, and NIK. However, the subsequent organization of NALT seems to be controlled by these cytokine signaling cascades since the maturation of NALT structure is generally incomplete in those cytokine cascade-deficient mice. NALT as well as PP and PLN are completely absent in Id2(-/-) mice. NALT organogenesis is initiated following the adoptive transfer of CD3(-)CD4(+)CD45(+) cells into Id2(-/-) mice, constituting direct evidence that CD3(-)CD4(+)CD45(+) inducer cells can provide an IL-7R-, LTalpha1beta2/LTbetaR-, and NIK-independent tissue organogenesis pathway for secondary lymphoid tissue development.