論文

Background: Isolated sphenoid sinus diseases are relatively rare, and various approaches to treating diseases limited to the sphenoid sinus have been repoted. We examined the usefulness and limitations of sphenoid sinus opening via the endoscopic transnasal transseptal approach employed at our department. Subjects: Fifteen cases of isolated sphenoid sinus diseases managed by sphenoid sinus opening via the endoscopic transnasal transseptal approach among 982 endoscopic surgeries performed at our department between April 2012 and December 2020 were included in this study. Results: The diseases comprised 7 cases of papilloma, 4 cases of fungal sphenoid sinusitis, 2 cases of bacterial sphenoid sinusitis, and 2 cases of sphenoid sinus cysts. There were 11 cases of initial surgeries and 4 cases of revision surgeries. The diseases that needed revision surgeries included 3 cases of papilloma, 1 case of bacterial sphenoid sinusitis, and 1 case of sphenoid sinus cyst. The postoperative observation period ranged from 25 to 2964 days (median, 370 days). Except for one case, the postoperative course was favorable, with no recurrence observed in any of the patients until date. Conclusion: This endoscopic transnasal transseptal approach is considered as being useful for widely opening the sphenoid sinus for treating fungal infections and papillomas. Isolated sphenoid sinus lesions are rare and given the presence of important organs around the sinus, preparation for complications is crucial before surgery.

Subtotal petrosectomy (STP) refers to the procedure in which the entire middle ear cavity is drilled and the transected space is filled with fat or other materials and the external auditory canal is closed. It is necessary in such patients to reduce the number of local therapies, including otorrhea suction and removal of debris, because they sometimes cause dizziness and pain. It is indicated for patients who need to make frequent visits to the hospital for otorrhea caused by recurrent cholesteatoma or cavity problems. It is highly curative and does not require any postoperative treatment. In this study, we retrospectively examined patient characteristics, diseases, postoperative complications, recurrence rate, and number of hospital visits before and after surgery in 18 patients who underwent STP at our department between January 2015 and September 2022. The most common disease was cholesteatoma, followed by postoperative cerebrospinal fluid leak. The postoperative complications included fistula in one case (5.6%) and facial nerve palsy in one case (5.6%). Recurrence was observed in one patient (5.6%). The average number of visits to the hospital during the 12-month period before and after surgery were 17 and 3, respectively. The number of local therapies that cause vertigo decreased from 11 before surgery to 0 after surgery. The complication rate in this study was similar to that reported previously. Although the recurrence rate was higher than in previous reports, this may be due to the small number of cases included in this study, and we would like to accumulate more cases in the future. STP is a safe and curative procedure for certain aural diseases that eliminates the need for frequent local therapies, and contributes to improving the quality of life of the patients.

Relapsing polychondritis (RP) is a rare chronic inflammatory disease characterized by recurrent inflammation of cartilages throughout the body, with treatment-resistant dizziness and hearing loss in 40%-50% of patients with RP. Although rare, severe binaural hearing loss in RP is an indication for cochlear implantation (CI). Therefore, there are only a few reports on CI insertion in cases of RP. This report describes a 68-year-old woman who developed binaural hearing loss due to RP. She was treated with steroids and immunosuppressive drugs; however, her hearing did not improve significantly, and she relied on written communication for conversation. Subsequently, the patient underwent CI in the right ear. The patient showed improvement in speech perception; at 14 months postoperatively, she was able to speak with lipreading, and at 2 years postoperatively, she was able to speak without lipreading. Previous case reports on CI in patients with RP have shown varying degrees of postoperative hearing improvement. Our case demonstrates the effectiveness of CI in improving hearing and speech recognition in patients with RP having semicircular canal calcification. However, previous reports have shown that speech recognition declines 13 years after CI for RP. Therefore, continuous long-term follow-up is necessary.

A vestibular schwannoma is a benign tumor; however, the schwannoma itself and interventions can cause sensorineural hearing loss. Most vestibular schwannomas are unilateral tumors that affect hearing only on one side. Attention has focused on improving the quality of life for patients with unilateral hearing loss and therapeutic interventions to address this issue have been emphasized. Herein, we encountered a patient who was a candidate for hearing preservation surgery based on preoperative findings and had nonserviceable hearing after the surgery, according to the Gardner–Robertson classification. Postoperatively, the patient had decreased listening comprehension and ability to localize sound sources. He was fitted with bilateral hearing aids, and his ability to localize sound sources improved. Although the patient had postoperative nonserviceable hearing on the affected side and age-related hearing loss on the unaffected side, hearing aids in both ears were useful for his daily life. Therefore, the patient was able to maintain a binaural hearing effect and the ability to localize the sound source improved. This report emphasizes the importance of hearing preservation with vestibular schwannomas, and the demand for hearing loss rehabilitation as a postoperative complication can increase, even if hearing loss is nonserviceable.

Background: Salivary duct carcinoma (SDC) is a high-grade adenocarcinoma with a 5-year survival rate of 40%. Although drug therapy has improved patients' prognosis, the impact of brain metastasis (BM) remains poorly understood. We aimed to retrospectively examine the incidence of BM in patients with SDC (n = 464) and develop a tool to estimate their prognoses. Methods: We retrospectively examined 464 patients with SDC enrolled in a multicenter study. We investigated the incidence of BM, overall survival (OS) rates, and factors affecting prognosis in patients with BM. We also developed an SDC-graded prognostic assessment (GPA) score for disease prognostication. Results: Sixty-five (14%) patients had BM. The median OS (mOS) was 13.1 months. On univariate and multivariate analyses, factors such as Eastern Cooperative Oncology Group Performance Status >1, human epidermal growth factor receptor 2-negative status, and locoregional uncontrolled disease were associated with poor OS. SDC-GPA scores according to the prognostic factors were 0, 1, 2, and 3 points, and mOS estimates were 50.5, 16.1, 3.9, and 1.2 months, respectively (p < 0.001). Conclusion: The SDC-GPA score emerged as a useful prognostication tool for patients with BM.

High potassium concentration in the cochlear endolymph electrically drives hair cell activity. Sodium potassium ATPase (Na+/K+-ATPase) is an essential pump for ion homeostasis in the cochlea. Most of our knowledge regarding Na+/K+-ATPase has been obtained from rodent models, and knowledge of its distribution in primates, including humans, is limited. This study investigated the distribution of Na+/K+-ATPase in a common marmoset primate model. We investigated expression patterns of Na+/K+-ATPase α1 (ATP1A1), Na+/K+-ATPase α2 (ATP1A2), Na+/K+-ATPase α3 (ATP1A3), Na+/K+-ATPase β1 (ATP1B1), Na+/K+-ATPase β2 (ATP1B2), and Na+/K+-ATPase β3 (ATP1B3) in the cochlea of the neonates and the embryos of the common marmoset. We have described the distributions of specific pairs of Na+/K+-ATPase α and β subunits in each cochlear part, including spiral ganglion neurons, stria vascularis, and the organ of Corti. We also described developmental changes in Na+/K+-ATPases in common marmosets. The distribution of Na+/K+-ATPases in the common marmoset is similar to that in humans and is suitable for furthering our understanding of human cochlear development. The distribution established in this report will aid the study of primate-specific ion homeostasis in the inner ear.

Carcinoma of the external auditory canal is a rare tumor, accounting for about 1% of all head and neck cancers. Although no treatment method has been established yet, surgical treatment is the primary treatment method in cases where resection is possible. At our institution, we adopt surgical treatment, mainly lateral temporal bone resection （LTBR）, for cases with T1―T3 disease, and chemoradiation therapy（CCRT）for cases with T4 disease, as the treatment of first choice. We have adopted cartilage conduction hearing aids（CC―HAs）in some cases following LTBR. We examined the short―term outcomes, at two years, in the patients treated at our department. This study was a retrospective case review of 22 ears with carcinoma of the external auditory canal in 21 patients who underwent initial treatment at our institution between January 2012 and June 2018. The observation period was 2 to 81 months（median 26 months）. The tumors were analyzed using the modified Pittsburgh tumor staging system. The tumor T stage was T1 in four ears, T2 in nine ears, T3 in six ears, and T4 in three ears. CCRT was performed in three ears with T4 disease and one ear with T2 disease, heavy ion radiotherapy was performed in one ear with T2 disease, and surgery（LTBR in 16 ears and partial external auditory meatus resection in one ear）was performed for all the other cases. The surgical margin after LTBR was positive in three out of six cases with T3 disease and negative in all of the cases with T1 and T2 disease. The positive surgical margin was mainly found in the medial wall of the tympanic cavity or cartilaginous portion of the external acoustic meatus. The overall 2―year survival rate was 87.4%; the rate was 100% in the T1 cases, 87.5% in the T2 cases, 75.0% in the T3 cases, and 100% in the T4 cases. Four out of five patients who tried CC―HAs continued to use them after the LTBR. The indication for LTBR should be carefully judged in cases with T3 disease. The appropriate indication for LTBR in cases with T3 disease are: 1）a small amount of soft tissue shadow beyond the tympanum in the preoperative CT, and/ or 2）a clear boundary between the tumor and the soft tissue around the external acoustic meatus in the preoperative enhanced MRI. In cases with T3 disease not fulfilling these criteria, CCRT should be selected as the treatment of first choice. However, considering the side effects after CCRT, including sensorineural hearing loss and persistent otorrhea in some cases, LTBR with postoperative CC―HAs is one of the optimal treatment options that would allow the remaining hearing ability to be utilized.

There has been no attempt to clarify the status of patients with carotid body tumor (CBT) in Japan. This multi-institutional survey analyzed patients with CBT throughout Japan by gathering information on these patients from institutions that performed head and neck surgeries. Information from a total of 150 patients from 25 institutions from the past 20 years was employed in the present survey. There were 87 females and 63 males, and their mean age was 48.0 years old. The most common chief complaint was a neck mass and the mean suffering period was 46.1 months. Eighteen patients had a family history of paragangliomas and fifteen patients had bilateral CBTs. Among the 94 patients who underwent surgery to remove a CBT, 23 patients had tumors classified as Shamblin type I, 59 had type II and 12 had type III. The most frequent feeding artery of these CBTs was the ascending pharyngeal artery. Preoperative embolization of these arteries was effective in reducing blood loss; however, the operation time in Shamblin type I and II tumors was not improved. Thus these results revealed the status of patients with CBT and their treatment throughout Japan.

The molecular characteristics of therapeutically-relevant targets and their clinicopathological implications in salivary duct carcinomas (SDCs) are poorly understood. We investigated the gene alterations and the immunoexpression of crucial oncogenic molecules in 151 SDCs. The mutation rates that were identified, in order of frequency, were as follows: TP53, 68%; PIK3CA, 18%; H-RAS, 16%; BRAF, 4%; and AKT1, 1.5%. PIK3CA/H-RAS/BRAF mutations were more common in de novo SDC than in SDC ex-pleomorphic adenoma. Furthermore, these mutations were mutually exclusive for HER2 overexpression/amplification. TP53 mutations were frequently detected in cases with the aberrant p53 expression, and TP53 missense and truncating mutations were associated with p53-extreme positivity and negativity, respectively. DISH analysis revealed no cases of EGFR amplification. The rates of PI3K, p-Akt, and p-mTOR positivity were 34%, 22%, and 66%, respectively; PTEN loss was observed in 47% of the cases. These expressions were correlated according to the signaling axis. Cases with PI3K negativity and PTEN loss appeared to show a lower expression of androgen receptor. In the multivariate analysis, patients with SDC harboring TP53 truncating mutations showed shorter progression-free survival. Conversely, p-Akt positivity was associated with a favorable outcome. This study might provide information that leads to advances in personized therapy for SDC.

Salivary duct carcinoma (SDC) is a rare, aggressive malignancy that histologically resembles high-grade mammary duct carcinoma. Because of the rarity of this entity, data verifying the association between histologic features and patient survival are limited. We conducted a comprehensive histologic review of 151 SDC cases and performed an analysis of the association between various histomorphologic parameters and the clinical outcome with the aim of developing a histologic risk stratification model that predicts the prognosis of SDC patients. A multivariate analysis revealed that prominent nuclear pleomorphism (overall survival [OS]: P=0.013; progressionfree survival [PFS]: P= 0.019), ≥30 mitoses/10 HPF (PFS: P= 0.013), high tumor budding (OS: P= 0.011; PFS: P< 0.001), and high poorly differentiated clusters (OS: P<0.001; PFS: P< 0.001) were independent prognostic factors. Patients with vascular invasion demonstrated a marginally significant association with shorter PFS (P= 0.064) in a multivariate analysis. We proposed a 3-tier histologic risk stratification model based on the total number of positive factors among 4 prognostically relevant parameters (prominent nuclear pleomorphism, ≥30 mitoses/10 HPF, vascular invasion, and high poorly differentiated clusters). The OS and PFS of patients with low-risk (0 to 1 point) (23% of cases), intermediate-risk (2 to 3 points) (54% of cases), and highrisk (4 points) (23% of cases) tumors progressively deteriorated in this order (hazard ratio, 2.13 and 2.28, and 4.99 and 4.50, respectively; Ptrend <0.001). Our histologic risk stratification model could effectively predict patient survival and may be a useful aid to guide clinical decision-making in relation to the management of patients with SDC.

Background: Pulmonary nocardiosis frequently develops as an opportunistic infection in cell-mediated immunosuppressive patients, and sometimes requires differentiation from pulmonary malignancy. Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is a neoplastic disorder which leads to impaired cell-mediated immunity, and is commonly associated with small cell lung cancer (SCLC). Because pulmonary infection and causative malignancy can appear as pulmonary lesions with EAS, differentiation of these diseases remains a critical issue for physicians. Case presentation: A 52-year-old woman with progressive lower limb paralysis and general fatigue was referred to us. She had been diagnosed with olfactory neuroblastoma (ONB) and treated with surgery and radiation therapy 10 years before the referral and had required stereotactic radiosurgery and chemotherapy 4 years later for a relapse of the ONB. On referral, she presented with Cushing's syndrome with elevated cortisol and ACTH levels. Potassium supplement improved her symptoms; however, a month later, she was urgently hospitalized due to acute pleuritic chest pain on inspiration. Chest computed tomography revealed left lower lobular consolidations and a contralateral nodule in the right middle lobe. The clinical history and laboratory work-up suggested that her Cushing's syndrome had most likely arisen from EAS. Additionally, the lungs were suspected as the ACTH source due to high levels of progastrin-releasing peptide and progressive pulmonary consolidation with a contralateral nodule, suggesting SCLC. However, histological examination from bronchoscopy revealed no evidence of malignancy, and Nocardia cyriacigeorgica was isolated from bronchoalveolar lavage fluid. Sulfamethoxazole/trimethoprim improved her pulmonary lesions. Somatostatin receptor scintigraphy revealed strong tracer uptake in the ONB lesions, indicating that the origin of the EAS was the olfactory tumor. However, histological examination of ONB specimens resected 10 years earlier showed no intracytoplasmic immunopositivity for ACTH. Conclusions: We highlight a rare case of pulmonary nocardiosis, which was associated with EAS mimicking SCLC, and was related to ONB transformation. Nocardiosis has to be considered even though anamnestic, clinical, and radiological aspects suggest the presence of metastasis. Additionally, physicians should carefully monitor patients with ONB for the development of Cushing's symptoms because the tumor can transform into an ACTH-producing form, even after long-term follow-up.

Cyclooxygenase-2 (Cox-2) has been shown to promote cancer initiation and progression through pleiotropic functions including induction of epithelial-to-mesenchymal transition (EMT) via its predominant product prostaglandin E that binds to the cognate receptor EP2. Hence, pharmacological inhibition at the level of EP2 is assumed to be a more selective alternative with less risk to Cox-2 inhibition. However, little is known regarding the anti-cancer effect of an EP2 antagonist on the malignant properties of cancers including hypopharyngeal squamous cell carcinoma (HPSCC). The present study found that both the Cox-2 inhibitor celecoxib and the EP2 antagonist PF-04418948 upregulated CDH-1 expression, restored membranous localization of E-cadherin, and reduced vimentin expression, by downregulating the transcriptional repressors of E-cadherin in BICR6 and FaDu cells. Such Cox-2 or EP2 inhibition-induced EMT reversal led to repressed migration ability in both cells. Immunohistochemical analysis of surgical HPSCC specimens demonstrated an inverse relationship in expression between Cox-2 and E-cadherin both in the context of statistics (P = 0.028) and of reciprocal immunolocalization in situ. Multivariate logistic regression revealed that overexpression of Cox-2 (P < 0.001) and downregulation of E-cadherin (P = 0.016) were both independently predictive of neck metastasis. These results suggest that suppression of cell migration ability via reversing EMT by inhibiting the Cox-2/EP2 signaling may contribute to preventing the development and progression of lymphatic metastasis. Collectively, targeting Cox-2/EP2, especially using EP2 antagonist, can be a promising therapeutic strategy by exerting an anti-metastatic effect via EMT reversal for improving the treatment outcomes of patients with various cancers including HPSCC. 2

This paper presents an extremely rare case of synovial sarcoma arising from the maxillary sinus, which resulted in a clinically complete response to chemotherapy. Synovial sarcoma is a rare soft tissue malignant tumor, most commonly affecting the extremities. While ∼10% occur in the head and neck region, synovial sarcoma of the sinonasal tract is extremely rare, with only 11 cases having been reported previously. As with other sarcomas, the standard treatment is complete resection while allowing for a safe margin, but this is often difficult in the head and neck area due to the complicated anatomy there. This makes the treat­ment of head and neck sarcoma challenging and leads to the need for a multimodal approach in advanced cases. However, the exact efficacy of chemotherapy is not well understood. In this report, we present a case of unresectable maxillary sinus synovial sarcoma that was success­fully treated by chemotherapy followed by radiation therapy. A 53-year-old Japanese man was referred to our hospital with a history of left nose obstruction over the previous couple of years. Computed tomography/magnetic resonance imaging revealed a tumor arising from the maxillary sinus that extended to adjacent tissues. A biopsy was performed, and the tumor was diagnosed as synovial sarcoma. Since the tumor was unresectable, neoadjuvant chemotherapy was administered. The response was excellent, and the tumor became undetectable under endoscopy and radiological imaging. This provided us with a clinical evaluation of “complete response”. The treatment was concluded with definitive radiotherapy and two more cycles of adjuvant chemotherapy. The patient remains free of disease 12 months after treatment. Synovial sarcoma of the head and neck is a rare entity; complete resection is the treatment of choice but (neo)adjuvant chemotherapy can be considered in unresectable cases, as we show here in the present case.

Salivary duct carcinoma (SDC) is an aggressive, uncommon tumor histologically comparable to high-grade mammary ductal carcinoma. SDCs are usually androgen receptor (AR)–positive and often HER2-positive. Recently, therapies targeting these molecules for SDC have attracted attention. Lipid metabolism changes have been described in association with biological behavior in various cancers, although no such relationship has yet been reported for SDC. We therefore analyzed the clinicopathological relevance of the immunohistochemical expression of adipophilin (ADP) and fatty acid synthase (FASN), representative lipid metabolism–related proteins, in 147 SDCs. ADP and FASN were variably immunoreactive in most SDCs (both 99.3%), and the ADP and FASN expression was negatively correlated (P = 0.014). ADP-positive (≥ 5%) SDCs more frequently exhibited a prominent nuclear pleomorphism and high-Ki-67 labeling index than those ADP-negative (P = 0.013 and 0.011, respectively). In contrast, a high FASN score, calculated by the staining proportion and intensity, (≥ 120) was correlated with the high expression of AR and FOXA1 (P < 0.001 and = 0.003, respectively). The ADP and FASN expression differed significantly among the subtypes based on biomarker immunoprofiling, as assessed by the AR, HER2, and Ki-67 status (P = 0.017 and 0.003, respectively). A multivariate analysis showed that ADP-positive expression was associated with a shorter overall and progression-free survival (P = 0.018 and 0.003, respectively). ADP was associated with an aggressive histopathology and unfavorable prognosis, and FASN may biologically interact with the AR signaling pathway in SDC. ADP may, therefore, be a new prognostic indicator and therapeutic target in SDC.

Aims: Salivary duct carcinoma (SDC) is an uncommon, aggressive tumour that, histologically, resembles high-grade mammary ductal carcinoma, and is characterised by the expression of androgen receptor (AR). The androgen signalling pathway, a potential therapeutic target, can be regulated by FOXA1. This study aimed to evaluate the clinicopathological implications of FOXA1 in SDC. Methods and results: We examined the relationship between the immunoexpression of FOXA1 and FOXA1 mutations and clinicopathological factors, including the biomarker status and clinical outcome, in 142 SDCs. FOXA1 was expressed in 128 SDCs (90.1%); the immunoexpression was heterogeneous. SDCs with a higher FOXA1 labelling index (LI) (≥20%) more frequently showed less advanced tumors on T classification (P = 0.002). FOXA1 LI was correlated positively with the AR expression value (r = 0.430, P < 0.001). PI3K and p-mTOR positivity, and intact-PTEN, were associated with a higher FOXA1 LI. Twenty-two of 121 SDCs (18.2%) harboured FOXA1 gene mutations at the flanking regions in and around the forkhead DNA binding domain; however, the given gene mutation and the expression of FOXA1 were not significantly correlated. A multivariate analysis revealed that SDCs with a higher FOXA1 LI were associated with longer overall survival and progression-free survival (P = 0.029 and 0.016, respectively). Conclusions: In SDC, FOXA1, which may biologically interact with the AR and PI3K signalling pathways, is a putative biomarker that may be associated with a favourable prognosis. Further studies are needed to apply the findings to the development of targeted personalised therapy for patients with SDC.