Published papers

Surgical removal of pterygopalatine fossa (PPF) tumors with endoscopic endonasal approach is still challenging. The present study aimed to evaluate our endoscopic endonasal management of PPF tumors based on the tumor pathology and purpose of the surgery. This comprised both a single nostril approach for biopsy and a binostril approach for complete resection of benign and noninfiltrating tumors. Based on this strategy, 12 patients underwent endoscopic endonasal surgery for PPF tumors between 2013 and 2018. The patients' data were analyzed retrospectively to demonstrate the significance of our treatment scheme. The surgery was terminated only after taking a biopsy specimen in 6 patients. Other 6 patients underwent gross total resection or bulk tumor reduction. Final pathological diagnosis was malignant in 6 cases and benign in the remaining 6. Post-operative treatment was needed in 7 patients. Four operations for the 6 patients who underwent either debulking or radical surgery were performed by the binostril approach; while 5 surgeries for the 6 biopsy patients were performed by the single nostril approach. Postoperative complications were tolerable. Endoscopic resection should be adopted preferentially for benign tumors that can be removed in a piecemeal fashion. However, as most malignant tumors were impossible to resect with a negative margin, priority should be given to tumor biopsy using an endoscopic approach, which is less invasive than an open approach, and an appropriate treatment customized to the pathological diagnosis should be administered.

AbstractRecent advances in endoscopic intranasal technology have allowed for a safe approach to the pterygopalatine fossa lesion. However, we consider that there is still scope of improvement to approach a broader area with better operability and minimal invasiveness. A 51-year-old man underwent endoscopic endonasal surgery due to the recurrence of chordoma at the left pterygopalatine fossa. To access the lower and lateral part of the pterygopalatine fossa, we performed endoscopic endonasal transmaxillary removal via an inferior turbinate incision. During surgery, a wide operative field and good operability could be secured by inserting an endoscope from the right nostril through a window of the nasal septum. Subtotal removal of the tumor was achieved without any complication during the surgery. Endoscopic endonasal transinfraturbinate approach with nasoseptal window was effective in the removal of the pterygopalatine fossa tumor because it is less invasive and provides a good surgical view with better operability.

We report the establishment of two human induced pluripotent stem cell (iPSC) lines from individuals without auditory disorders. Extensive audiometry tests were performed to confirm normal hearing. The generated iPSC lines expressed pluripotency genes and showed differentiation capability into the three germ layers. The iPSC lines will be used as controls for pathological analysis and drug screening for ear disorders.

Molecular targets and predictive biomarkers for prognosis in salivary duct carcinoma (SDC) have not been fully identified. We conducted comprehensive molecular profiling to discover novel biomarkers for SDC. A total of 67 SDC samples were examined with DNA sequencing of 464 genes and transcriptome analysis in combination with the clinicopathological characteristics of the individuals. Prognostic biomarkers associated with response to combined androgen blockade (CAB) treatment were explored using mRNA expression data from 27 cases. Oncogenic mutations in receptor tyrosine kinase (RTK) genes or genes in the MAPK pathway were identified in 55 cases (82.1%). Alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway were identified in 38 cases (56.7%). Interestingly, patient prognosis could be predicted using mRNA expression profiles, but not genetic mutation profiles. The risk score generated from the expression data of a four-gene set that includes the ADAMTS1, DSC1, RNF39, and IGLL5 genes was a significant prognostic marker for overall survival in the cohort (HR = 5.99, 95% confidence interval (CI) = 2.73–13.1, p = 7.8 × 10−6). Another risk score constructed from the expression of CD3E and LDB3 was a strong prognostic marker for progression-free survival for CAB treatment (p = 0.03). Mutations in RTK genes, MAPK pathway genes, and PI3K/AKT pathway genes likely represent key mutations in SDC tumorigenesis. The gene expression profiles identified in this study may be useful for stratifying patients who are good candidates for CAB treatment and may benefit from additional systemic therapies.

Objective: We sought to elucidate the long-term surgical outcomes and incidence of recurrence and reoperation of endoscopic endonasal cyst fenestration for Rathke cleft cyst (RCC). Methods: A retrospective review of the chart and operation record of RCC surgical cases between January 2008 and August 2021 at our institution was conducted. Patient characteristics, intraoperative findings, and postoperative follow-up outcomes were evaluated. Results: A total of 27 patients were analyzed, with a median postoperative follow-up period of 52 months (range, 1–150 months). Preoperative symptoms were visual dysfunction (59%), headache (41%), and pituitary dysfunction (22%). Endoscopic cyst fenestration was performed in all patients. Ten (37%) patients had intraoperative cerebrospinal fluid leakage. Among them, the only patient in whom sellar floor reconstruction was not performed experienced a repair operation due to postoperative cerebrospinal fluid leakage. No patients experienced postoperative hypopituitarism. Preoperative headache, visual dysfunction, and pituitary hormone disorder improved in 73%, 75%, and 67% of patients, respectively. Although postoperative cyst regrowth was observed in 8 patients (30%), no patient experienced worsening or novel symptoms and none required reoperation. Conclusions: Patients with a symptomatic RCC can be effectively treated with endoscopic endonasal cyst fenestration. Reversal of the presenting symptoms resulted, including headache, visual dysfunction, and pituitary hormone dysfunction, in the majority of patients. In our series, appropriate reconstruction of the sellar floor reduced the risk of postoperative cerebrospinal fluid leakage without impacting cyst regrowth. This simple technique appears to effectively disrupt cyst progression in most cases, even after a relatively long-term follow-up period.

Introduction: The well-regulated development of the sensory epithelium is essential for hearing. This process involves the specification of a pro-sensory epithelium containing common progenitors that differentiate into hair and supporting cells. Notch signaling is one of the most critical pathways during these processes, and its modification is thought to be a feasible approach for treating hearing loss. Despite interspecies differences between rodents and primates or humans, most of our current knowledge regarding cochlear development has been obtained from rodent models. Methods: We therefore examined and mapped the expression patterns of Notch signal components in the developing cochlea of the common marmoset (Callithrix jacchus), a small monkey species native to the New World, a primate model animal. Results: In contrast to the preserved expression patterns of the Notch signaling components in the hair cell differentiation between primates and rodents, we unveiled relatively large interspecies differences during the maturation of supporting cells. Discussion: This improved knowledge of Notch signaling during primate cochlear development will facilitate the development of future regenerative therapies.

Carotid body tumor (CBT) is classified as a paraganglioma (PGL). Here, we report the genetic background, protein expression pattern, and clinical findings of 30 Japanese CBT cases. Germline pathogenic or likely pathogenic (P/LP) variants of genes encoding succinate dehydrogenase subunits (SDHs) were detected in 15 of 30 cases (50%). The SDHB variants were the most frequently detected, followed by SDHA and SDHD variants. One case with SDHAF2 variant was bilateral CBT, and other two multiple PGL cases were not detected P/LP variants. The three cases with germline variants that could be tested did not have somatic P/LP variants of the same genes. Immunohistochemical analysis showed negative SDHB signals in CBT tissues in five cases with germline P/LP variants of SDHB, SDHD, or SDHA. In addition, SDHB signals in CBT tissues were negative in four of nine cases without germline P/LP variants of SDHs. These findings suggest the involvement of unidentified molecular mechanisms affecting SDHs.

Precise cochlear neuronal development is vital to hearing ability. Understanding the developmental process of the spiral ganglion is useful for studying hearing loss aimed at aging or regenerative therapy. Although interspecies differences have been reported between rodents and humans, to date, most of our knowledge about the development of cochlear neuronal development has been obtained from rodent models because of the difficulty in using human fetal samples in this field. In this study, we investigated cochlear neuronal development in a small New World monkey species, the common marmoset (Callithrix jacchus). We examined more than 25 genes involved in the neuronal development of the cochlea and described the critical developmental steps of these neurons. We also revealed similarities and differences between previously reported rodent models and this primate animal model. Our results clarified that this animal model of cochlear neuronal development is more similar to humans than rodents and is suitable as an alternative for the analysis of human cochlear development. The time course established in this report will be a useful tool for studying primate-specific neuronal biology of the inner ear, which could eventually lead to new treatment strategies for human hearing loss.

Many studies have reported the use of wearable devices to acquire biological data for the diagnosis and treatment of various diseases. Balance dysfunction, however, is difficult to evaluate in real time because the equilibrium function is conventionally examined using a stabilometer installed on the ground. Here, we used a wearable accelerometer that measures head motion to evaluate balance and examined whether it performs comparably to a conventional stabilometer. We constructed a simplified physical head-feet model that simultaneously records “head” motion measured using an attached wearable accelerometer and center-of-gravity motion at the “feet”, which is measured using an attached stabilometer. Total trajectory length (r = 0.818, p -false discovery rate [FDR] = 0.004) and outer peripheral area (r = 0.691, p -FDR = 0.026) values measured using the wearable device and stabilometer were significantly positively correlated. Root mean square area values were not significantly correlated with wearable device stabilometry but were comparable. These results indicate that wearable, widely available, non-medical devices may be used to assess balance outside the hospital setting, and new approaches for testing balance function should be considered.

Objective: The histological grade of parotid gland carcinoma (PGC) is an important prognostic factor; however, the diagnosis prior to treatment has been challenging to make. This study aimed to investigate whether the pretreatment clinical findings, including hematological inflammatory, nutritional, and immune markers, could predict the histological grade of PGC. Study Design: Retrospective study. Methods: We retrospectively enrolled 111 patients with PGC and evaluated the correlation between histological grade and pretreatment clinical findings such as age, sex, tumor staging, facial nerve paralysis, pain or tenderness, adhesion to the surrounding tissues or tumor immobility, and hematological markers. Results: Sixty patients (54%) were diagnosed with histological high-grade PGC. Univariate analysis revealed that age, T classification, N classification, TNM stage, facial nerve paralysis, adhesion/immobility, C-reactive protein (CRP), and CRP-to-albumin ratio (CAR) were significant predictors of PGC histological grade. On multivariate analysis, high T classification (T3, 4), high N classification (≥1), and elevated CRP (≥0.22 mg/dL) were independent predictors of high-grade PGC. Conclusions: Pretreatment T classification, N classification, and CRP are significant predictors of the histological grading of PGC. Our results are useful for treatment planning and obtaining appropriate informed consent from the patients before treatment. Level of Evidence: 4 Laryngoscope, 132:96–102, 2022.

Salivary duct carcinoma (SDC) is an aggressive type of salivary gland carcinoma. Recently, immunotherapies targeting immune checkpoints, including PD1, PD-L1, CTLA4, and LAG3, have had a considerable prognostic impact on various malignant tumors. The implementation of such immune checkpoint inhibitor (ICI) therapies has also been attempted in cases of salivary gland carcinoma. The tumor immune microenvironment (TIME) is implicated in tumorigenesis and tumor progression and is closely associated with the response to ICI therapies. However, the TIME in SDC has not been fully explored. We examined the immunohistochemical expression of CD8, FOXP3, PD1, PD-L1, CTLA4, LAG3, and mismatch repair (MMR) proteins, tumor-infiltrating lymphocytes (TILs), and microsatellite instability (MSI) status in 175 cases of SDC. The associations between these TIME-related markers and the clinicopathological factors and prognosis were evaluated. An elevated expression of CD8, FOXP3, PD1, CTLA4, and LAG3 was associated with more aggressive histological features and an advanced N and/or M classification, elevated Ki-67 index, and poor prognosis. Furthermore, cases with a high PD-L1 expression exhibited more aggressive histological features and adverse clinical outcomes than those with a low expression. Alternatively, there was no significant correlation between TILs and clinicopathological factors. No SDC cases with an MSI-high status or MMR deficiency were found. The coexistence of both an immunostimulatory and immunosuppressive TIME in aggressive SDC might play a role in the presence of T-cell exhaustion. The contribution of multiple immune escape pathways, including regulatory T cells and immune checkpoints, may provide a rationale for ICI therapy, including combined PD1/CTLA4 blockade therapy.

Background: The pterygovaginal artery (PtVA), a recurrent branch of the internal maxillary artery (IMA), can be a feeder of skull base tumors. Preoperative embolization can help endoscopic resection of hypervascular lesions, which is performed under a narrow surgical space with restricted instrumental maneuverability. Methods: We performed preoperative embolization in five cases with hypervascular skull base lesions supplied by the PtVA, four of which were resected via endoscopic endonasal approach. In two cases, selective PtVA embolization through the distal IMA was successfully conducted. Results: In all the cases, intraoperative bleeding during endoscopic resection was easily controlled. The medial and lateral origins of the PtVA from the IMA were demonstrated by cone-beam CT images reconstructed from three-dimensional rotational angiography, and anastomoses around the eustachian tube and soft palate were visualized by superselective angiography. Conclusions: The PtVA embolization can be an effective strategy before endoscopic skull base tumor resection. When embolizing through the PtVA, clinicians should be aware of its anatomical variations and dangerous anastomoses. Understanding the surrounding angioarchitecture by angiographic techniques helps ensure safe embolization.

Background: One of the major complications in endoscopic endonasal skull base surgery (EESBS) is postoperative cerebrospinal fluid (CSF) leaks. Recently, EESBS has been applied to various skull base diseases as well as more complicated cases influenced by previous treatment with or without various comorbidities. Aims/objectives: This study aimed to assess the factors that influence the results of postoperative CSF leak after EESBS with mixed patient backgrounds. Materials and methods: We conducted a retrospective analysis of the clinical records of patients undergoing EESBS in our institution from 2012 to 2017. Results: Out of a total of 230 cases of EESBS, 11 (4.8%) suffered from postoperative CSF leakage. The rate of CSF leakage for pituitary adenoma, Rathke’s cleft cyst, chordoma, and meningioma was 3.5%, 0%, 3.6% and 8.0%, respectively. Multiple variate analysis revealed that repeated surgery (p =.008) and intraoperative CSF leak (p =.044) were significant risk factors for postoperative CSF leakage. Conclusions and significance: The rate of postoperative CSF leakage in this study was comparable to previous reports, and repeated surgery may increase postoperative CSF leakage. The surgical strategy for tumor removal as well as skull base reconstruction should be given careful consideration according to tumor pathology and the patient’s condition.

Background Although the specific pathogenesis of idiopathic sudden sensorineural hearing loss (ISSNHL) remains unknown, vascular impairment is one of the leading causes of ISSNHL. Establishing diagnostic criteria for ISSNHL due to vascular impairment is essential. We hypothesized that isolated posterior semicircular canal dysfunction (IPSCD) in ISSNHL patients results from infarction of the vestibulo-cochlear artery (VCA). The aim of this preliminary retrospective study is to identify possible diagnostic characteristics of ISSNHL patients with IPSCD. Methods Seventeen ISSNHL patients were enrolled. They underwent video head impulse testing within 28 days of ISSNHL onset between September 2019 and November 2023. We obtained patient characteristics and clinical information, including results of audiometric and balance function tests. Eligible patients were divided into two groups according to the presence or absence of IPSCD. Patient characteristics and clinical information of the two groups were compared. Results Of the 17 ISSNHL patients included, 6 had IPSCD. Compared to the 11 patients without IPSCD, the 6 patients with IPSCD had significantly more coronary artery disease (odds ratio, infinite; p = 0.03) and had regularly used antithrombotic medications (odds ratio, infinite; p < 0.01). The audiogram shapes of the six ISSNHL-IPSCD patients were profound, flat, or high-frequency descending forms. Conclusions Given that VCA impairment is associated with profound, flat, and high-frequency hearing loss and consistent with the arterial anatomy of the inner ear, ISSNHL-IPSCD patients are more likely to have vascular impairment. Conducting trials that target ISSNHL-IPSCD patients may lead to the discovery of new and effective treatments for ISSNHL.

Tumoral lesions of the temporal bone include benign or malignant tumors and congenital or inflammatory lesions. Temporal bone lesions are difficult to approach. Therefore, making a preoperative diagnosis and considering whether the lesions require treatment are necessary; if they require treatment, then the type of treatment requires consideration. These tumors cannot be observed directly and must be diagnosed based on symptoms and imaging findings. However, the differentiation of temporal bone lesions is difficult because they are rare and large in variety. In this pictorial review, we divided temporal bone lesions by location such as along the facial nerve, along the internal jugular vein, around the endolymphatic sac, in the internal auditory canal/cerebellopontine angle, petrous apex, middle ear, and mastoid, focusing on the imaging findings of temporal bone lesions. Then, we created a diagnostic flowchart that suggested that the systematic separation of imaging findings is useful for differentiation. Although it is necessary to make comprehensive judgments based on the clinical symptoms, patient background, and imaging findings to diagnose temporal bone mass lesions, capturing imaging features can be a useful differentiation method.

Purpose: Anaplastic thyroid carcinoma (ATC) is a rare, aggressive malignancy with poor prognosis. Lenvatinib has demonstrated moderate efficacy and is approved for unresectable ATC treatment in Japan. However, some patients are unable to tolerate the standard 24 mg daily dose and require dose reductions or interruptions due to its high incidence of adverse effects. This study aimed to evaluate the therapeutic effects of lenvatinib in patients with ATC, particularly assessing outcomes with reduced dosages across multiple institutions. Methods: Sixteen patients diagnosed with ATC and treated with lenvatinib were evaluated retrospectively. Overall survival (OS) and progression-free survival (PFS) were calculated. In addition, patients were divided into two groups based on 24 mg daily dose or reduced initial dose, and their therapeutic outcomes were compared. Results: The objective response rate was 31%, and the median OS and PFS were 2.2 and 1.7 months, respectively. Among the 16 patients, 11 (69%) initiated treatment with 24 mg daily, while the remaining 5 (31%) received a reduced dose. The median OS and PFS were 2.0 months and 1.4 months, respectively, among patients in the 24 mg daily group, compared to 6.2 months and 2.4 months, respectively, among patients in the reduced dosage group. Conclusion: Our study demonstrated that lenvatinib has moderate efficacy for ATC. In addition, initiating treatment at a reduced dose could provide therapeutic benefit. Lenvatinib may serve as a treatment option for unresectable ATC when targeted therapies, including BRAF, RET, and NTRK inhibitors, are unavailable. Furthermore, although the standard 24 mg daily dose is recommended, a lower initial dosage may be effective for patients unable to tolerate the full dose.

Purpose: The retrolabyrinthine approach is a surgical method designed to preserve hearing after surgery. When paired with intraoperative monitoring and an endoscope, this approach has demonstrated high rates of postoperative hearing preservation. However, the long-term prognosis of hearing preservation after utilizing this approach for vestibular schwannomas remains unexplored. This study aimed to examine the long-term outcomes of preserved hearing, providing insights into the suitability of the retrolabyrinthine approach for hearing preservation surgery. Methods: This study included 34 patients with preserved hearing after vestibular schwannoma surgery using the retrolabyrinthine approach at a single center. Long-term hearing prognosis and requirement for additional interventions were retrospectively examined. Results: Immediate after post-operative hearing preservation rate was 71.7%. Among the 34 patients with preserved hearing post-vestibular schwannoma surgery, four (11.8%) required additional interventions. Other patients experienced a gradual deterioration in their hearing status, with an approximate 10 dB decline during the 5-year follow-up; however, a serviceable hearing level persisted long after the surgery in these individuals. Conclusions: This study indicated the rationale for the retrolabyrinthine approach as a hearing preservation surgery for vestibular schwannomas, emphasizing its long-term hearing prognosis.

Recurrent respiratory papilloma (RRP) often presents multiple lesions in the respiratory tract and sometimes becomes fatal because of severe airway obstruction. We report the case of a 69-year-old woman who had juvenile-onset RRP in the trachea that was refractory to surgical treatment, and complete remission was achieved by low-dose cisplatin combined with de-escalated radiotherapy without any side effects. This case report is the first to illustrate the data on low-dose cisplatin for refractory benign RRP, and our experience reinforces the opinion that low-dose cisplatin combined with de-escalated radiotherapy can be an effective and safe treatment alternative for uncontrollable and lethal RRP. Laryngoscope, 134:2335–2337, 2024.