Search

BackgroundPersistent postural-perceptual dizziness (PPPD) is a chronic vestibular syndrome often triggered by acute or episodic vestibular syndromes, such as Meniere’s disease (MD). According to the diagnostic criteria, PPPD may coexist with other structural diseases, and the evidence of another active illness does not necessarily exclude PPPD diagnosis. However, persistent symptoms, even those meeting the PPPD criteria even long after Meniere’s attack, are often overlooked as potential PPPD precipitated by MD. Some clinicians overlook PPPD in such patients, treating them solely for MD once diagnosed. Since a treatment strategy for PPPD is completely different from that for MD, this may result in the deprivation of adequate treatments.ObjectivesTo emphasize the importance of diagnosing PPPD coexisting with MD including not treating such patients solely for MD, and to compare the clinical features of PPPD and MD.MethodsVestibular function tests, including canal paresis (CP)%, c- and o-vestibular myogenic potentials, vestibulo-ocular reflex-direction preponderance, and posturography and clinical symptom scales, including the Dizziness Handicap Inventory, Niigata PPPD Questionnaire, and Hospital Anxiety and Depression Scale, were compared between 105 PPPD patients with MD or other precipitants and 130 patients with MD alone. The clinical symptom scales were further compared between 23 patients with PPPD coexisting with MD and those with MD alone.ResultsThe CP% was significantly higher in patients with MD than in those with PPPD. However, the total and subscores of all three clinical symptom scales were higher in patients with PPPD than in those with MD. The total score on all clinical symptom scales was higher in patients with PPPD coexisting with MD than in those with MD alone.ConclusionPersistent postural-perceptual dizziness development from a precipitating MD may be associated with more severe clinical symptoms. Thus, clinical symptom scales may be useful for detecting PPPD in patients with Meniere’s disease.

BackgroundIn view of improving biomarkers predicting the efficacy of immunotherapy for head and neck squamous cell carcinoma (R/M HNSCC), this multicenter retrospective study aimed to identify clinical, tumor microenvironmental, and genomic factors that are related to therapeutic response to the anti- Programmed cell death protein 1 (PD-1) antibody, nivolumab, in patients with R/M HNSCC. MethodsThe study compared 53 responders and 47 non-responders, analyzing formalin-fixed paraffin-embedded samples using 14-marker multiplex immunohistochemistry and targeted gene sequencing.ResultsOf 100 patients included, responders had significantly lower smoking and alcohol index, higher incidence of immune related adverse events, and higher PD-1 ligand (PD-L1) expression in immune cells as well as PD-L1 combined positive score (CPS) than non-responders. The frequency of natural killer cells was associated with nivolumab response in patients with prior cetuximab use, but not in cetuximab-naïve status. Age-stratified analysis showed nivolumab response was linked to high CPS and lymphoid-inflamed profiles in patients aged ≥ 65. In contrast, lower NLR in peripheral blood counts was associated with response in patients aged < 65. Notably, TP53 mutation-positive group had lower CPS and T cell densities, suggesting an immune-excluded microenvironment. Patients with altered tumor suppressor gene pathways, including TP53, CDKN2A, and SMAD4 mutations, had lower CPS, higher smoking index, and were associated with poor responses. ConclusionNivolumab treatment efficacy in HNSCC is influenced by a combination of clinical factors, age, prior treatment, immune environmental characteristics, and gene mutation profiles.

IntroductionPersistent postural-perceptual dizziness (PPPD) is a functional chronic vestibular syndrome with symptom exacerbation by upright posture, motion, and complex visual stimuli. Among these exacerbating factors, visual exacerbation is the most specific characteristic of PPPD requiring further investigation. We hypothesized that stimulus-induced changes occur in the functional connectivity (FC) rather than simple neural activation that is involved in visual stimulation. The present study aimed to identify the neural basis of PPPD by investigating FC before and after visual stimulation.MethodsEleven patients with PPPD and 11 age- and sex-matched healthy controls (HCs) underwent resting-state fMRI (rs-fMRI) before and after task-based fMRI with visual stimuli.ResultsAt pre-stimulus, FC between the vestibular cortex and visual areas was low, while that between the somatosensory and visual areas was high in PPPD compared with that in HCs. FC between the visuospatial (parahippocampal gyrus) and spatial cognitive areas (inferior parietal lobule) was elevated in PPPD even in the pre-stimulus condition, which no longer increased at post-stimulus as observed in HCs. In the post-stimulus condition, FC between the visual and spatial cognitive areas and that between the visual and prefrontal areas increased compared with that in the pre-stimulus condition in PPPD. Task-based fMRI demonstrated that no brain regions showed different activities between the HC and PPPD groups during visual stimulation.DiscussionIn PPPD, vestibular inputs may not be fully utilized in the vestibulo-visuo-somatosensory network. Given that the FC between visuospatial and spatial cognitive areas increased even in HCs after visual stimuli, elevated status of this FC in combination with the high FC between the somatosensory and visual areas would be involved in the visual exacerbation in PPPD. An increase in FC from the visual areas to spatial cognitive and prefrontal areas after visual stimuli may account for the prolonged symptoms after visual exacerbation and anxious status in PPPD.

BackgroundHead and neck mucosal melanoma (HNMM) is a rare and aggressive subtype of melanoma. HNMM often develops as a recurrent or metastatic disease, and its prognosis is worse than that of cutaneous melanoma. Recent large-scale clinical studies have reported favorable outcomes with immune checkpoint inhibitors (ICIs) for melanoma. However, these clinical trials included only a small number of HNMM cases. This study aimed to estimate treatment outcomes and prognostic predictors of ICIs for advanced HNMM.MethodsCases of advanced HNMM, defined as unresectable or metastatic HNMM at the initial diagnosis (five patients) or development of recurrent/metastatic HNMM after initial treatment (27 patients), were included in this study. Survival analysis and a search for prognostic factors were performed for these 32 patients. Furthermore, the detailed clinical course of patients who received ICI treatment was investigated.ResultsThe median overall survival (OS) of 32 patients with advanced HNMM was 25.3 months. The estimated 1-, 3-, and 5-year OS rates were 68.4%, 42.8%, and 34.3%, respectively. Fourteen patients (43.7%) received ICIs, whereas 18 (56.3%) did not. Univariate analysis showed that ICI treatment was the only factor associated with a better 1-year OS. Patients who received ICI treatment had significantly longer OS (median OS: not reached, 1-year OS: 85.7%) than those who did not (median OS: 11.3 months, 1-year OS: 54.5%). The overall response and disease control rates of patients who received ICI treatment were 50% and 64.3%, respectively. Patients who achieved complete response (CR) or partial response (PR) to ICI treatment survived significantly longer (1-year OS: 100%) than those who did not (1-year OS: 71.4%). Among the five patients who discontinued ICI treatment due to severe immune-related adverse events (irAEs), four did not receive salvage treatments but showed durable treatment effects and survived for 9.8–54.2 months at the end of the follow-up period.ConclusionsICI treatment achieved a favorable OS for advanced HNMM. CR/PR to ICI treatment and discontinuation owing to severe irAEs were favorable predictors of OS.

ObjectiveThe global standard for chemoradiation therapy (CCRT) for head and neck squamous cell carcinoma is cisplatin 100 mg/m2 administered once every three weeks, although cisplatin 80 mg/m2 is also widely used as an alternative treatment to reduce adverse events in Japan. We aimed to assess the long-term survival outcomes and late adverse events associated with CCRT with a 3-weekly cisplatin dose of 80 mg/m2.MethodsA phase 2 study on CCRT with a 3-weekly cisplatin dose of 80 mg/m2 was performed in 47 patients between April 2015 and December 2016 at four centers in Japan. Survival outcomes and late adverse events at 5 years after this phase 2 trial were investigated.ResultsThe median follow-up period was 61 months. The 5-year progression-free survival/overall survival of all 47 patients was 66.0%/76.6%, while that of patients with stage III, IV disease (UICC) was 65.6%/71.9%. Seventeen patients (36%) experienced dysphagia as a late adverse event. Univariate and multivariate analyses revealed a significant association between acute mucositis/low body mass index (BMI) during CCRT and late dysphagia.ConclusionThe survival outcomes of CCRT with a 3-weekly cisplatin dose of 80 mg/m2 may be comparable to the previously reported dose of 100 mg/m2. Acute mucositis and low BMI at CCRT were risk factors for late dysphagia, indicating the importance of managing these conditions during CCRT to prevent late adverse events. Caution and care for acute mucositis and swallowing training in patients with low BMI may be important for preventing late-stage dysphagia.

IntroductionPersistent postural-perceptual dizziness (PPPD) is a chronic vestibular syndrome lasting more than 3 months. The core vestibular symptoms are dizziness, unsteadiness, and non-spinning vertigo, which are exacerbated by upright posture or walking, active or passive motion, and exposure to moving or complex visual stimuli. Among these, visual exacerbation is a key feature of PPPD for which the neural mechanisms are unknown. We hypothesized that vestibular symptoms may be exacerbated by visual stimuli through gaze behavioral change after exposure to moving or complex visual stimuli. The study aimed to examine gaze stability after exposure to moving visual stimuli in patients with PPPD.MethodsFourteen healthy controls (HCs), 27 patients with PPPD, and 12 patients with unilateral vestibular hypofunction (UVH), showing chronic vestibular symptoms for >3 months, were enrolled in the study. The participants were instructed to fixate on the gazing point at the center of a screen for 30 s before and after 90 s of exposure to moving visual stimuli. Gaze stability, best represented by the bivariate contour ellipse area (BCEA), was compared among three groups, both before and after exposure to the moving visual stimuli. Comparisons between pre- and post-moving visual stimuli in BCEA were also conducted. Correlation between the post/pre ratio of BCEA and vestibular tests, several clinical symptom scales including the Dizziness Handicap Inventory, Niigata PPPD Questionnaire, and Hospital Anxiety and Depression Scale, and the exacerbation of dizziness by exposure to moving visual stimuli was examined in the PPPD group.ResultsBCEA, both before and after exposure to moving visual stimuli in the PPPD group, was not different from that in HC and UVH groups. In the PPPD group, BCEA increased significantly after exposure to moving visual stimuli. The post/pre ratio of BCEA correlated with the occurrence of exacerbation of the dizziness sensation by exposure to moving visual stimuli; however, it did not correlate with vestibular tests or clinical symptom scales.ConclusionPatients with PPPD were more likely to exhibit gaze instability after exposure to moving visual stimuli, which potentially exacerbated vestibular symptoms. This phenomenon may help elucidate the neural mechanisms of visual exacerbation in patients with PPPD.

ObjectiveBasal information of head and neck small-cell carcinoma (HNSmCC) including epidemiology, primary site, treatment, and prognosis remains sparse due to its rarity. We report here a multicenter retrospective study on the diagnosis, treatment, and outcomes of patients with HNSmCC.Materials and methodsThis study involved 47 patients with HNSmCC from 10 participating institutions. Eight patients were excluded for whom no pathological specimens were available (n = 2) and for discrepant central pathological judgements (n = 6). The remaining 39 patients were processed for data analysis.ResultsAs pretreatment examinations, computed tomography (CT) was performed for the brain (n = 8), neck (n = 39), and chest (n = 32), magnetic resonance imaging (MRI) for the brain (n = 4) and neck (n = 23), positron emission tomography-CT (PET-CT) in 23 patients, bone scintigraphy in 4, neck ultrasonography in 9, and tumor markers in 25. Primary sites were oral cavity (n = 1), nasal cavity/paranasal sinuses (n = 16), nasopharynx (n = 2), oropharynx (n = 4), hypopharynx (n = 2), larynx (n = 6), salivary gland (n = 3), thyroid (n = 2), and others (n = 3). Stages were II/III/IV-A/IV-B/IV-C/Not determined = 3/5/16/6/5/4; stage IV comprised 69%. No patient had brain metastases. First-line treatments were divided into 3 groups: the chemoradiotherapy (CRT) group (n = 27), non-CRT group (n = 8), and best supportive care group (n = 4). The CRT group included concurrent CRT (CCRT) (n = 17), chemotherapy (Chemo) followed by radiotherapy (RT) (n = 5), and surgery (Surg) followed by CCRT (n = 5). The non-CRT group included Surg followed by RT (n = 2), Surg followed by Chemo (n = 1), RT alone (n = 2), and Chemo alone (n = 3). The 1-year/2-year overall survival (OS) of all 39 patients was 65.3/53.3%. The 1-year OS of the CRT group (77.6%) was significantly better compared with the non-CRT group (31.3%). There were no significant differences in adverse events between the CCRT group (n = 22) and the Chemo without concurrent RT group (n = 9).ConclusionNeck and chest CT, neck MRI, and PET-CT would be necessary and sufficient examinations in the diagnostic set up for HNSmCC. CCRT may be recommended as the first-line treatment. The 1-year/2-year OS was 65.3%/53.3%. This study would provide basal data for a proposing the diagnostic and treatment algorithms for HNSmCC.

BackgroundEarly detection of head and neck carcinoma (HNC) as superficial HNC (SHNC) identified using recently developed optical techniques, such as magnifying endoscopy and narrow-band imaging (NBI), in combination with endoscopic surgeries enables minimally invasive treatment with favorable outcomes for HNC. This study aimed to identify the predictive factors for the rare but important clinical issue of SHNC, namely cervical lymph node metastasis (CLNM), following endoscopic resection.MethodsSixty-nine patients with SHNC who underwent endoscopic resection were enrolled in the study. Clinical data, preoperative endoscopic findings, pathological findings, and treatment outcomes were retrospectively reviewed. Because the pharyngeal mucosa lacks the muscularis mucosa, we measured tumor thickness in permanent pathology as an alternative to the depth of invasion. Correlations with the occurrence of CLNM were statistically examined.ResultsThe 5-year disease-specific survival rate was 100%. Of 69 patients, 3 (4.3%) developed CLNM. All had subepithelial but not epithelial tumors. The 0-IIa type in the macroscopic findings, type B2/B3 vessels in narrow-band imaging, tumors ≥ pathological stage T2, lymphatic invasion, positive surgical margins, and tumor thickness >1,000 μm showed significant correlations with CLNM following endoscopic resection. Furthermore, the classification of type B vessels was significantly associated with tumor thickness.ConclusionThe treatment outcomes following endoscopic resection for SHNC were favorable. The risk of CLNM following endoscopic resection in SHNC can be predicted by several preoperative endoscopic and postoperative pathological findings. Among them, the classification of type B vessels, which correlated with both tumor thickness and CLNM, might be a useful predictive factor.

Objective: To develop a diagnostic algorithm for chronic vestibular syndromes by determining significant items that differ among diagnoses.Methods: Two hundred thirty-one patients with chronic vestibular syndromes lasting for >3 months were included. Full vestibular tests and questionnaire surveys were performed: bithermal caloric test, cervical and ocular vestibular-evoked myogenic potential assessment, video head impulse test (vHIT), posturography, rotatory chair test, dizziness handicap inventory, hospital anxiety and depression scale (HADS), and Niigata persistent postural-perceptual dizziness (PPPD) questionnaire (NPQ). Differences in each item of the vestibular tests/questionnaires/demographic data were tested among the diagnoses. A receiver operating characteristic (ROC) curve was created for the significant items. The value that provided the best combination of sensitivity/specificity on the ROC curve was adopted as a threshold for diagnosing the targeted disease. Multiple diagnostic algorithms were proposed, and their diagnostic accuracy was calculated.Results: There were 92 patients with PPPD, 44 with chronic dizziness due to anxiety (CDA), 31 with unilateral vestibular hypofunction (UVH), 37 with undifferentiated dizziness (UD), and 27 with other conditions. The top four diagnoses accounted for 88% of all chronic vestibular syndromes. Five significant items that differed among the four diseases were identified. The visual stimulation and total NPQ scores were significantly higher in the patients with PPPD than in those with UVH and UD. The percentage of canal paresis (CP %) was significantly higher in the patients with UVH than in those with PPPD, CDA, and UD. The patients with CDA were significantly younger and had higher anxiety scores on the HADS (HADS-A) than those with UVH and UD. Moreover, catch-up saccades (CUSs) in the vHIT were more frequently seen in the patients with UVH than in those with PPPD. The most useful algorithm that tested the total and visual stimulation NPQ scores for PPPD followed by the CP%/CUSs for UVH and HADS-A score/age for CDA showed an overall diagnostic accuracy of 72.8%.Conclusions: Among the full vestibular tests and questionnaires, the items useful for differentiating chronic vestibular syndromes were identified. We proposed a diagnostic algorithm for chronic vestibular syndromes composed of these items, which could be useful in clinical settings.

Objective: We aimed to compare the outcomes and safety of chemoradiotherapy (CRT) between elderly and non-elderly patients with head and neck squamous cell carcinoma (HNSCC). It is difficult to assess the causal effect of age because of possible differences in general conditions among individuals. Therefore, we adjusted the background factors of elderly and non-elderly patients using propensity score matching (PSM).Methods: A total of 146 patients with HNSCC who received CRT were divided into an elderly (≥70 years, n = 35) and non-elderly group (

We examined the role of lateral temporal bone resection (LTBR) in the treatment of external ear canal (EAC) carcinoma between 2007 and 2018. The estimated 3-year disease-free survival (DFS) and disease-specific survival (DSS) according to the tumor stage and treatments were investigated in 36 patients with EAC squamous cell carcinoma. T stage classification according to the University of Pittsburgh staging system was as follows: 14 patients in T1, four patients in T2, nine patients in T3, and nine patients in T4. The 3-year DFS rate was 77.4% for T1 tumors, 100% for T2, 44.4% for T3 tumors, and 11.1% for T4 tumors (p < 001). The 3-year DSS rate was 100% for T1/T2 tumors, 87.5% for T3 tumors, and 11.1% for T4 tumors (p < 0.01). T1/T2 patients received mostly LTBR. Among nine T3 tumors, five patients (56%) received LTBR combined with preoperative chemotherapy and/or postoperative radiation (RT). Four of them had negative surgical margin and survived with no evidence of disease. The DFS of T3 patients who underwent concurrent chemoradiotherapy and LTBR was 0 and 80%, respectively (p = 0.048). For T1/T2 tumors, surgery achieved an excellent outcome. For T3 tumors, LTBR achieved negative surgical margin and showed good survival when combined with preoperative chemotherapy and/or postoperative RT. In contrast, the prognosis of T3 patients who could not undergo surgery was as poor as that of T4 patients. Therefore, in addition to subtotal temporal bone resection, LTBR-based treatment strategy may be a treatment option for limited cases of T3 patients.

Hearing loss affects >5% of the global population and therefore, has a great social and clinical impact. Sensorineural hearing loss, which can be caused by different factors, such as acoustic trauma, aging, and administration of certain classes of drugs, stems primarily from a dysfunction of the cochlea in the inner ear. Few therapeutic strategies against sensorineural hearing loss are available. To develop effective treatments for this disease, it is crucial to precisely determine the behavior of ototoxic and therapeutic agents in the microenvironment of the cochlea in live animals. Since the 1980s, a number of studies have addressed this issue by different methodologies. However, there is much less information on pharmacokinetics in the cochlea than that in other organs; the delay in ontological pharmacology is likely due to technical difficulties with accessing the cochlea, a tiny organ that is encased with a bony wall and has a fine and complicated internal structure. In this review, we not only summarize the observations and insights obtained in classic and recent studies on pharmacokinetics in the cochlea but also describe relevant analytical techniques, with their strengths, limitations, and prospects.

Background: Persistent postural-perceptual dizziness (PPPD) is a persistent chronic vestibular syndrome exacerbated by upright posture/walking, active or passive motion, and exposure to moving or complex visual stimuli. PPPD has four precursors: phobic postural vertigo, space-motion discomfort, visual vertigo, and chronic subjective dizziness. These four diseases share clinical features that form the basis of the diagnostic criteria for PPPD. Semiological similarities do not necessarily mean that PPPD is a single entity. However, if PPPD is not a single disorder but just a composite of four precursors, it may be subdivided according to the characteristics of each precursor.Objective: To test whether PPPD is a single disorder, we attempted a subtyping of PPPD.Methods: One-hundred-eight untreated patients with PPPD were enrolled in the study, who filled out the Niigata PPPD Questionnaire (NPQ) that consists of 12 questions on exacerbating factors for PPPD. A factor analysis of the patients' answers to the NPQ and a subsequent cluster analysis of the patients with PPPD using factors revealed by the factor analysis were performed. To validate our cluster classification, cluster differences were assessed using analysis of variance. Multiple comparison analyses were performed on demographical data, precipitating diseases, the Dizziness Handicap Inventory, the Hospital Anxiety and Depression Scale, and several vestibular tests to characterize each cluster.Results: Factor analysis revealed three underlying factors among the exacerbating factors in the NPQ. Exacerbation by visual stimuli (visual factor) accounted for 47.4% of total variance in the questionnaire. Exacerbation by walking/active motion (active-motion factor) and by passive motion/standing (passive-motion/standing factor) accounted for 12.0 and 7.67% of variance, respectively. Cluster analysis revealed three clusters: the visual-dominant subtype (n = 49); the active motion-dominant subtype (n = 20); and the mixed subtype (n = 39). The patients in the active motion-dominant subtype were significantly older than those in the visual-dominant subtype. There were no significant differences among the subtypes in other demographical data or conventional vestibular tests.Conclusions: The most common main exacerbating factor of PPPD was the visual factor. PPPD may be categorized into three subtypes. Conventional vestibular tests failed to point the characteristics of each subtype.

Background: Vestibular Meniere's disease (American Academy of Ophthalmology and Otolaryngology, 1972) also known as possible Meniere's disease (American Academy of Otolaryngology Head and Neck Surgery, 1995) or vestibular type of atypical Meniere's disease (V-AMD) (Japan Society for Equilibrium Research, 2017) is characterized by an episodic vertigo without hearing loss. Though named as Meniere's disease (MD), this entity may not be caused solely by endolymphatic hydrops (EH).Objective: To estimate the role of EH in vestibular Meniere's disease in comparison with definite Meniere's disease.Methods: Thirty patients with unilateral definite MD and 16 patients with vestibular Meniere's disease were included. Those who met the criteria for definite or probable vestibular migraine were excluded. All patients underwent vestibular assessments including inner ear MRI 4 h after intravenous gadolinium injection, bithermal caloric testing, directional preponderance of vestibulo-ocular reflex in rotatory chair test, cervical- and ocular-vestibular evoked myogenic potential, stepping test, dizziness handicap inventory (DHI), and hospital anxiety and depression scale (HADS). All above tests and frequency/duration of vertigo spells were compared between vestibular Meniere's disease and MD.Results: Even in unilateral MD, cochlear and vestibular endolymphatic hydrops (c-, v-EH) were demonstrated not only in the affected side but also in the healthy side in more than half of patients. Positive rate of v-EH in vestibular Meniere's disease (68.8%) was as high as that of MD (80%). In vestibular Meniere's disease, the number of bilateral EH was higher in the vestibule (56.3%) than that in the cochlea (25.0%). There were no differences in vestibular tests and DHI between vestibular Meniere's disease and MD; however, the frequency of vertigo spells was lower in vestibular Meniere's disease (p = 0.001). The total HADS score in the MD group was significantly higher than that in the vestibular Meniere's disease group.Conclusions: MD is a systemic disease with bilateral involvement of inner ears. V-EH is a major pathophysiology of vestibular Meniere's disease, which would precede c-EH in the development of vestibular Meniere's disease, a milder subtype of MD. MRI is useful for differentiating MD from other vertigo attacks caused by different pathologies in bringing EH into evidence.