BackgroundMucopolysaccharidosis type II (MPS II) is caused by deficiency in the lysosomal enzyme. This study aimed to evaluate audiological characteristics and longitudinal hearing changes in patients with MPS II.MethodsWe retrospectively reviewed 17 patients with MPS II whose hearing thresholds could be examined using pure-tone audiometry (PTA) at our institution for at least two years. Hearing was evaluated using auditory brainstem responses (ABR) and PTA. Longitudinal changes in hearing were analyzed to assess the progression and exploratory treatment-related effects.ResultsSeventeen patients (34 ears) met the inclusion criteria for longitudinal analysis. All patients demonstrated sensorineural hearing loss at a mild or higher degree at baseline or during follow-up. Air conduction thresholds (AC) and bone conduction thresholds (BC) were significantly higher at the final assessment than at the initial visit. The mean annual change rate of AC and BC were 1.24±1.37 dB HL/year and 1.11±1.44 dB HL/year, respectively. During follow-up, 4 patients (8 ears) received pabinafusp alfa. Improvement in AC deterioration was observed in 5 of 8 ears (62.5%) and BC deterioration in 6 of 8 ears (75.0%).ConclusionsHearing impairment in both the AC and BC was highly prevalent and progressive in patients with MPS II. The present study provided preliminary observations in a small subset of patients suggesting that pabinafusp alfa may attenuate the progression of hearing loss in patients with MPS II. Improvement in BC might support the hypothesis that the deposition of glycosaminoglycans in the inner ear contributes to sensorineural hearing loss in MPS II.

OBJECTIVE:This study examined patterns of cellular and neural degeneration in the peripheral vestibular system following head trauma, comparing cases with and without skull/temporal bone fractures. METHODS:We analyzed 26 temporal bones (17 cases) with head trauma with fractures (six cases, nine ears) and ones without fractures (11 cases, 17 ears). Appropriate age-matched control groups comprising temporal bones without temporal bone pathology were included for comparative purposes. Histopathological analyses included counts of Scarpa's ganglion cells (ScGCs) in the superior and inferior vestibular nerves (SVN and IVN), and counts of vestibular hair cells (HCs) in the utricle, saccule, lateral semicircular canal (LSCC), and posterior semicircular canal (PSCC). Mann-Whitney U tests were used for statistical analyses. RESULTS:The group without fractures showed a significant reduction in total ScGCs (SVN + IVN) compared to controls (p = 0.040), with a pronounced decrease in the SVN (p = 0.014). Significant reductions in type I and type II HCs were observed in the utricle (p = 0.008 and p = 0.035) and in type I HCs in the LSCC (p = 0.037). In the group with fractures, only type I HCs in the utricle were significantly reduced (p = 0.038). CONCLUSION:Head trauma without fractures is associated with more severe vestibular cell degeneration and greater loss of ganglion cells in the SVN in our specimens. These findings suggest that head trauma without fractures may pose a higher risk for vestibular cell damage compared with trauma with fractures. LEVEL OF EVIDENCE:NA.

BACKGROUND:The most critical complication of Kawasaki disease (KD) is the development of coronary artery lesions (CALs). Several parameters have been investigated as potential biomarkers for predicting CAL development, but none have been deemed accurate. Therefore, this study aimed to identify novel biomarkers for detecting emergent CALs using liquid chromatography-mass spectrometry (LC/MS). METHODS:We recruited five patients with and five without CALs among the 299 KD patients. An LC/MS-based proteomic analysis of the sera of KD patients was employed to examine the candidate proteins associated with CAL development. RESULTS:Six proteins presenting lower ratios in patients with CALs compared to those without were identified. Among these proteins, histidine-rich glycoprotein (HRG) had the lowest concentration and p-value, and its serum levels were lower in patients with CALs than in those without CALs. CONCLUSIONS:The findings indicate HRG to be a potential biomarker for predicting CAL development in KD patients.

Inosine, a bacterial metabolite and agonist of the adenosine A2A receptor, modulates antitumor immunity. However, its precise effects on immune checkpoint inhibitors remain unclear. This study aimed to evaluate the impact of inosine on the efficacy of anti-programmed cell death protein 1 (PD-1) therapy and explore strategies to counteract any potential inhibitory effects. In in vitro co-culture systems, inosine selectively suppressed cancer cell growth without impairing T-cell viability. In a murine subcutaneous tumor model, inosine treatment reduced tumor growth and was associated with elevated interferon-gamma levels in the tumor microenvironment, along with increased infiltration by tumor-infiltrating lymphocytes and enhanced splenic CD4⁺ and CD8⁺ T-cell frequencies. However, the combination of inosine with anti-PD-1 therapy attenuated the antitumor effect and increased cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression in splenic T cells compared to levels after anti-PD-1 monotherapy. To overcome this inhibitory effect, we tested whether adding an anti-CTLA-4 antibody could restore antitumor immunity. Notably, the combination of inosine with both anti-PD-1 and anti-CTLA-4 antibodies significantly enhanced antitumor efficacy. These findings suggest that inosine may synergize with dual ICI therapy and represent a promising adjunct to improve immunotherapeutic outcomes.

ABSTRACT The concept of genome–microbiome interactions, in which the microenvironment determined by host genetic polymorphisms regulates the local microbiota, is important in the pathogenesis of human disease. In otolaryngology, the resident bacterial microbiota is reportedly altered in non-infectious ear diseases, such as otitis media pearls and exudative otitis media. We hypothesized that a single-nucleotide polymorphism in the ATP-binding cassette sub-family C member 11 ( ABCC11 ) gene, which determines earwax properties, regulates the ear canal microbiota. We analyzed ABCC11 gene polymorphisms and ear canal microbiota in healthy individuals to understand the relationship between genome–microbiome interactions in the ear canal. The study included 21 subjects who were divided into two groups: 538GA (9) and 538AA (12). Staphylococcus auricularis and Corynebacterium spp. were observed in the 538GA group, whereas Methylocella spp. was observed in the 538AA group. PICRUSt analysis revealed significant enrichment of certain pathways, such as superpathway of N-acetylglucosamine, N-acetylmannosamine and N-acetylneuraminate degradation, chlorosalicylate degradation, mycothiol biosynthesis, and enterobactin biosynthesis in the GA group, whereas allantoin degradation IV (anaerobic), nitrifier denitrification, starch degradation III, L-valine degradation I, and nicotinate degradation I were significantly enriched in the AA group. The ABCC11 gene polymorphism regulates the composition of the ear canal microbiota and its metabolic pathways. This study revealed a genome–microbiome interaction within the resident microbiota of the external auditory canal that may help to elucidate the pathogenesis of ear diseases and develop novel therapies. IMPORTANCE The ABCC11 gene polymorphism, which determines earwax characteristics, regulates the composition of the ear canal microbiota and its metabolic pathways. We determined the presence of genome–microbiome interactions in the resident microbiota of the ear canal. Future studies should focus on ABCC11 gene polymorphisms to elucidate the pathogenesis of ear diseases and develop therapeutic methods.

The low response rate of immune checkpoint inhibitors (ICIs) is a challenge. The efficacy of ICIs is influenced by the tumour microenvironment, which is controlled by the gut microbiota. In particular, intestinal bacteria and their metabolites, such as short chain fatty acids (SCFAs), are important regulators of cancer immunity; however, our knowledge on the effects of individual SCFAs remains limited. Here, we show that isobutyric acid has the strongest effect among SCFAs on both immune activity and tumour growth. In vitro, cancer cell numbers were suppressed by approximately 75% in humans and mice compared with those in controls. Oral administration of isobutyric acid to carcinoma-bearing mice enhanced the effect of anti-PD-1 immunotherapy, reducing tumour volume by approximately 80% and 60% compared with those in the control group and anti-PD-1 antibody alone group, respectively. Taken together, these findings may support the development of novel cancer therapies that can improve the response rate to ICIs.

Natural killer group 2 member D ligands (NKG2DLs) are expressed as stress response proteins in cancer cells. NKG2DLs induce immune cell activation or tumor escape responses, depending on their expression. Human pancreatic cancer cells, PANC-1, express membrane MHC class I polypeptide-related sequence A/B (mMICA/B), whereas soluble MICB (sMICB) is detected in the culture supernatant. We hypothesized that sMICB saturates NKG2D in NKG2DLow T cells and inhibits the activation signal from mMICB to NKG2D. Knockdown of MICB by siRNA reduced sMICB level, downregulated mMICB expression, maintained NKG2DLow T cell activation, and inhibited NKG2DHigh T cell activation. To maintain mMICB expression and downregulate sMICB expression, we inhibited a disintegrin and metalloproteinase (ADAM), a metalloproteinase that sheds MICB. Subsequently, the shedding of MICB was prevented using ADAM17 inhibitors, and the activation of NKG2DLow T cells was maintained. In vivo xenograft model revealed that NKG2DHigh T cells have superior anti-tumor activity. These results elucidate the mechanism of immune escape via sMICB and show potential for the activation of NKG2DLow T cells within the tumor microenvironment.

OBJECTIVES:Obliteration of the round window (RW) in cases of otosclerosis presents a significant clinical challenge due to its association with more severe hearing loss and a poorer prognosis for functional recovery after stapes surgery. The objective is to assess and characterize the occurrence of RW involvement in otosclerosis cases and to identify patterns of disease progression that may indicate a potential for RW obliteration. METHODS:We selected archival temporal bones from donors with otosclerosis. We evaluated the degree of RW obliteration using a semi-quantitative scale and the location of the foci within the temporal bone, and whether the foci were continuous or isolated. RESULTS:Most of the foci were located anteriorly to the oval window (89.2%), while RW area involvement was seen in 26.9% of the ears. In cases with fenestral foci, 68.1% directly involved and/or fixed the footplate. Among donors with bilateral otosclerosis, foci affected both ears in a similar pattern in 64.2%. Among donors with RW involvement, ones with continuous, large lesions that extended from the oval window associated with complete RW obliteration, while ones with smaller degrees of obliteration had solitary foci scattered within the otic capsule. CONCLUSION:Our results demonstrate a high rate of RW involvement in cases of otosclerosis. Ears with continuous lesions extending from the oval window region to the RW area were more likely to present with complete RW obliteration. These results provide insights that could lead to better prognostic assessment of patients with otosclerosis in the future. LEVEL OF EVIDENCE:NA Laryngoscope, 135:324-330, 2025.

Vascular smooth muscle cell (VSMC) migration plays an important role in cardiovascular diseases, including atherosclerotic plaque formation and restenosis after vascular intervention. The mechanisms involved in VSMC migration are complex and have not been fully elucidated. Recently, we discovered a novel interaction, direct binding of active Fyn-paxillin at focal adhesions, which plays an important role in actin stress fiber formation and migration in VSMCs. In this review, we highlight paxillin as an intermediate signaling molecule that mediates actin stress fiber formation and VSMC migration through the Fyn/paxillin/Rho-kinase signaling pathway by directly binding to active Fyn. We also discuss the inhibition of VSMC migration by blocking the active Fyn-paxillin interaction and the potential of this interaction as a therapeutic target for cardiovascular diseases.

ObjectiveMeasure the volume of air-containing space in children with cleft palate and assess age-related changes, recurrence rate of otitis media with effusion (OME) after tube removal, and temporal bone development trend based on time of tube placement.DesignInterventional prospective study.SettingCleft Lip and Palate Center at a Tertiary-level institution.Patients/ParticipantsOne hundred sixty-eight ears of 86 patients who visited our center from January 2018 to December 2019.InterventionsWe performed tympanometry (impedance audiometry) after tube placement.Main Outcome MeasuresRecurrence (at least one episode of OME after tympanic membrane closure), tympanic cavity volumes, and timing of tube placement.ResultsThe mean air-containing cavity volume was 1.62 mL, 2.99 mL, and 3.29 mL in patients aged 1, 2, and 3 years, respectively. A rapid increase in volume was observed around 2 years of age. Twenty-two (42.3%) of the 52 ears with pneumatic cavity volumes <3 mL, and four (14.3%) of the 28 ears with pneumatic cavity volumes ≥3 mL had recurrence. Tubes were placed at ages <1 year and ≥1 year in 28 and 62 ears, respectively. The pneumatic cavity volume tended to be greater in the ears with tube placement at age <1 year.ConclusionThis study provided insights into using pneumatic cavity volume measurements to determine the appropriate timing for tube removal. Tubes should be placed as early as possible (before the age of 2 years) for prolonged OME associated with children with cleft palate.

Soft tissue eosinophilic granulomatosis (Kimura’s disease) is a benign disease with a chronic course that manifests as painless soft tissue masses or enlarged lymph nodes. These masses frequently occur in the head and neck region, especially around the parotid gland, while there are few reports of involvement of the ear canal.

As antibiotic resistance has become a global problem, the intervention of an antimicrobial stewardship team (AST) is warranted. In hematological disorders, infectious complications are crucial owing to abnormal neutrophil function and decreased cell-mediated immunity. Despite the widespread implementation of AST intervention, the effectiveness of stewardship practices for immunocompromised patients remains uncertain. We determined the effect of AST interventions on carbapenem therapy in the department of hematology. Patients admitted to the department and undergoing carbapenem therapy were enrolled. We compared carbapenem use between the pre-AST (April 2016–March 2018) and post-AST (April 2018–March 2021) periods. Factors associated with long-term carbapenem therapy were investigated. Overall, 515 episodes of carbapenem therapy in 264 patients in the department were evaluated. According to the interrupted time series analysis, the number of days of therapy decreased with AST intervention (β = −0.263, p = 0.011). In multivariate analysis, predictive factors associated with long-term carbapenem therapy (>8 days) were outpatient onset, chronic obstructive pulmonary disease, acute myeloid leukemia, multiple myeloma, and infection with resistant bacteria (such as extended spectrum β-lactamases and AmpC) (95% confidence interval, 1.030–2.818, 1.067–66.667, 1.057–2.782, 0.168–0.742, and 1.382–5.750, respectively). The AST intervention reduced carbapenem use in patients with hematological disorders.

Metastasis is the leading cause of death in breast cancer patients due to the lack of effective therapies. Elevated levels of paxillin expression have been observed in various cancer types, with tyrosine phosphorylation shown to play a critical role in driving cancer cell migration. However, the specific impact of the distinct tyrosine phosphorylation events of paxillin in the progression of breast cancer remains to be fully elucidated. Here, we found that paxillin overexpression in breast cancer tissue is associated with a patient’s poor prognosis. Paxillin knockdown inhibited the migration and invasion of breast cancer cells. Furthermore, the phosphorylation of paxillin tyrosine residue 31 (Tyr31) was significantly increased upon the TGF-β1-induced migration and invasion of breast cancer cells. Inhibiting Fyn activity or silencing Fyn decreases paxillin Tyr31 phosphorylation. The wild-type and constitutively active Fyn directly phosphorylate paxillin Tyr31 in an in vitro system, indicating that Fyn directly phosphorylates paxillin Tyr31. Additionally, the non-phosphorylatable mutant of paxillin at Tyr31 reduces actin stress fiber formation, migration, and invasion of breast cancer cells. Taken together, our results provide direct evidence that Fyn-mediated paxillin Tyr31 phosphorylation is required for breast cancer migration and invasion, suggesting that targeting paxillin Tyr31 phosphorylation could be a potential therapeutic strategy for mitigating breast cancer metastasis.

Abstract Natural killer group 2 member D ligands (NKG2DLs) are expressed as stress response proteins in cancer cells. NKG2DLs induce the activation of immune cells or tumor escape responses, depending on their expression. Human pancreatic cancer cells, Panc-1, express membrane MICA/B (mMICA/B), whereas soluble MICB (sMICB) is detected in the culture supernatant. We hypothesized that sMICB saturates NKG2D in NKG2DLow T cells and inhibits the activation signal from mMICB to NKG2D. The findings revealed that downregulation of MICB reduced sMICB, downregulated mMICB, maintained activation of NKG2DLow T cells, and inhibited activation of NKG2DHigh T cells. To maintain mMICB expression and reduce sMICB expression, we inhibited ADAM, a metalloproteinase that sheds MICB. Subsequently, the shedding of MICB was prevented by ADAM17 inhibitors, and the activation of NKG2DLow T cells was maintained. These results elucidate the mechanism of immune escape via sMICB and show promising potential for the activation of NKG2DLow T cells within the tumor microenvironment.

Introduction: Rendu-Osler-Weber disease (Osler’s disease) is an autosomal-dominant genetic disease that is associated with peripheral vasodilatation and a tendency towards bleeding due to abnormal vascular wall formation. In the field of otolaryngology, we often encounter cases with recurrent and refractory nasal bleeding associated with this disease.

近年, 新生児聴覚スクリーニングが普及したことによって, 1歳未満で難聴の精査のため耳鼻咽喉科の受診をするダウン症児は増加している. ダウン症児の難聴は滲出性中耳炎 (以下 OME) によるものが多いが, その対応については悩むことも多い. 1歳未満で難聴が疑われて受診したダウン症児に対してその後の経過を調査し, またチューブ留置を行った症例の合併症の頻度・再発率・聴力変化を調査することで早期治療介入の有効性について検討した. 対象は2014~2018年に1歳未満で難聴が疑われて初診した92例とし, 受診後の経過を調査したところ92例中22例にチューブ留置を行っていた. 留置が2歳前と2歳以降での合併症頻度を比較したが, 早期に施行したとしても耳漏や永久穿孔の頻度に有意差は認めなかった. チューブ抜去後の再発率は高く, 約半数で再留置が行われており, 繰り返しチューブ留置が必要になる可能性を家族に理解してもらう必要があると考えられた. また22例中20例でチューブ留置前後の聴力検査を施行しており, 留置前の平均聴力は 52.2dB だったが, 留置後は 37.3dB へ有意に改善していた. 10dB 以上の聴力改善は1歳台に留置した11例中10例 (90.9%), 2歳以降に留置した7例中4例 (57.1%) で認められた. 以上からダウン症児に OME が認められる場合には早期からチューブ留置を検討してもよいのではないかと考えられた.

RATIONALE:IgG4-related diseases cause lesions in various organs throughout the body. In otorhinolaryngology, IgG4-related Mikulicz's disease is suspected and diagnosed based on the presence of lesions of the head and neck, salivary and lacrimal gland enlargement, and bilateral sinus opacity concentrated on the maxillary sinuses. However, in some cases, it is necessary to consider about differentiation between IgG4-related Mikulicz's disease and Sjögren syndrome.PATIENT CONCERNS AND DIAGNOSIS:A 75-years-old male patient visited our hospital with bilateral otitis media with effusion, which was resistant to conservative treatment. Other symptoms at presentation included enlarged bilateral submandibular and sublingual glands marked oral dryness, severe decrease in saliva secretion (1 mL/10 minutes), and dry eyes. We conducted a Schirmer's and fluorescent dye tests, both of which were positive. High serum IgG4 levels were observed, and although the Sjögren syndrome (SS)-A/SS-B antibodies were negative, marked hypolacrimation and tear secretion were observed. Therefore, a detailed examination considering both IgG4-related Mikulicz's disease and SS was conducted. Salivary gland scintigraphy performed prior to the salivary gland biopsy revealed a marked decrease in uptake, which satisfied the diagnostic criteria for SS; however, it was difficult to diagnose IgG4-related disease based on the diagnostic definition.INTERVENSIONS:Although a definitive diagnosis of SS was made, the persistent otitis media with effusion that was resistant to conservative treatment and bilateral mixed hearing loss were confirmed. As mixed hearing loss is considered an otological symptom of IgG4-related disease, oral steroid treatment was administered.OUTCOME:Thereafter, marked recovery of hearing and reduced swelling and induration of the bilateral parotid and submandibular glands were observed. Clinically, IgG4-related Mikulicz's disease was strongly suspected, but a definite diagnosis of SS was made.LESSONS:In the absence of an IgG4-related Mikulicz's disease diagnosis, careful differentiation between IgG4-related Mikulicz's disease and 2 diseases and their diagnostic criteria was essential.