Current status of head and neck sarcomas in Japan in 2016-2019: an analysis using the national cancer registry.

BACKGROUND: Head and neck sarcomas are especially rare in Asia, leading to limited clinical evidence. This study aimed to investigate the incidence, clinical features, treatment status, and outcome of these sarcomas using data from the National Cancer Registry in Japan. METHODS: All head and neck sarcomas diagnosed between 2016 and 2019 and recorded in the National Cancer Registry were analyzed. Data on sex, age, primary site, histological type, stage, treatment modality, and prognostic information were collected. Age-adjusted incidence and 3-year survival rates of patients with head and neck sarcomas were calculated. RESULTS: Overall, 635 head and neck sarcoma patients were identified. Head and neck sarcoma occurred more frequently in men and patients in their 70 s. The age-adjusted annual incidence rate was 0.125 per 100,000 patients in the 2015 Japanese model or 0.089 per 100,000 patients in the world population model. The nasal cavity and paranasal sinuses were the most frequent primary sites, with rhabdomyosarcoma as the most common histologic type. Treatment typically involved chemotherapy and/or radiation therapy for rhabdomyosarcoma and Ewing's sarcoma, whereas surgical approaches for other types. Three-year survival rate of head and neck sarcoma patients was 64.8%. CONCLUSIONS: Head and neck sarcomas occurred rarely, but most frequently in the nasal cavity and paranasal sinuses in Japan. Poor outcomes were observed for sarcoma patients than for non-sarcoma head and neck cancer patients.

Time to Treatment Initiation for Six Cancer Types: An Analysis of Data from a Nationwide Registry in Japan.

BACKGROUND: Delay in the time to treatment initiation (TTI) may adversely affect the survival of patients, but its current status in Japan is unknown. This study aims to describe the TTI for six cancer types: lung, breast, colorectal, stomach, head and neck (H&N), and cervical. Data for this study were derived from a nationwide registry in Japan. METHODS: This observational study employed the national database of hospital-based cancer registries (HBCRs) and health services utilization data. Using HBCR data, we identified all patients with cancer who started their cancer therapy at the same hospitals between January 1 and December 31, 2017. We calculated the TTI for each cancer type and treatment option, stratifying the results by age group and geographical region. RESULTS: The overall median TTI was 33 days, with shorter TTIs for colorectal and H&N cancers and chemotherapy. The TTI was the shortest for younger patients and the longest for the elderly, especially for lung cancer. When categorized by eight Japanese geographical regions, Tohoku and Kanto had the longest TTI. The result remained the same even after adjusting cancer type, treatment, age, and stage information. CONCLUSION: For colorectal and H&N cancers, in which a longer TTI is associated with a poorer prognosis, TTI was found to be particularly shorter. Although we could not discuss our results in light of the patient survival in this study, future research should explore the best balance between thorough evaluation before treatment and necessary time for that.

HMGB1-mediated chromatin remodeling attenuates Il24 gene expression for the protection from allergic contact dermatitis.

Dysregulation of inflammatory cytokines in keratinocytes promote the pathogenesis of the skin inflammation, such as allergic contact dermatitis (ACD). High-mobility group box 1 protein (HMGB1) has been implicated in the promotion of skin inflammation upon its extracellular release as a damage-associated molecular pattern molecule. However, whether and how HMGB1 in keratinocytes contributes to ACD and other skin disorders remain elusive. In this study, we generated conditional knockout mice in which the Hmgb1 gene is specifically deleted in keratinocytes, and examined its role in ACD models. Interestingly, the mutant mice showed exacerbated skin inflammation, accompanied by increased ear thickening in 2,4-dinitrofluorobenezene-induced ACDs. The mRNA expression of interleukin-24 (IL-24), a cytokine known to critically contribute to ACD pathogenesis, was elevated in skin lesions of the mutant mice. As with constitutively expressed, IL-4-induced Il24 mRNA, expression was also augmented in the Hmgb1-deficient keratinocytes, which would account for the exacerbation of ACD in the mutant mice. Mechanistically, we observed an increased binding of trimethyl histone H3 (lys4) (H3K4me3), a hallmark of transcriptionally active genes, to the promoter region of the Il24 gene in the hmgb1-deficient cells. Thus, the nuclear HMGB1 is a critical "gate keeper" in that the dermal homeostasis is contingent to its function in chromatin remodeling. Our study revealed a facet of nuclear HMGB1, namely its antiinflammatory function in keratinocytes for the skin homeostasis.

Cellular cartography of the organ of Corti based on optical tissue clearing and machine learning.

The highly organized spatial arrangement of sensory hair cells in the organ of Corti is essential for inner ear function. Here, we report a new analytical pipeline, based on optical clearing of tissue, for the construction of a single-cell resolution map of the organ of Corti. A sorbitol-based optical clearing method enabled imaging of the entire cochlea at subcellular resolution. High-fidelity detection and analysis of all hair cell positions along the entire longitudinal axis of the organ of Corti were performed automatically by machine learning-based pattern recognition. Application of this method to samples from young, adult, and noise-exposed mice extracted essential information regarding cellular pathology, including longitudinal and radial spatial characteristics of cell loss, implying that multiple mechanisms underlie clustered cell loss. Our method of cellular mapping is effective for system-level phenotyping of the organ of Corti under both physiological and pathological conditions.

A Novel Technique for Imaging and Analysis of Hair Cells in the Organ of Corti Using Modified Sca/eS and Machine Learning.

Here, we describe a sorbitol-based optical clearing method, called modified Sca/eS that can be used to image all hair cells (HCs) in the mouse cochlea. This modification of Sca/eS is defined by three steps: decalcification, de-lipidation, and refractive index matching, which can all be completed within 72 h. Furthermore, we established automated analysis programs that perform machine learning-based pattern recognition. These programs generate 1) a linearized image of HCs, 2) the coordinates of HCs, 3) a holocochleogram, and 4) clusters of HC loss. In summary, a novel approach that integrates modified Sca/eS and programs based on machine learning facilitates quantitative and comprehensive analysis of the physiological and pathological properties of all HCs.

Revisiting the role of IRF3 in inflammation and immunity by conditional and specifically targeted gene ablation in mice.

IFN regulatory factor 3 (IRF3) is a transcription regulator of cellular responses in many cell types that is known to be essential for innate immunity. To confirm IRF3's broad role in immunity and to more fully discern its role in various cellular subsets, we engineered Irf3-floxed mice to allow for the cell type-specific ablation of Irf3 Analysis of these mice confirmed the general requirement of IRF3 for the evocation of type I IFN responses in vitro and in vivo. Furthermore, immune cell ontogeny and frequencies of immune cell types were unaffected when Irf3 was selectively inactivated in either T cells or B cells in the mice. Interestingly, in a model of lipopolysaccharide-induced septic shock, selective Irf3 deficiency in myeloid cells led to reduced levels of type I IFN in the sera and increased survival of these mice, indicating the myeloid-specific, pathogenic role of the Toll-like receptor 4-IRF3 type I IFN axis in this model of sepsis. Thus, Irf3-floxed mice can serve as useful tool for further exploring the cell type-specific functions of this transcription factor.

Influence of the location of nasal polyps on olfactory airflow and olfaction.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) often results in decreased olfaction. In this study, we examined the relationship between nasal polyp location and olfactory airflow and odorant transport changes using virtual nasal polyp models at different locations and computational fluid dynamics (CFD) analysis. We also compared olfactory airflow and olfaction between patients with nasal polyps at different locations using CFD analysis and an olfactory test. METHODS: Nasal computed tomography images were used to generate a normal model and 4 virtual nasal polyp models based on polyp locations, including the olfactory region (all-olfactory model), the region anterior to the olfactory region (preolfactory model), the middle meatus (middle-meatus model), and the superior meatus (superior-meatus model). Various airflow parameters were compared between these models and a normal model without polyps. We then performed a similar comparison between the 3-dimensional (3D) reconstruction models of patients with nasal polyps, and retrospectively investigated the correlation between olfaction and nasal polyp location in those patients. RESULTS: Virtual nasal polyp analysis revealed dispersion of olfactory airflow in the all-olfactory model. Olfactory airflow and odorant transport showed maximum decrease in the preolfactory model and a slight decrease in the superior-meatus model. Olfactory airflow by polyps was further decreased by blockade of the olfactory airflow inlet than of the outlet. The findings obtained by patients corresponded well to those of the virtual polyp analysis. CONCLUSION: Olfactory airflow and olfaction are differentially affected by nasal polyp location. This finding is important for planning polyp-removal surgeries from the perspective of improving patient olfaction.

Macrophage recruitment, but not interleukin 1 beta activation, enhances noise-induced hearing damage.

It has been suggested that macrophages or inflammatory monocytes participate in the pathology of noise-induced hearing loss (NIHL), but it is unclear how extensively these cells contribute to the development of temporary and/or permanent NIHL. To address this question, we used clodronate liposomes to deplete macrophages and monocytes. After clodronate liposome injection, mice were exposed to 4-kHz octave band noise at 121 dB for 4 h. Compared to vehicle-injected controls, clodronate-treated mice exhibited significantly reduced permanent threshold shifts at 4 and 8 kHz and significantly smaller outer hair cell losses in the lower-apical cochlear turn. Following noise exposure, the stria vascularis had significantly more cells expressing the macrophage-specific protein F4/80, and this effect was significantly suppressed by clodronate treatment. These F4/80-positive cells expressed interleukin 1 beta (IL-1ß), which noise exposure activated. However, IL-1ß deficient mice did not exhibit significant resistance to intense noise when compared to wild-type mice. These findings suggest that macrophages that enter the cochlea after noise exposure are involved in NIHL, whereas IL-1ß inhibition does not reverse this cochlear damage. Therefore, macrophages may be a promising therapeutic target in human sensorineural hearing losses such as NIHL.