Severe Type 2 Inflammation Leads to High Platelet-Activating-Factor-Associated Pathology in Chronic Rhinosinusitis with Nasal Polyps-A Hierarchical Cluster Analysis Using Bulk RNA Barcoding and Sequencing.

Platelet-activating factor (PAF) is a phospholipid-derived inflammatory mediator that triggers various inflammatory conditions, including eosinophil activation and recruitment. This study aimed to evaluate the expressions of PAF-metabolism-associated genes, namely genes coding the enzymes involved in PAF synthesis (LPCAT1, LPCAT2, LPCAT3, and LPCAT4), PAF degradation (PAFAH1B2, PAFAH1B3, and PAFAH2), and the gene for the PAF receptor (PTAFR) in subtypes of CRSwNP classified by clinical- or hierarchal-analysis-based classifications. Transcriptomic analysis using bulk RNA barcoding and sequencing (BRB-seq) was performed with CRSwNP, including eosinophilic CRS (ECRS) (n = 9), nonECRS (n = 8), ECRS with aspirin-exacerbated respiratory disease (Asp) (n = 3), and controls with a normal uncinate process mucosa (n = 6). PTAFR was only upregulated in ECRS and nonECRS. In the hierarchical cluster analysis with clusters 1 and 2 reflecting patients with low-to-moderate and high levels of type 2 inflammation, respectively, cluster 1 exhibited a significant downregulation of LPCAT2 and an upregulation of PTAFR expression, while cluster 2 showed an upregulation of LPCAT1, PAFAH1B2, and PTAFR and downregulation of PAFAH2 expression. Understanding this strong PAF-associated pathophysiology in the severe type 2 inflammation group could provide valuable insights into the treatment and management of CRSwNP.

Artificial intelligence-based diagnosis of the depth of laryngopharyngeal cancer.

OBJECTIVE: Transoral surgery (TOS) is a widely used treatment for laryngopharyngeal cancer. There are some difficult cases of setting the extent of resection in TOS, particularly in setting the vertical margins. However, positive vertical margins require additional treatment. Further, excessive resection should be avoided as it increases the risk of bleeding as a postoperative complication and may lead to decreased quality of life, such as dysphagia. Considering these issues, determining the extent of resection in TOS is an important consideration. In this study, we investigated the possibility of accurately diagnosing the depth of laryngopharyngeal cancer using radiomics, an image analysis method based on artificial intelligence (AI). METHODS: We included esophagogastroduodenoscopic images of 95 lesions that were pathologically diagnosed as squamous cell carcinoma (SCC) and treated with transoral surgery at our institution between August 2009 and April 2020. Of the 95 lesions, 54 were SCC in situ, and 41 were SCC. Radiomics analysis was performed on 95 upper gastrointestinal endoscopic NBI images of these lesions to evaluate their diagnostic performance for the presence of subepithelial invasion. The lesions in the endoscopic images were manually delineated, and the accuracy, sensitivity, specificity, and area under the curve (AUC) were evaluated from the features obtained using least absolute shrinkage and selection operator analysis. In addition, the results were compared with the depth predictions made by skilled endoscopists. RESULTS: In the Radiomics study, the average cross-validation was 0.833. The mean AUC for cross-validation calculated from the receiver operating characteristic curve was 0.868. These results were equivalent to those of the diagnosis made by a skilled endoscopist. CONCLUSION: The diagnosis of laryngopharyngeal cancer depth using radiomics analysis has potential clinical applications. We plan to use it in actual surgery in the future and prospectively study whether it can be used for diagnosis.

Swallowing Exercise Evaluated Using High-Density Surface Electromyography in Patients with Head and Neck Cancer: Supplementary Analysis of an Exploratory Phase II Trial.

Background and Objectives: Muscle strength evaluation using high-density surface electromyography (HD-sEMG) was recently developed for the detailed analysis of the motor unit (MU). Detection of the spatial distribution of sEMG can detect changes in MU recruitment patterns resulting from muscle-strengthening exercises. We conducted a prospective study in 2022 to evaluate the safety and feasibility of transcutaneous electrical sensory stimulation (TESS) therapy using an interferential current device (IFCD) in patients with head and neck squamous cell carcinoma (HNSCC) undergoing chemoradiotherapy (CRT), and reported the safety and feasibility of TESS. We evaluated the efficacy of swallowing exercises in patients with HNSCC undergoing CRT and determined the significance of sEMG in evaluating swallowing function. Materials and Methods: In this supplementary study, the patients performed muscle-strengthening exercises five days a week. The association of the effects of the exercises with body mass index, skeletal muscle mass index, HD-sEMG, tongue muscle strength, and tongue pressure were evaluated. Results: We found significant correlations between the rate of weight loss and skeletal muscle mass index reduction and the rate of change in the recruitment of the MU of the suprahyoid muscle group measured using HD-sEMG. Conclusions: We believe that nutritional supplementation is necessary in addition to muscle strengthening during CRT.

Exhaled Nitric Oxide and Olfactory Dysfunction in Patients with Asthma: Association with Chronic Rhinosinusitis.

Objectives: Olfactory dysfunction is a clinical sign that is important to detect with coexistent upper airway comorbidities in patients with asthma. This study aimed to investigate the etiology of olfactory dysfunction in patients with asthma and the relationship between fractional exhaled nitric oxide (FeNO) levels. Materials and Methods: This study included 47 asthma patients who were evaluated for olfactory dysfunction at Hiroshima University Hospital between 2012 and 2020. The etiologies of olfactory dysfunction were evaluated, and they were classified according to the FeNO levels of patients with asthma. Results: Olfactory dysfunction was observed in 30 patients with asthma, with chronic rhinosinusitis (77%) being the most prevalent etiology. Eosinophilic chronic rhinosinusitis (ECRS) was the most prevalent etiology of olfactory dysfunction in asthma patients with high FeNO levels (≥25 ppb), while non-eosinophilic chronic rhinosinusitis (NCRS) was the most prevalent etiology in asthma patients with low FeNO levels (<25 ppb). Additionally, the prevalence of ECRS was significantly higher in asthma patients with olfactory dysfunction and high FeNO levels (74%) than in those with either high FeNO levels or olfactory dysfunction and those with low FeNO levels and no olfactory dysfunction (12% and 9%, respectively). Conclusions: We found that ECRS was the predominant cause of olfactory dysfunction in patients with high FeNO levels, while NCRS was more common in those with low FeNO levels. The present study showed that both ECRS and NCRS are common etiologies of olfactory dysfunction in patients with asthma. Additionally, this study supports the link between upper and lower airway inflammation in patients with asthma complicated with olfactory dysfunction.

Evaluation of the Safety of Percutaneous Sensory Nerve Stimulation in Patients with Head and Neck Cancer Receiving Chemoradiotherapy.

Chemoradiotherapy (CRT) is the standard treatment for locally advanced head and neck cancer; however, CRT may cause post-treatment dysphagia. Transcutaneous electrical sensory stimulation (TESS), developed in recent years for swallowing rehabilitation, is used at many medical facilities. Although TESS has been used for dysphagia in several fields, its safety and efficacy in patients with head and neck cancer remain to be clarified. Therefore, this study evaluated the safety of TESS in ten patients with head and neck cancers undergoing CRT. Swallowing rehabilitation intervention and TESS implementation were performed for all patients during CRT. Non-blood-toxicity adverse events (AEs), such as dermatitis and mucositis, occurred during CRT; however, the severity was less than grade 3. No patient experienced pain due to TESS. As survival time analysis using the Kaplan-Meier method for interferential current device implementation rates revealed a feasibility of 100% for up to 60 Gy and a feasibility of 78% for up to 70 Gy, TESS may be feasible until 70 Gy. This study confirmed the feasibility and safety of TESS in the head and neck region during CRT. Although the precise mechanism of TESS on dysphagia remains unclear, its continued use has great potential for improving sensory disturbance.

Severe multiple simultaneous immune-related adverse events in a patient with head and neck cancer.

Nivolumab, an immune checkpoint inhibitor (ICI) against the programmed death-1 pathway, has been used for the treatment of recurrent metastatic head and neck cancer. However, the management of immune-related adverse events (irAEs), a unique side effect of ICI therapy, can be problematic. Although severe irAEs have been reported to result from multi-ICI therapy, we report a case of multiple severe irAEs caused by single-agent nivolumab treatment. Nivolumab was administered to treat a case of hypopharyngeal cancer recurrence. However, when first-line chemotherapy of nivolumab was replaced with a second chemotherapeutic agent because of insufficient effectiveness, the patient showed anorexia, dermatitis, and mucositis; upper gastrointestinal endoscopy yielded a diagnosis of irAEs. Additional examinations revealed simultaneous multiple irAEs, including hypothyroidism, dermatitis, eyelid conjunctivitis, tracheal mucositis, upper gastrointestinal ulcer, and type 1 diabetes. Since all symptoms improved after steroid treatment, the patient was treated with subsequent chemotherapy. However, he died from uncontrolled cancer recurrence. Thus, even a single ICI agent can cause life-threatening irAEs. Moreover, the management of irAEs requires early recognition and close multidisciplinary collaboration in accordance with the countermeasure manual.

Determining Invasion Depth in Superficial Pharyngeal Carcinoma by Transoral Ultrasonography.

OBJECTIVES: To examine the clinical usefulness of transoral ultrasonography (US) in determining the invasion depth of superficial pharyngeal carcinoma (SPC). Determining the invasion depth of SPC is crucial for transoral surgery including determining treatment strategy. This study aimed to examine the usefulness of transoral US in determining the invasion depth of SPC. METHODS: Forty-six patients with 51 lesions who underwent both magnifying endoscopy with narrow-band imaging (ME-NBI) and transoral US were included. The primary outcomes were the sensitivity, specificity, positive (PPV), and negative predictive values (NPV) of ME-NBI and transoral US findings for pathological tumor depth in SPCs. RESULTS: The accuracy (82.4%), sensitivity (85.2%), PPV (82.1%), and NPV (82.6%) rates of US for subepithelial propria (SEP) were higher than those of ME-NBI and macroscopic classification, indicating that transoral US is superior to ME-NBI in determining the invasion depth. All cases where the SEP was clearly invaded (SEP deep) could be diagnosed as SEP by transoral US. CONCLUSIONS: Transoral US may be useful in determining the invasion depth of SPCs. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:2192-2197, 2023.

Effectiveness of Expanded Instantaneous Input Dynamic Range Adjustment on Speech Perception.

Instantaneous input dynamic range (IIDR), as defined by Cochlear Ltd. (Sydney, Australia), refers to the acoustic level of short-term input dynamic range (IDR). Our aim was to evaluate the efficacy of expanding IIDR to improve speech understanding. We enrolled 11 unilateral Cochlear Ltd. patients with post-lingual hearing loss. The two types of IIDR settings (T-SPL/C-SPL of 25/65 dB (default IIDR) and 25/80 dB (wide IIDR)) were blindly assigned, and only one IIDR setting selected according to their preference was used for at least three months. Each IIDR group was evaluated with both default and wide IIDR conditions using the recorded word and sentence test materials of the Japanese CD speech discrimination scoring system (CI-2004 test) in quiet and noise with a signal-to-noise ratio (SNR) of +10 dB, presented at 65/80 dB SPL. Wide IIDR significantly improved speech perception in all tests, except for sentences in quiet conditions at a presentation level of 65 dB. Improvements during loud conversations in noisy environments were obtained without any adaptation period. Wide IIDR should become a new individual configuration setting method in Cochlear Ltd. devices to improve hearing in loud conversations and noisy environments.

Deep Association between Transglutaminase 1 and Tissue Eosinophil Infiltration Leading to Nasal Polyp Formation and/or Maintenance with Fibrin Polymerization in Chronic Rhinosinusitis with Nasal Polyps.

Transglutaminase (TGM) isoform catalyze the cross-linking reaction of identical or different substrate proteins. Eosinophil has been recognized in chronic rhinosinusitis with nasal polyps (CRSwNP) forming tissue eosinophil in nasal polyp (NP), and TGM isoforms are suggested to be associated with a critical role in asthma and other allergic conditions. The aim of this study was to reveal the association of specific TGM isoform with both the tissue eosinophil infiltration deeply concerning with the intractable severity of CRSwNP and the fibrin polymerization ability of TGM isoform associated with the tissue eosinophil infiltration, which lead to NP formation and/or maintenance in CRSwNP. NP tissues (CRSwNP group) and uncinate process (UP) (control group) were collected from patients with CRSwNP and control subjects. We examined: (1) the expression level of TGM isoforms by using a real-time polymerase chain reaction (PCR) and the comparison to the issue eosinophil count in the CRSwNP group, (2) the location of specific TGM isoform in the mucosal tissue using immunohistochemistry, (3) the inflammatory cell showing the colocalization of specific TGM isoform in Laser Scanning Confocal Microscopy (LSCM) imaging, and (4) the fibrin polymerase activity of specific TGM isoform using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). A certain level of TGM 1, 2, 3, 5 expression was present in both the CRSwNP group and the control group. Only TGM 1 expression showed a positive significant correlation with the tissue eosinophil count in the CRSwNP group. The localization of TGM 1 in NP (CRSwNP) laid mainly in a submucosal layer as inflammatory cells and was at the cytoplasm in the tissue eosinophil. Fibrin polymerase activity of TGM 1 showed the same polymerase ability of factor XIIIA. TGM 1 might influence the NP formation and/or maintenance in CRSwNP related to the tissue eosinophil infiltration, which formed fibrin mesh composing NP stroma.

Utility of plasma circulating tumor DNA and tumor DNA profiles in head and neck squamous cell carcinoma.

Early recurrence detection of head and neck squamous cell carcinoma (HNSCC) is important for improving prognosis. Recently, circulating tumor DNA (ctDNA) has been reported to be useful in early detection or treatment response determination in various carcinomas. This study aimed to identify the utility of ctDNA for predicting recurrent metastasis in patients with HNSCC. We collected pre-treatment tissues (malignant and normal tissues) and multiple plasma samples before and after treatment for 20 cases of HNSCC treated with radical therapy. ctDNA was detected in pre-treatment plasma in 10 cases; however, there were no significant associations with tumor recurrence and staging. During follow-up, ctDNA was detected in 5 of the 7 plasma samples of recurrent cases but not in the 13 recurrence-free cases. Moreover, there was a significant difference in post-treatment relapse-free survival time between the groups with and without detected ctDNA (20.6 ± 7.7 vs. 9.6 ± 9.1 months, respectively; log-rank test, p < 0.01). Moreover, for two of the five cases with ctDNA detected after treatment, ctDNA detection was a more sensitive predictor of recurrence than imaging studies. ctDNA detection during treatment follow-up was useful in patients with HNSCC for predicting the response to treatment and recurrent metastasis.

Swallowing function after transoral surgery for laryngopharyngeal cancer.

Transoral surgery (TOS) has been widely used to treat laryngopharyngeal cancers. Although TOS is a minimally invasive procedure, postoperative complications, such as postoperative dysphagia, may occur, which can lead to a poor quality of life for patients undergoing TOS. This study aimed to investigate factors that may affect swallowing function in patients who underwent TOS for laryngopharyngeal cancers. Swallowing function of 84 patients who underwent endoscopic resection for oropharyngeal, hypopharyngeal, and supraglottic lesions was evaluated by the Functional Outcome Swallowing Scale, and predictors for postoperative dysphagia were identified. Multivariate analysis identified the following factors as independent predictors for postoperative dysphagia: Eastern Cooperative Oncology Group Performance Status (ECOG PS, p = 0.008), prior neck radiation therapy (p = 0.008), and operative time (p = 0.021). This study suggests that patients with poor ECOG PS or those who received prior neck radiation therapy should be fully assessed for preoperative swallowing function. In the future, we would like to clarify the criteria for preoperative swallowing evaluation to create a system that can identify patients suitable for TOS.

Distinct Gene Set Enrichment Profiles in Eosinophilic and Non-Eosinophilic Chronic Rhinosinusitis with Nasal Polyps by Bulk RNA Barcoding and Sequencing.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory disease with a high symptom burden, including nasal congestion and smell disorders. This study performed a detailed transcriptomic analysis in CRSwNP classified as eosinophilic CRS (ECRS), nonECRS according to the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) criteria, and a group of ECRS with comorbid aspirin intolerant asthma (Asp). Gene expression profiles of nasal polyps and the uncinate process in CRSwNP patients and normal subjects (controls) were generated by bulk RNA barcoding and sequencing (BRB-seq). A differentially expressed genes (DEGs) analysis was performed using DESeq2 software in iDEP to clarify any relationship between gene expression and disease backgrounds. A total of 3004 genes were identified by DEGs analysis to be associated with ECRS vs control, nonECRS vs control, and Asp vs control. A pathway analysis showed distinct profiles between the groups. A Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) showed distinct phenotype-specific pathways of expressed genes. In the specific pathway of "cytokine-cytokine receptor interaction", the differentially expressed genes were widely distributed. This study indicates that transcriptome analysis using BRB-seq may be a valuable tool to explore the pathogenesis of type 2 inflammation in CRSwNP.

A Case of Primary Osteosarcoma of the Mandible That Responded to Preoperative Chemotherapy: p16 as a Potential Prognostic Factor.

We report a case of mandibular osteosarcoma in a Japanese woman in her 70s who was p16-positive. Despite the rapid growth of the tumor, the patient responded well to chemotherapy and was then able to undergo surgery. Head and neck osteosarcoma (HNOS) is a very rare cancer, and although the importance of surgery has been pointed out, the effectiveness of chemotherapy is unclear. Resection margin negativity and response to chemotherapy have been reported as prognostic factors; another report assessed the effectiveness of the immunohistochemical expression of p16 protein as a predictor of response to chemotherapy.

Association Between Subjective Voice Assessment and Psychological Distress After Thyroidectomy.

PURPOSE: This study aimed to determine the association between postoperative subjective voice function and psychological distress in patients without laryngeal nerve injury after thyroidectomy. DESIGN: A prospective cohort study. METHODS: We investigated the factors associated with subjective voice function in patients who underwent thyroidectomy without laryngeal nerve injury between October 2018 and July 2020. The Voice Handicap Index was used to assess subjective voice function, the GRBAS (grade, roughness, breathiness, asthenia, strain) scale to assess objective voice, and the Hospital Anxiety and Depression Scale to assess psychological distress. FINDINGS: Among 39 patients who underwent thyroidectomy, 32 had no postoperative laryngeal nerve injury. Postoperative Voice Handicap Index was significantly associated with Hospital Anxiety and Depression Scale-Anxiety score after surgery (rs = 0.448, P = .010). CONCLUSIONS: In this study, an association was observed between subjective voice function and anxiety following surgery. The finding suggested that nurses and medical practitioners need to consider postoperative anxiety when evaluating patients' voice function after thyroidectomy.

Baseline Neutrophil-to-Lymphocyte Ratio and Glasgow Prognostic Score are Associated with Clinical Outcome in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma Treated with Nivolumab.

Recurrent or metastatic head and neck squamous cell carcinoma (R/MHNSCC) has a poor prognosis. Although nivolumab is approved in Japan for treating R/MHNSCC, the response rate is low. Therefore, identifying pretreatment prognostic factors is necessary. This study assessed the utility of the neutrophil-to-lymphocyte ratio (NLR) and Glasgow Prognostic Score (GPS) as biomarkers of response to nivolumab. We retrospectively collected the data of 56 R/MHNSCC patients treated with nivolumab between May 2017 and December 2019. The Kaplan-Meier method and log-rank test were used to estimate overall survival (OS) and progression-free survival (PFS), and multivariate Cox hazard regression analysis was used to identify independent predictors of survival. Patients with a low pretreatment NLR had prolonged OS, and patients with a low pretreatment GPS had increased OS and PFS. A performance score (PS) of 0-1, development of immune-related adverse events, and GPS of 0-1 were significantly associated with OS in multivariate analysis. In summary, baseline pretreatment NLR and GPS are independently associated with OS in R/MHNSCC patients treated with nivolumab. Administration of nivolumab while maintaining the PS reflects a immune status of the host and leads to a good OS.

Baseline neutrophil-to-lymphocyte ratio (NLR) is associated with clinical outcome in recurrent or metastatic head and neck cancer patients treated with nivolumab.

Background: Nivolumab has been approved for recurrent or metastatic head and neck cancer (R/M HNC) on March 2017 in Japan. Recently, many researchers have been actively studying the prognostic and predictive markers. However, they have not been clarified. In this study, we evaluate the prognostic and predictive markers of the anticancer effect of nivolumab.Objective: This study assessed baseline neutrophil-to-lymphocyte ratio (NLR) as a prognostic and predictive marker for nivolumab efficacy in patients with recurrent/metastatic head and neck cancer (R/M HNC).Material and methods: This retrospective cohort study used medical records of patients with R/M HNC treated with nivolumab from May 2017 to January 2018 at a university hospital in Japan.Results: Twenty-nine patients (median age, 64 years) were included. In univariate analyses, baseline NLR ≥5 was significantly associated with overall survival (HR 4.88; p = .045) and progressive disease (HR 5.0; p = .046). More patients with baseline NLR ≥5 changed from nivolumab to best supportive care, compared to patients with baseline NLR <5 (64.3% vs 26.7%, respectively).Conclusions and significance: Baseline NLR was associated with clinical benefit from nivolumab in patients with R/M HNC. We propose that baseline NLR be used as a predictive or prognostic marker for nivolumab efficacy in these patients.

Efficacy of anti-PD-1 therapy in a patient with brain metastasis of parotid carcinoma: A case report.

CheckMate 141, an open-label, randomized phase III trial of nivolumab, indicated that treatment with nivolumab prolonged overall survival of patients with platinum-refractory, recurrent head and neck squamous cell carcinoma. Herein, we describe a case of brain metastasis of parotid carcinoma in which a good response was achieved after nivolumab treatment. The patient was a 67-year-old woman with parotid carcinoma (cT4bN0M0) who received induction chemotherapy followed by chemoradiation. Computed tomography and magnetic resonance imaging performed 10 weeks after the primary treatment revealed a residual tumor and brain and lung metastases. Thereafter, chemotherapy comprising cisplatin, 5-FU, and cetuximab was performed. Unfortunately, the tumor volume increased 5 months after chemotherapy, after which she received immunotherapy with biweekly nivolumab. After six cycles of nivolumab administration, the brain and lung metastases shrank markedly. Nivolumab had an intracranial effect in the patient with brain metastases of parotid carcinoma. This case report highlights the efficacy of nivolumab in the management of head and neck cancer with brain metastasis.