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Pathological ocular angiogenesis is a significant cause of irreversible vision loss and blindness worldwide. Currently, most studies have focused on the angiogenesis factors in ocular vascular diseases, and very few endogenous anti-angiogenic compounds have been found. Moreover, although inflammation is closely related to the predominant processes involved in angiogenesis, the mechanisms by which inflammation regulates pathological ocular angiogenesis remain obscure. In this study, a vascular endothelial cells (VECs)-specific anti-angiogenic factor is identified, apoptosis signal-regulating kinase 1(ASK1)-interacting protein-1 (AIP1) as a key pathogenic regulator in a typical ocular angiogenesis model, oxygen-induced retinopathy (OIR), using single-cell RNA sequencing. It is demonstrated that AIP1 inhibited pathological angiogenesis by preventing a particular inflammatory death pathway, namely pyroptosis, in retinal VECs. The assembly of a noncanonical inflammasome is further uncovered, the NLRP12-ASC-caspase-8 inflammasome, which is promoted by decreased AIP1 in OIR. This inflammasome elicited gasdermin D (GSDMD)-dependent endothelial pyroptosis, which in turn promoted the release of vascular endothelial growth factor (VEGF) and interleukin (IL)-1β. Suppression of NLRP12-CASP8-GSDMD axis and AIP1 upregulation reduced VEGF signaling, limiting new vessel formation. These findings reveal a previously uncharacterized inflammatory angiogenic process involving VECs pyroptosis-inducing retinal neovascularization, paving the way for promising therapeutic avenues targeting angiogenesis via AIP1 or pyroptosis., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Objective: To assess the prevalence of depression, anxiety, insomnia and somatic symptom disorder (SSD) in chronic rhinosinusitis (CRS) patients who were waiting for surgery and to predict these psychiatric disorders using the 22-item Sinonasal Outcome Test (SNOT-22)., Design: A prospective cross-sectional study., Setting: The rhinology ward at our institution, a tertiary hospital., Participants: Adult patients (> 18 years) diagnosed with CRS who were admitted to the rhinology ward for endoscopic sinus surgery and were able to understand and complete the study questionnaires., Main Outcome Measures: Patient Health Questionnaire-9 (PHQ-9), Generalised Anxiety Disorder-7 (GAD-7), Insomnia Severity Index (ISI), Patient Health Questionnaire-15 (PHQ-15) and SNOT-22., Results: Of the 159 participants recruited, 58 were at risk of depression (defined by PHQ-9 > 4, while 25 with PHQ-9 > 9), 49 were at risk of anxiety (defined by GAD-7 > 4, while 25 with GAD-7 > 9), 81 were at risk of insomnia (defined by ISI > 7, while 51 with ISI > 14) and 69 were at risk of SSD (defined by PHQ-15 > 4, while 24 with PHQ-15 > 9). The SNOT-22 score was closely correlated with the scores of psychometric tests and was an independent predictor of these psychiatric disorders. Patients with a high SNOT-22 score (> 30) are likely to be affected by comorbid psychiatric disorders and should be further evaluated by otolaryngologists., Conclusion: Depression, anxiety, insomnia and SSD are prevalent in CRS patients. Otolaryngologists should have a low threshold to ask the patient about psychiatric symptoms, especially for patients with an SNOT-22 score > 30., (© 2024 John Wiley & Sons Ltd.)

Objective: To analyze the characteristics of patients with chronic rhinosinusitis (CRS) in the South China region based on pathological tissue biomarkers for regional comparison. Methods: The study population consisted of CRS in-patients in the First Affiliated Hospital of Sun Yat-sen University from October 2019 to June 2022. Among all the 181 cases, 123 of them were male and 58 were female, with an average age of 40. Retrospectively collected clinical data included demographic information, preoperative symptom scores, preoperative endoscopic images, preoperative paranasal sinus computed tomography scanning images, and inflammatory serological features. In addition, 52 variables of pathological tissue biomarkers including cytokines, chemokines and remodeling factors were collected for analysis. Cluster analysis was performed on the integrated data of training set through centroid-based clustering algorithm, and the inflammatory characteristics, post-operation control status, and airway diseases comorbidity of each endotype were analyzed. R project (version 4.2.2) was used in statistical analysis. Results: Cluster analysis divided 181 patients with CRS into 4 endotypes. Cluster 1 ( n =101, 55.80%) showed a locally low inflammatory status. Cluster 2 ( n =23, 12.71%) showed a mixed type of inflammation with predominantly neutrophilic inflammation and tissue remodeling. Cluster 3 ( n =11, 6.08%) was characterized by type Ⅱ inflammation without tissue remodeling. Cluster 4 ( n =46, 25.41%) was mainly characterized by type Ⅱ inflammation with tissue remodeling, showing higher comorbidity rate of asthma and allergic rhinitis. This cluster presented more severe symptoms, significant olfactory dysfunction, extensive overall inflammation based on objective examination results, a notable increase in total eosinophil count and proportion in peripheral blood, and the highest uncontrolled rate observed one year post-surgery. In comparison to other regions, the endotype classification of CRS in Southern China was characterized by a predominant pattern of locally low inflammatory status, a moderate level of type Ⅱ inflammation with tissue remodeling, and a lesser presence of neutrophilic inflammation. Conclusion: CRS distribution in Southern China is mainly characterized by low inflammatory endotype and type Ⅱ inflammation with tissue remodeling. The latter shows more severe clinical manifestations and higher uncontrol rate after surgery.

Purpose: The optimal treatment strategy for oropharyngeal cancer (OPC) is undetermined. We aim to compare the survival outcomes of OPC patients treated with upfront surgery versus definitive radiotherapy (RT)., Methods: A total of 8057 cases were retrieved from the Surveillance, Epidemiology, and End Results database. Primary endpoints were cancer-specific and noncancer mortalities, which were estimated using cumulative incidence function and compared by Gray's test. Univariate and multivariate Fine-Gray subdistribution hazard models were used to estimate the effects of treatment modality on mortality. Subgroup analyses were performed in propensity-score-matched cohorts. All the analyses were conducted separately in human papillomavirus (HPV)-negative and HPV-positive cohorts., Results: In the HPV-negative cohort, definitive RT was independently associated with increased risk of cancer-specific mortality (adjusted subdistribution hazard ratio [SHR], 1.31; 95% confidence interval [CI], 1.05-1.64; P = 0.017) and noncancer mortality (adjusted SHR, 1.59; 95% CI 1.13-2.25; P = 0.008). In the HPV-positive cohort, definitive RT was independently associated with increased risk of cancer-specific mortality (adjusted SHR, 1.51; 95% CI 1.23-1.85; P < 0.001) and noncancer mortality (adjusted SHR, 1.53; 95% CI 1.11-2.12; P = 0.009)., Conclusion: Upfront surgery is a superior treatment modality compared with definitive RT in terms of lowering cancer-specific and noncancer mortality in OPC patients, regardless of HPV status. Further prospective clinical trials are needed to confirm our findings., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Surgical treatment is playing an increasingly important role in the management of nasopharyngeal carcinoma (NPC). This consensus focuses on the indications for optimal surgery, and surgical methods in the whole process of treatment for NPC to provide a useful reference to assist these difficult clinical decisions., Methodology: A thorough review of available literature on NPC and surgery was conducted by the Association for the prevention and treatment of nasopharyngeal carcinoma in China, international exchange and promotion Association for medicine and healthcare, and the Committee on nasopharyngeal cancer of Guangdong provincial anticancer association. A set of questions and a preliminary draft guideline was circulated to a panel of 1096 experienced specialists on this disease for voting on controversial areas and comments. A refined second proposal, based on a summary of the initial voting and different opinions expressed, was recirculated to the experts in two authoritative medical science and technology academic groups in the prevention and treatment of NPC in China for review and reconsideration., Results: The initial round of questions showed variations in clinical practice even among similar specialists, reflecting the lack of high-quality supporting data and resulting difficulties in formulating clinical decisions. Through exchange of comments and iterative revisions, recommendations with high-to-moderate agreement were formulated on general treatment strategies and details of surgery, including indications and surgical approaches., Conclusion: By standardizing the surgical indications and practice, we hope not only to improve the surgical outcomes, but also to highlight the key directions of future clinical research in the surgical management of NPC.

Background: Induction chemotherapy (ICT) has become an initial treatment for head and neck squamous cell carcinoma (HNSCC). However, myelosuppression, an unavoidable side effect of ICT, significantly impacts follow-up treatment and prognosis. The main objective of this study is to identify the risk factors and predictors of myelosuppression and its different severity after ICT for ICT., Methods: We retrospectively reviewed medical records of 102 patients with hypopharyngeal cancer or oropharyngeal cancer who received initial ICT from 2013 to 2022. Univariate and multivariate logistic regression analyses were performed to identify risk factors for myelosuppression. Receiver-operating characteristic (ROC) curves were generated using the results of multiple logistic regression analysis to identify data with the highest sensitivity and lowest false-negative rate., Results: Pretreatment lymphocyte count (PLC) and the pretreatment platelet count (PPC) were identified as independent risk factors of myelosuppression ( P  < .05). Pretreatment hemoglobin count (PHC) was an independent risk factor for predicting myelosuppression in patients with grades III to IV disease. Patients with myelosuppression after ICT are more sensitive to chemotherapy., Conclusions: The PLC and PPC predicted myelosuppression in patients with HNSCC-administered ICT, and the PHC predicted grades III to IV myelosuppression. Myelosuppressed patients were more chemosensitive after ICT., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Background: Asthma is closely associated with lower socioeconomic status (SES), while the causal relationship between asthma and SES is undetermined. We aim to examine bidirectional relationships between asthma and SES using two-sample bidirectional Mendelian randomization (MR) for assessing potential causal inference., Methods: Education attainment (years of schooling), household income, and Townsend deprivation index (TDI) were 3 indicators of SES considered in our study. The genetic summary data for SES and asthma were retrieved from publicly available genome-wide association studies (GWASs) conducted in participants of European ancestry. The MR estimates from each genetic instrument were combined using random effects inverse variance weighted (IVW) meta-analysis, with alternate methods (eg, MR-Egger, weighted median). Horizontal pleiotropy was assessed by sensitivity analyses. Analyses were performed using the package TwoSampleMR in R., Results: The genetically instrumented years of schooling, household income, and TDI were not associated with the risk of asthma. However, according to the IVW method, 1.72 times increase in the odds ratio (OR) for asthma will lead to 0.024 standard deviation (SD) decrease in the years of schooling, 0.026 SD decrease in the household income, and 0.016 SD increase in the TDI. Although the substantial heterogeneity may undermine the reliability of results to some extent, sensitivity analyses further supported the causation of low household income by asthma., Conclusion: Our study indicated that genetically predicted asthma may play a causal role in lowering the household income. However, the causal role of lower SES in asthma development was not supported by our MR analyses. Considering the heterogeneity in the current study, additional MR studies are needed to validate the results in the future., (© 2023 The Authors.)

Objective: To compare the survival outcomes of early-stage oropharyngeal cancer (OPC) patients treated with upfront surgery versus definitive radiotherapy (RT)., Study Design: Retrospective observational study., Setting: Publicly available database., Methods: A total of 1877 patients with T1-2N0-1M0 OPC were retrieved from the Surveillance, Epidemiology, and End Results database. Primary endpoints were cancer-specific and noncancer mortalities, which were estimated using cumulative incidence function and compared by Gray's test. Univariate and multivariate Fine-Gray subdistribution hazard models were used to estimate the effects of treatment modality on mortality. Subgroup analyses were performed in propensity-score-matched cohorts. All the analyses were conducted separately in human papillomavirus (HPV)-negative and HPV-positive cohorts., Results: In the HPV-negative cohort, definitive RT was independently associated with increased risk of cancer-specific mortality (adjusted subdistribution hazard ratio [SHR], 2.29; 95% confidence interval [CI], 1.42-3.68; p = .001) and noncancer mortality (adjusted SHR, 2.74; 95% CI, 1.50-5.02; p = .001). In the HPV-positive cohort, definitive RT and upfront surgery could achieve similar cancer-specific and noncancer survival outcomes., Conclusion: Upfront surgery is associated with lower cancer-specific and noncancer mortality in HPV-negative early-stage OPC patients. However, in the setting of HPV-positive early-stage OPC with better prognosis, the 2 treatment modalities have similar efficacy in terms of cancer-specific and noncancer survival outcomes. In the future, carefully designed prospective clinical trials are needed to confirm our findings., (© 2023 American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

Objective: To investigate the prognoses of advanced (T3-T4) sinonasal malignancies (SNM). Methods: The clinical data of 229 patients with advanced (T3-4) SNM who underwent surgical treatments in the First Affiliated Hospital of Sun Yat-sen University from 2000 to 2018 were retrospectively analyzed, including 162 males and 67 females, aged (46.8±18.5) years old. Among them, 167 cases received endoscopic surgery alone, 30 cases received assisted incision endoscopic surgery, and 32 cases received open surgery. The Kaplan-Meier method was used to estimate the 3-year and 5-year overall survival (OS) and event-free survival (EFS). Univariate and multivariate Cox regression analyses were performed to explore significant prognostic factors. Results: The 3-year and 5-year OS were respectively 69.7% and 64.0%. The median OS time was 43 months. The 3-year and 5-year EFS were respectively 57.8% and 47.4%. The median EFS time was 34 months. The 5-year OS of the patients with epithelial-derived tumors was better than that of the patients with mesenchymal-derived tumors and malignant melanoma (5-year OS was respectively 72.3%, 47.8% and 30.0%, χ 2 =36.01, P <0.001). Patients with microscopically margin-negative resection (R0 resection) had the best prognosis, followed by macroscopically margin-negative resection (R1 resection), and debulking surgery was the worst (5-year OS was respectively 78.4%, 55.1% and 37.4%, χ 2 =24.63, P <0.001). There was no significant difference in 5-year OS between the endoscopic surgery group and the open surgery group (65.8% vs . 53.4%, χ 2 =2.66, P =0.102). Older patients had worse OS ( HR =1.02, P =0.011) and EFS ( HR =1.01, P =0.027). Patients receiving adjuvant therapy had a lower risk of death ( HR =0.62, P =0.038). Patients with a history of nasal radiotherapy had a higher risk of recurrence ( HR =2.48, P =0.002) and a higher risk of death ( HR =2.03, P =0.020). Conclusion: For patients with advanced SNM, the efficacy of endoscopic surgery can be comparable to that of open surgery when presence of safe surgical margins, and a treatment plan based on transnasal endoscopic surgery as the main comprehensive treatment is recommended.

Background: The impact of prior cancer history on survival of hypopharyngeal cancer patients remains unknown. The present study assessed the impact of prior cancer history on survival of patients with hypopharyngeal cancer., Methods: Patients with primary hypopharyngeal cancer diagnosed between 2004 and 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was conducted to balance baseline characteristics. One-to-one PSM, Kaplan-Meier method, and log-rank test were performed for survival analysis., Results: We included 5017 patients with hypopharyngeal cancer. Prior cancer history had no significant impact on overall survival of hypopharyngeal cancer patients in comparison with those without prior cancer history (p = 0.845, after PSM). Subgroup analysis showed that prior cancer history had no significant effect on overall survival of hypopharyngeal cancer patients., Conclusion: More hypopharyngeal cancer patients with prior cancer history should be considered for clinical trials. However, further prospective studies are needed., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: A growing number of clinical studies have confirmed that mRNA vaccines are effective in the treatment of malignant tumors; however, their efficacy in head and neck squamous cell carcinoma (HNSCC) has not been determined. This study aimed to identify the potential antigens of HNSCC for mRNA vaccine development and further distinguish the immune subtypes of HNSCC to select suitable patients for vaccination., Methods: We obtained gene expression profiles and corresponding clinical information of HNSCC from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). We visualized the genetic alterations of potential antitumor antigens using cBioPortal and obtained the immune gene set from Immport. The correlation between the expression of the identified antigens and the infiltration of antigen-presenting cells was visualized by Tumor Immune Estimation Resource (TIMER). We evaluated the potential biological functions of different samples and described the immune landscape., Results: Increased expression of three potential tumor antigens, CCR4, TMCO1, and SPACA4, associated with superior prognoses and infiltration of antigen-presenting cells, was identified in HNSCC. Three immune subtypes (C1-C3) with different molecular, cellular, and clinical characteristics were defined. Patients with C3 tumor had a better prognosis, representing an immune "cold" phenotype, which may be more suitable for mRNA vaccination. In addition, different immune characteristics were observed among the three immune subtypes, including markers of immune cells, mutation burden, expression of immune checkpoints, and immune modulators. Finally, the immune landscape of HNSCC showed a high degree of heterogeneity between individual patients., Conclusion: CCR4, TMCO1, and SPACA4 may be potential antigens for developing mRNA vaccines against HNSCC, especially for patients with C3 tumor. This study could provide a theoretical basis for the development of an mRNA vaccine against HNSCC.

Objective: To perform a cost-effectiveness analysis of endoscopic surgery versus intensity-modulated radiotherapy in the treatment of locally recurrent nasopharyngeal carcinoma (rNPC) from a health-economic perspective. Methods: From September 30, 2011 to January 16, 2017, a total of 200 patients were enrolled in the First Affiliated Hospital of Sun Yat-sen University, the First People's Hospital of Foshan, and Sun Yat-sen University Cancer Center. These patients were diagnosed as locally rT1-rT3 stage rNPC and were randomly assigned 1︰1 to the endoscopic surgery group (ENPG) and the intensity-modulated radiotherapy group (IMRT). There were 69 males and 31 females in ENPG, aging from 38 to 55 years. There were 72 males and 28 females in IMRT aging from 41 to 54 years. A retrospective cost-effectiveness analysis of the cohort was conducted using a Markov model. For each modality, data on survival and quality-adjusted life year (QALY) were sourced from relevant articles, and cost prices were included regarding treatment. Weibull distribution was used to estimate time-dependent transition probability. Beta-regression was used to convert the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) to utility. Results: The total cost of ENPG was 29 611.88 yuan, and the total cost of IMRT was 110 082.51 yuan. The incremental cost-effectiveness ratio (ICER) of ENPG versus radiotherapy for locally rNPC was -85 555.88 yuan/QALY, which was less than 3 times of Chinese gross domestic product (GDP) per capita. Sensitivity analysis showed that the cost of IMRT had the greatest impact on ICER. ICER was stable within 10% fluctuation of all the parameters. Conclusion: It is economical cost-effective to treat locally rNPC with ENGP versus IMRT.

Objective: To analyze the epidemiological characteristics of pulmonary tuberculosis (TB) in Guangdong province from 2016 to 2020 and provide evidence for the prevention and control of pulmonary TB. Methods: Descriptive epidemiological methods were used to analyze the incidence data of pulmonary TB reported in Guangdong from 2016 to 2020. Dynamic geometric series averaging and circular distribution methods were used to reveal the epidemic pattern. Results: A total of 356 748 pulmonary TB cases were reported in Guangdong from 2016 to 2020. The reported incidence of pulmonary TB decreased from 71.82/100 000 to 50.40/100 000 (trend χ 2 =6 905.57, P <0.001) , with an annual decline rate of 8.47%. Results from the circular distribution methods showed that the incidence peak would occur on May 4 th -5 th ( Z =1 176.96, P <0.05), and the incidence was relatively higher in May compared with other months. The area distribution of the pulmonary TB epidemic was uneven, and the reported average annual incidence was in the order of the eastern area (72.15/100 000), the northern area (68.14/100 000), the western area (65.31/100 000) and the Pearl River Delta area (60.05/100 000). Results of dynamic geometric series averaging analysis showed a declining trend in the reported incidence of pulmonary TB in all areas, except Dongguan, with the average growth rate less than 0.00. The decline rate in the eastern area (-10.90%) and northern area (-10.63%) was higher than the provincial average (-8.47%). The male to female ratio of the cases was 2.63∶1 (258 562∶98 186). The reported average annual pulmonary TB incidence in men (88.37/100 000) was higher than that in women (36.86/100 000), the difference was significant ( χ 2 =75.19, P <0.001). The reported incidence of pulmonary TB generally increased with age (trend χ 2 =123 849.44, P <0.001), and reached peak in age group ≥65 years (164.54/100 000). Dynamic geometric series averaging analysis showed an increasing trend of the reported pulmonary TB incidence in age groups 5-14 years and 15-24 years, with the average growth rate of 0.05% and 3.60%. Conclusions: The reported annual incidence of pulmonary TB showed a declining trend year by year in Guangdong from 2016 to 2020. However, an increasing incidence was reported in children and adolescents. Active case finding should be strengthened in the elderly and other key populations. With comprehensive TB prevention and control measures, it is still necessary to pay attention to the prevention and control of pulmonary TB in men, low-income groups and less developed areas in Guangdong and strengthen the comprehensive prevention and control in winter and spring.

Purpose: This study was performed to introduce a modified procedure involving a combination of bilateral vocal fold mucosal flaps and microsurgical sutures for the management of anterior glottic webs and to study its efficacy in decreasing the recurrence rate and improving voice quality., Methods: We retrospectively reviewed 102 patients with anterior glottic webs who underwent surgical treatment by a carbon dioxide laser incision with or without microsurgical suturing in our hospital from May 2014 to April 2021. We focused on the reoperation rate and the voice outcomes based on the 30-item Voice Handicap Index., Results: This study included 102 patients with anterior glottic webs, which were caused by papilloma excision and endoscopic laryngocarcinoma resection in 97 (95.1%) of the 102 patients; less common causes were infection and traumatic injury. All incisions were performed along the midline with a carbon dioxide laser under microscopy and a self-retaining laryngoscope; 37 (36.3%) patients underwent microsurgical suturing and 65 (63.7%) patients did not. The microsuture group had a lower reoperation rate (χ 2 = 7.069, P = 0.0078) and higher voice quality (t = 2.054, P = 0.0462) than the non-microsuture group., Conclusions: We introduced a modified procedure that can both decrease the recurrence rate and improve the voice quality in patients with anterior glottic webs. Hence, this combination therapy involving bilateral vocal fold mucosal flaps and microsurgical sutures is worthy of clinical application and promotion., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2022 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose: The aim of this study was to retrospectively evaluate the oncologic outcomes of sinonasal malignancies (SNMs) of various histologic subtypes and investigate the impact of multimodality treatment on prognosis of SNM., Methods: SNM patients treated with curative-intent surgery from 2000 to 2018 were included. The primary outcomes were overall survival (OS). Survival was then assessed through Cox proportional hazards models., Results: Three hundred and three patients were eligible for the analysis. The 5-year OS and event-free survival (EFS) were 61.0% (95% CI: 55.4%-67.1%) and 46.2% (95% CI: 40.4%-52.7%). The 5-year OS was the worst for malignant melanoma and the best for adenocarcinoma. Patients who received surgery had better OS than those who only received radiotherapy and/or chemotherapy. Endoscopic surgery had better OS than the open approach ( p < 0.05). Microscopically margin-negative resection (R0 resection) significantly benefited OS and EFS ( p < 0.001). No significant difference in OS was observed between patients who received macroscopic complete resection (R1 resection) followed by adjuvant therapy and patients who received R0 resection. Older age (HR = 1.02, p = 0.02), R1 resection (HR = 1.99, p = 0.02), sinonasal surgical history of more than 3 months before diagnosis (HR = 2.77, p = 0.007), and radiotherapy history (HR = 3, p = 0.006) are risk factors for worse EFS., Conclusions: Curative-intent surgery is irreplaceable in the treatment of SNM. The endoscopic approach is an effective alternative to the open approach. EFS is worse among patients with older age, R1 resection, sinonasal surgical history of more than 3 months before diagnosis, and radiotherapy history., Competing Interests: All authors have completed the ICMJE uniform disclosure form. Y-HW reports that he is funded by the National Natural Science Foundation of China (NSFC) grants (81900918). W-PW reported that he was funded by the National Natural Science Foundation of China (NSFC) grants (82020108009 and 81870696), Guangdong Natural Science Foundation of China grants (2018B030312008), Guangdong Research Program of Key Fields in Province (2020B1111300003), and the Key-Area Research and Development of Guangdong Province (2020B1111190001). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Wen, Wei, Chen, Huang, Lu, Zheng, Li, Wen and Wen.)

Background: PD-1/PD-L1 blockade is a promising immunotherapeutic strategy with the potential to improve the outcomes of various cancers. However, there is a critically unmet need for effective biomarkers of response to PD-1/PD-L1 blockade., Materials and Methods: Potential biomarkers of response to PD-1/PD-L1 blockade were obtained from the Cancer Treatment Response gene signature Database (CTR-DB). A comprehensive pan-cancer analysis was done on The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) datasets. Correlations between gene expression and infiltration by immune cells were assessed using TIMER, EPIC, MCPcounter, xCell, CIBERSORT, and quanTIseq. Immunophenoscore (IPS) was used to assess the potential application of the biomarkers to all TCGA tumors., Results: Analysis of CTR-DB data identified CD69 and SBK1 as potential biomarkers of response to PD-1/PD-L1 blockade. Correlation analysis revealed that in various TCGA cancer datasets, CD69 expression level correlated positively with most immune checkpoints and tumor-infiltrating immune cells, while SBK1 expression level correlated negatively with infiltrating immune cells. IPS analysis demonstrated the ability of CD69 and SBK1 to predict PD-1/PD-L1 blockade responses in various cancers., Conclusion: CD69 and SBK1 are potential predictors of response to cancer immunotherapy using PD-1/PD-L1 blockade. These biomarkers may guide treatment decisions, leading to precise treatment and minimizing the waste of medical resources., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer SW declared a shared affiliation with the authors to the handling editor at time of review., (Copyright © 2022 Hu, Sun, Wen, Ma, Chen, Chen, Lei and Wen.)

Background: Treatments for cT1-2, N0 glottic squamous cell carcinoma (GLSCC) include endoscopic resection, open surgery, and radiotherapy. The purpose of this study was to compare the outcomes of three treatment modalities and provide reference data for treatment selection., Methods: In all, 4274 patients with cT1-2, N0 GLSCC underwent these three treatment modalities from 2004 to 2015 were identified from the Surveillance, Epidemiology, and End Results-18 database. Overall survival (OS) and disease-specific survival (DSS) of patients treated with the three modalities were compared., Results: In the entire cohort, there were no significant differences in 5-year OS and 5-year DSS among the three treatment groups. In subgroup analyses based on stage and age, endoscopic resection provided significantly better 5-year survival than radiotherapy for cT1, N0 patients aged <65 years, with an OS rate of 89.0% vs. 82.3% ( p  = 0.009) and a DSS rate of 95.6% vs. 88.2% ( p  = 0.021). For 5-year DSS, open surgery also had better outcomes than patients who received radiotherapy (5-year DSS: 98.5% vs. 88.2%, respectively; p  = 0.046)., Conclusions: To summarize, for cT1, N0 GLSCC patients younger than 65 years, surgical treatment (either endoscopic or open) appears to be superior to the radiotherapy, and endoscopic resection should probably be the first consideration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liang, Peng, Liao, Huang, Wen and Sun.)

Objectives: This study was performed to evaluate the significance of intraoperative preservation of the internal branch of the superior laryngeal nerve (ibSLN) during surgery for hypopharyngeal squamous cell carcinoma (HSCC)., Methods: Twelve patients with HSCC underwent surgery between January 2017 and December 2018. Sensation in the hypopharyngeal mucosa was tested using a flexible laryngeal endoscope on postoperative day 5., Results: Surgeries were successfully performed in 10 patients with HSCC arising from the internal wall of the pyriform fossa and in 2 patients with HSCC arising from the posterior wall of the hypopharynx. The main trunk of the ibSLN was preserved in all patients. Testing of sensation in the hypopharyngeal mucosa revealed the presence of the cough reflex in all patients. All patients achieved a full normal oral diet at a median of 8.5 days (range, 6-11 days) and removal of the tracheal tube at a median of 10 days (range, 7-12 days)., Conclusions: Our results showed that preservation of the ibSLN during surgery for HSCC is feasible and important in the recovery of sensation in the hypopharyngeal mucosa.

Macrophages constitute a major component in human hepatocellular carcinoma (HCC) and perform various functions to facilitate disease progression. Reprogramming or reconstituting the tumor surveillance phenotypes of macrophages represents an attractive immunotherapeutic strategy in cancer treatments. The current study identified CD169 as a potential target for macrophage repolarization since it signified a population of macrophages positively correlated with an activated immune signature and better prognosis of patients with HCC. In vitro experiments revealed that a low dose of type I interferon (IFN) could effectively reprogram human monocyte-derived macrophages to upregulate CD169 expression, and such induced CD169 + macrophages exhibited significantly enhanced phagocytotic and CD8 + T cell-activating capacities compared to controls. A low dose of IFNα also inhibited hepatoma growth in mice in vivo, presumably through polarizing the CD169 + macrophage population and enhancing CD8 + T cell activities. Notably, IFNα also induced substantial PD-L1 expression on macrophages in vivo, and thus blockade of PD-L1 could further increase the anti-tumor efficacy of IFNα in the treatment of HCC. We propose a low dose of IFNα in combination with a PD-L1 blocking agent as a potential anti-tumor therapeutic strategy via its effects on macrophage polarization., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Whether patients with medullary thyroid carcinoma (MTC) who have unresectable synchronous distant metastases should undergo primary surgical resection (PTR) remains controversial. This study aimed to identify predictive factors associated with the survival of such patients., Methods: We conducted a retrospective study of patients with MTC who were registered in the Surveillance, Epidemiology, and End Results registry. The overall and cancer-specific mortality rates were assessed using risk-adjusted Cox proportional hazards regression modeling and stratified propensity score matching., Results: One hundred and eight matched patients were assessed. Patients in the PTR group had lower overall mortality than did those in the non-PTR group. The 1-, 3-, and 5-year overall and cancer-specific survival rates in the PTR group were significantly higher., Conclusions: PTR appears to be the most appropriate intervention for patients with good performance status. Such patients are likely to benefit from surgery and to experience long-term stable disease., (© 2021 Wiley Periodicals LLC.)

Objective: To investigate the role of ferroptosis, an iron-dependent form of non-apoptotic cell death, in the head and neck squamous cell carcinoma (HNSCC) immune microenvironment., Materials and Methods: A list of ferroptosis-related genes was obtained from the FerrDb database. Gene expression data were acquired from the cancer genome atlas (TCGA) and analyzed using the R language. Protein-protein interaction analysis was conducted using STRING and GeneMANIA. The correlations between gene expression levels and a patient's survival were analyzed using GEPIA, the Kaplan-Meier estimate, and a multivariate Cox proportional hazards model. The expression results were verified using Oncomine and Human Protein Atlas data. We used the TIMER, GEPIA2, GEPIA2021, and TIMER2 databases to investigate the relationships between gene expression and infiltrating immune cells., Results: Analysis of differentially expressed genes (DEGs) identified nine each ferroptosis drivers and ferroptosis suppressors, among which four genes correlated with survival as follows: two drivers ( SOCS1 , CDKN2A ) associated with better survival and two suppressors ( FTH1 , CAV1 ) associated with poorer survival. Multivariate Cox survival analysis identified SOCS1 and FTH1 as independent prognostic factors for HNSCC, and their higher expression levels were verified using Oncomine and HPA data. The results acquired using TIMER, GEPIA2, GEPIA2021, and TIMER2 data revealed that the driver SOCS1 and the suppressor FTH1 independently correlated with M1 and M2 macrophage infiltration., Conclusions: The ferroptosis driver SOCS1 and suppressor FTH1 are independent prognostic factors and that correlate with M1 and M2 macrophage infiltration in HNSCC. Targeting ferroptosis-immunomodulation may serve as a strategy to enhance the activity of immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hu, Wen, Ma, Chen, Zeng, Wen and Sun.)

S100A9 is differentially expressed in various cell types and is associated with the development, progression and metastasis of various cancers. However, the expression, distribution, and clinical significance of S100A9 in hepatocellular carcinoma (HCC) remain unclear. In the present study, The Cancer Genome Atlas (TCGA) database was used to examine S100A9 gene expression in HCC; we found that S100A9 expression was associated with HCC prognosis. In addition, S100A9 protein expression was assessed by immunohistochemistry analysis of tissues from 382 HCC patients. We found that the infiltration of S100A9 + cells in both tumor and nontumor tissues could predict poor overall survival ( P = 0.0329, tumor; P = 0.0003, nontumor) and a high recurrence risk ( P = 0.0387, tumor; P = 0.0015, nontumor) in our tissue microarray analysis. Furthermore, immunofluorescence double staining revealed that the primary S100A9-expressing cells in adjacent nontumoral tissue were CD15 + neutrophils, and both CD68 + macrophages and CD15 + neutrophils expressed S100A9 in HCC tumor tissues. Taken together, the results suggest that high S100A9 + cell density predicts a poor prognosis in HCC patients, and S100A9 expression could potentially serve as an independent prognostic marker for HCC.

Background: Recent studies have shown that human nasal epithelial progenitor cells (hNEPCs) are characterized by poor proliferation capacities during chronic nasal inflammation., Objective: We sought to investigate the key molecular functions and candidates that contribute to the reduced growth potential of hNEPCs in chronically inflamed nasal mucosa., Methods: Nasal biopsy specimens were obtained from 28 patients with nasal polyps (NPs) and 13 healthy controls. hNEPCs from nasal samples were cultured for 3 consecutive passages, and their molecular and functional profiles were analyzed by RNA sequencing. The minichromosome maintenance protein (MCM) family gene MCM2 was validated in hNEPCs and tissue samples from patients with NPs and control subjects by cell cycle, quantitative PCR, and Western blot analyses; small interfering RNA-mediated knockdown assay; and immunofluorescent staining., Results: Compared with control hNEPCs, NP-derived hNEPCs showed (1) reduced growth kinetics, as evidenced by the colony-forming efficiency and doubling time; (2) inhibited cell cycle progression, as evidenced by gene ontology and/or pathway and cell cycle analyses; and (3) downregulated expression of MCM2, the key protein of the MCM complex, which is critical for DNA replication at the G1/S checkpoint. Moreover, hNEPCs with MCM2 knockdown showed a decreased proliferation rate, and the MCM2 protein level in basal cells was significantly lower in abnormally remodeled nasal epithelium than in normal epithelium., Conclusion: These results demonstrate inhibited cell cycle progression and MCM2 downregulation in basal or progenitor nasal epithelial cells from NP tissue, which may contribute to the decreased growth potential of hNEPCs in chronically inflamed upper airways., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Ferritin is the most important iron storage form and is known to influence tumor immunity. We previously showed that expression of ferritin light chain (FTL) and ferritin heavy chain (FTH1) subunits is increased in head and neck squamous cell carcinoma (HNSC). Here, we analyzed solid tumor datasets from The Cancer Genome Atlas and Genotype-Tissue Expression databases to investigate correlations between FTL and FTH1 expressions and (i) patient survival, using univariate, multivariate, Kaplan-Meier and Receiver Operator Characteristic analysis; and (ii) tumor-infiltrating immune cell subsets, using the bioinformatics tools Estimation of Stomal and Immune cells in Malignant Tumor tissues, Microenvironment Cell Population-counter, Tumor Immune Estimation Resource, and Tumor Immunology Miner. We found that FTL and FTH1 are upregulated and downregulated, respectively, in most of the human cancers analyzed. Tumor FTL levels were associated with prognosis in patients with lower grade glioma (LGG), whereas FTH1 levels were associated with prognosis in patients with liver hepatocellular carcinoma, HNSC, LGG, and kidney renal papillary cell carcinoma. In many cancers, FTL and FTH1 levels was significantly positively correlated with tumor infiltration by tumor-associated macrophages and T regulatory cells. These results suggest an important role for FTL and FTH1 in regulating tumor immunity to solid cancers.

Background: The role of surgery compared with reirradiation in the primary treatment of patients with resectable, locally recurrent nasopharyngeal carcinoma (NPC) who have previously received radiotherapy is a matter of debate. In this trial, we compared the efficacy and safety outcomes of salvage endoscopic surgery versus intensity-modulated radiotherapy (IMRT) in patients with resectable locally recurrent NPC., Methods: This multicentre, open-label, randomised, controlled, phase 3 trial was done in three hospitals in southern China. We included patients aged 18-70 years with a Karnofsky Performance Status score of at least 70 who were histopathologically diagnosed with undifferentiated or differentiated, non-keratinising, locally recurrent NPC with tumours confined to the nasopharyngeal cavity, the post-naris or nasal septum, the superficial parapharyngeal space, or the base wall of the sphenoid sinus. Eligible patients were randomly assigned (1:1) to receive either endoscopic nasopharyngectomy (ENPG group) or IMRT (IMRT group). Randomisation was done manually using a computer-generated random number code and patients were stratified by treatment centre. Treatment group assignment was not masked. The primary endpoint was overall survival, compared between the groups at 3 years. Efficacy analyses were done by intention to treat. Safety analysis was done in patients who received treatment according to the treatment they actually received. This trial was prospectively registered at the Chinese Clinical Trial Registry, ChiCTR-TRC-11001573, and is currently in follow-up., Findings: Between Sept 30, 2011, and Jan 16, 2017, 200 eligible patients were randomly assigned to receive either ENPG (n=100) or IMRT (n=100). At a median follow-up of 56·0 months (IQR 42·0-69·0), 74 patients had died (29 [29%] of 100 patients in the ENPG group and 45 [45%] of 100 patients in the IMRT group). The 3-year overall survival was 85·8% (95% CI 78·9-92·7) in the ENPG group and 68·0% (58·6-77·4) in the IMRT group (hazard ratio 0·47, 95% CI 0·29-0·76; p=0·0015). The most common grade 3 or worse radiation-related late adverse event was pharyngeal mucositis (in five [5%] of 99 patients who underwent ENPG and 26 [26%] of 101 patients who underwent IMRT). Five [5%] of the 99 patients who underwent ENPG and 20 [20%] of the 101 patients who underwent IMRT died due to late toxic effects specific to radiotherapy; attribution to previous radiotherapy or trial radiotherapy is unclear due to the long-term nature of radiation-related toxicity., Interpretation: Endoscopic surgery significantly improved overall survival compared with IMRT in patients with resectable locally recurrent NPC. These results suggest that ENPG could be considered as the standard treatment option for this patient population, although long-term follow-up is needed to further determine the efficacy and toxicity of this strategy., Funding: Sun Yat-sen University Clinical Research 5010 Program., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: To investigate the role of interleukin-33 (IL-33) in head and neck squamous cell carcinoma (HNSCC)., Materials and Methods: RNA-seq data of 520 cases of HNSCC were retrieved from The Cancer Genome Atlas. The tumor microenvironment was deconstructed by xCell using bulk RNA-seq data. The cohort was dichotomized by the median IL-33 expression level. Immune cell components and molecular markers were compared between the high and low IL-33 groups. The prognostic value of IL-33 was evaluated by the log-rank test. Differential gene expression analysis and KEGG pathway enrichment analysis were also conducted. The relationship between the IL-33 expression level and the abundance of its potential cellular sources was evaluated by Pearson's partial correlation test. Subgroup analysis was conducted in laryngeal, oropharyngeal, and oral cavity squamous cell carcinoma (LSCC, OPSCC, and OCSCC)., Results: The role of IL-33 in HNSCC was heterogeneous among tumors at different sites. In LSCC, IL-33 may increase the extent of malignancy of tumor cells and act as a pro-tumor factor. In OCSCC, IL-33 may play a role in orchestrating the immune responses against tumor cells and act as an antitumor factor. The role of IL-33 in OPSCC was undetermined. IL-33 in LSCC was mainly derived from endothelial cells, while IL-33 in OCSCC was mainly derived from endothelial and epithelial cells., Conclusion: According to the different sources of IL-33 in LSCC and OCSCC, we propose a hypothesis that stroma-derived IL-33 could favor tumor progression, while epithelial-derived IL-33 could favor antitumor immune responses in HNSCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Peng, Sun, Chen and Wen.)

Background: The prognostic role of the interval between disease onset and hospital admission (O-A interval) was undetermined in patients with the coronavirus disease 2019 (COVID-19)., Methods: A total of 205 laboratory-confirmed inpatients admitted to Hankou hospital of Wuhan from January 11 to March 8, 2020 were consecutively included in this retrospective observational study. Demographic data, medical history, laboratory testing results were collected from medical records. Univariate and multivariate logistic regression models were used to evaluate the prognostic effect of the O-A interval (≤7 versus >7 days) on disease progression in mild-to-moderate patients. For severe-to-critical patients, the in-hospital mortality and the length of hospital stay were compared between the O-A interval subgroups using log-rank test and Mann-Whitney U test, respectively., Results: Mild-to-moderate patients with a short O-A interval (≤7 days) are more likely to deteriorate to severe-to-critical stage compared to those with a long O-A interval (>7 days) [unadjusted odds ratio =2.93, 95% confidence interval (CI), 1.32-6.55; adjusted odds ratio =3.44, 95% CI, 1.20-9.83]. No association was identified between the O-A interval and the mortality or the length of hospital stay of severe-to-critical patients., Conclusions: The O-A interval has predictive values for the disease progression in mild-to-moderate COVID-19 patients. Under circumstances of the specific health system in Wuhan, China, the spontaneous healthcare-seeking behavior is usually determined by patients' own heath conditions. Hence, the O-A interval can be reflective of the natural course of COVID-19 to some extent. However, our findings should be validated further in other cohorts and in other health systems., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-5320). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Objective: To investigate the clinical efficacy of acellular dermis matrix combined with cervical strap muscle (ADM-CSM) as a composite tissue flap for repairing the laryngeal defect after partial laryngectomy. Methods: The medical records of 33 patients with laryngeal cancer who were diagnosed and treated at the First Affiliated Hospital of Sun Yat-sen University from January 2014 to December 2016 were retrospectively reviewed. The patients consisted of 32 males and 1 female with age range from 39 to 76 years. Laryngeal defects were repaired with ADM-CSM in 14 patients (2 for supraglottic laryngeal cancer, 12 for glottic laryngeal cancer) and with CSM fascial flaps in 19 patients (3 for supraglottic laryngeal cancer, 16 for glottic laryngeal cancer). Kaplan-Meier method was used to calculate the 3-year overall survival and local control rate. The functions of voice and swallowing after operation were evaluated by voice handicap index-30 (VHI-30) and MD Anderson dysphagia inventory. Univariate logistic regression analysis, t -test, and Mann-Whitney U test were used to compare the variables between the two groups. Results: The incidence of laryngeal stenosis was 2/14 in ADM-CSM group and 4/19 in CSM group. In the ADM-CSM group, 3-year overall survival and local control rates were 92.9% and 85.7%, respectively. In the CSM group, 3-year overall survival and local control rates were 78.9% and 84.2%, respectively. The time of operation(3 h vs . 4 h, Z =193.5, P <0.05), time of retaining the feeding tube(14 d vs . 17 d, Z =206.0, P <0.05), and length of stay(18.5 d vs . 22.1 d, t =-2.62, P <0.05) in the ADM-CSM group were significantly less than those in the CSM group. The quality of voice in the CSM group was better than that in the ADM-CSM group (66.85±27.65 vs .45.80±23.19, t =2.19, P <0.05), while swallowing function in the ADM-CSM group was better than that in the ACSM group (80.00[60.00, 80.00] vs .60.00[40.00, 80.00], Z =48.0, P <0.05). Conclusion: ADM-CSM is user-friendly control and safe composite tissue flap for repairing the laryngeal defect after partial laryngectomy, with less scar hyperplasia and higher satisfaction of swallowing function after operation.

Objectives: To develop a model that can predict the risk of hypothyroidism (HT) after intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC), and to accordingly recommend dose constraints., Materials and Methods: NPC patients treated between 2011 and 2015 were retrospectively reviewed. HT was defined by an abnormally high level of thyrotropin. The dosimetry parameters V x (percentage of thyroid volume receiving more than x Gy of radiation) and V a,b (percentage of thyroid volume receiving >a Gy, while ≤b Gy radiation) were calculated. The primary endpoint was the development of HT within the first 2 years after IMRT. The least absolute shrinkage and selection operator and multivariate logistic regression were used to identify predictors of HT., Results: A total of 545 patients were included in the analyses, with a median follow-up of 36 months. Of the 545 patients, 138 developed HT within 2 years, and the 2-year incidence of HT was 25.3%. In patients with thyroid volume >20 cm 3 , the 2-year incidence of HT was 11.7% (16/137); in patients with thyroid volume ≤20 cm 3 and V 30 , 60 ≤ 80%, the 2-year HT incidence was 19.9% (33/166); in patients with thyroid volume ≤20 cm 3 and V 30 , 60 > 80%, the 2-year incidence of HT was 36.8% (89/242)., Conclusion: Thyroid volume and V 30 , 60 could be reliable predictors of HT after IMRT for NPC. For patients with thyroid volume ≤20 cm 3 , thyroid V 30 , 60 ≤ 80% might be a useful dose constraint to adopt during IMRT planning., (Copyright © 2020 Peng, Mao, Huang, Guo, Ma, Wen and Tang.)

Background: The treatment effects of cumulative cisplatin dose (CCD) during radiotherapy (RT) following induction chemotherapy (IC) have not been determined for patients with locoregionally advanced nasopharyngeal carcinoma (NPC)., Methods: A total of 3460 patients with locoregionally advanced NPC who were treated with IC plus cisplatin-based concurrent chemoradiotherapy or RT alone were included in this retrospective study. Three CCD groups (0 mg/m 2  ⩽ CCD <100 mg/m 2 , 100 mg/m 2  ⩽ CCD <200 mg/m 2 , CCD ⩾200 mg/m 2 ) were balanced through the inverse probability of treatment weighting based on propensity scores estimated by a general boosted model. The primary endpoint was overall survival (OS); the secondary endpoints were distant metastasis-free survival (DMFS) and locoregional recurrence-free survival (LRFS)., Results: CCD ⩾200 mg/m 2 and <200 mg/m 2 exhibited similar treatment effects for OS and DMFS, and were both superior to CCD <100 mg/m 2 for OS and DMFS in patients with stage IVa NPC. The three CCD groups achieved similar treatment effects for patients with stage II-III NPC. After IC, CCD during RT appeared to exert little treatment effect on LRFS., Conclusion: The CCD during RT exerts treatment effects and improves OS by reducing the risk of distant metastasis for patients with stage IVa NPC following IC, and CCD <200 mg/m 2 (mainly 160 mg/m 2 in this group) is recommended. However, RT alone may be sufficient after IC in patients with stage II-III NPC., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2020.)

Objective: Studies on factors affecting pharyngocutaneous fistulas (PCFs) and PCF repair methods have been widely reported. However, the healing phases of PCF are unclear, and their elucidation could guide clinical treatment., Methods: Clinical stages of the PCF healing process were identified by a retrospective study of 39 patients with head and neck cancer who developed a PCF., Results: Different conservative treatments were performed in turn according to three defined stages of the PCF healing process: stage I (drainage and debriding period), stage II (pressure dressing period), and stage III (healing period). A 7-day course of antibiotic therapy was only performed in stage I in 23 patients. The PCF was cured in 30 (76.9%) of 39 patients; the remaining 9 patients underwent subsequent surgical interventions for PCF healing., Conclusion: The three stages of PCF healing have a certain reference value in guiding clinical treatments. Moreover, antibiotics should be used in stage I when signs of infection are present, but they should not be used in all three phases of conservative treatment., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Wei Sun et al.)

Objectives/hypothesis: Histopathological analysis of hair cell survival in human temporal bone sections has historically been binarized such that each hair cell row is rated as either present or absent, thereby greatly underestimating the amount of hair cell loss. Here, we describe and validate a technique to reliably assess fractional hair cell survival in archival sections stained with hematoxylin and eosin (H&E) using high-resolution light microscopy and optical sectioning., Study Design: Technique validation., Methods: Hair cell counts in archival temporal bone slide sets were performed by several observers using either differential interference contrast (DIC) or confocal microscopy of the endogenous eosin fluorescence in hair cells. As a further cross-check, additional decelloidinized sections were immunostained with hair cell markers myosin VI and VIIa., Results: Cuticular plates and stereocilia bundles are routinely resolvable in DIC imaging of archival H&E-stained human material using standard research-grade microscopes, allowing highly accurate counts of fractional hair cell survival that are reproducible across observer and can be verified by confocal microscopy., Conclusions: Reanalysis of cases from the classic temporal bone literature on presbycusis suggests that, contrary to prior reports, differences in audiometric patterns may be well explained by the patterns of hair cell loss., Level of Evidence: NA Laryngoscope, 130:487-495, 2020., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Sorafenib is the most widely used first-line treatment for patients with advanced hepatocellular carcinoma (HCC), but such treatment provides only limited survival benefits that might be related to the immune status of distinct tumor microenvironments. A fundamental understanding of the distribution and phenotypes of T lymphocytes in tumors will undoubtedly lead to the development of novel immunotherapeutic strategies that could possibly enhance the efficacy of sorafenib treatments., Methods: Flow cytometry, immunohistochemistry and immunofluorescence analyses were performed to detect the infiltration and distribution of various leukocyte populations, and the expression of different immune checkpoint molecules in fresh HCC tumor tissues. Correlations among indicating genes were calculated in 365 patients with HCC from The Cancer Genome Atlas (TCGA) data set, and the cumulative overall survival time was calculated using the Kaplan-Meier method. Moreover, role of adenosinergic pathway on sorafenib anti-tumor efficacy was investigated using both subcutaneous and orthotopic transplantation tumor model in immune competent C57BL/6 mice., Results: We revealed that levels of CD3 + and CD8 + T cells were significantly downregulated in HCC tumor tissue, so were the infiltration of CD169 + cells (a Mφ subpopulation with T cell activation capacities) and their contact with CD8 + cells in tumor milieus. Moreover, levels of PD-1 and CD39 expression were significantly upregulated in human HCC-infiltrating CD4 + and CD8 + T cells, and CD39 + CD8 + T cells exhibited a CD69 + PD-1 + perforin low IFNγ low "exhausted" phenotype. Levels of both CD39 + T cells infiltration and adenosine receptor ADORA2B expression in tumor tissues were negatively correlated with overall survival of patients with HCC. Accordingly, mice treated with sorafenib in combination with adenosine A 2B receptor blockage reagents exhibited significantly reduced tumor progression compared with control groups., Conclusions: These results suggest that adenosinergic pathway might represent an applicable target for sorafenib-combined-therapies in human HCC.

Objective: To investigate the anatomical and surgical approaches to middle cranial fossa through orbital lateral wall under endoscope. Methods: Cadaveric formalin fixed specimens and fresh colored silicone injected specimens were used for this study. All anatomic technical measurements were performed under 0° and 30° endoscope and infrared rays navigation. The surgical approach was designed with the bony opening on the lateral wall of orbit through which the lateral side of the middle cranial fossa could be directly entered under endoscope. One case of recurrent meningioma was performed through this surgical approach. SPSS 20.0 software was used for statistical analysis. Results: The approach can directly enter the middle cranial fossa and expose anatomic landmarks including superior orbital fissure, lateral side of cavernous sinus, foramen rotundum, foramen ovale, foramen spinosum, petrosal bone and others as well as Ⅱ, Ⅲ, Ⅳ, Ⅴ, Ⅵ cranial nerves under endoscope. The maximal bony opening through the lateral wall of orbit was measured, with a horizontal diameter of (1.38±0.68) cm, a vertical diameter of (2.02±0.32) cm, a depth of (1.44±0.42) cm from bony opening margin to the dura. The recurrent meningioma involving lateral side of the middle skull base was successfully removed by this surgical approach through lateral wall of orbit. Conclusion: Lateral transorbital endoscopic approach to the lateral side of middle skull base is a safe, feasible, and minimally invasive method, which allows surgeons to directly manipulate diseases involving this area with good visualization and minimal invasion under endoscope.

Background: There are currently no data predicting chemosensitivity of induction chemotherapy (ICT) for hypopharyngeal squamous cell carcinomas (SCC)., Methods: Associations between immune cells and overall response (OR) to ICT and changes in immune cells during ICT were observed in 40 patients with hypopharyngeal SCC undergoing ICT., Results: CD4 + and CD8 + T-cell and regulatory T-cell (Treg) frequencies reached diagnostic accuracy for OR to ICT. OR rate was significantly higher in CD4 + -high T cell, CD8 + -high T cell, and low Treg groups. A transient reduction in Tregs and increases in Tregs in the non-OR and OR groups were observed during the course of ICT. Conversely, increases in CD8 + T cells and reductions in CD8 + T cells in the non-OR and OR groups were observed., Conclusion: High CD4 + T-cell, high CD8 + T-cell, and low Treg frequencies can be predictors for high efficacy of ICT in patients with hypopharyngeal SCC., (© 2019 Wiley Periodicals, Inc.)

Regulatory T cells (Tregs) mediate immunosuppressive signals that can contribute to the progression of head and neck squamous cell carcinoma (HNSCC). Interleukin-33 (IL-33) is defined as an 'alarmin', an endogenous factor that is expressed during tissue and cell damage, which has been shown to promote Treg proliferation in non-lymphoid organs. However, the interaction between IL-33 and Tregs in the HNSCC tumor microenvironment remains uncertain. In this study, we examined IL-33 + and Foxp3 + cells by immunohistochemistry in 68 laryngeal squamous cell cancer patients, followed by functional analysis of IL-33 in Tregs. In addition, the suppressive function of Tregs was assessed by cell proliferation assays. The level of stromal IL-33 was significantly upregulated in advanced versus early stage HNSCC patients and positively correlated with Foxp3 + Treg infiltration as well as a poor prognosis. ST2 is regarded as the only receptor of IL-33. Infiltrated ST2-expressing Tregs were responsive to IL-33, and the percentage of Tregs was increased upon IL-33 stimulation. Functional investigation demonstrated that IL-33 increased the proportion of Foxp3 + GATA3 + Tregs and improved the suppressive functions of Tregs by inducing IL-10 and TGF-β1 as well as decreasing the proliferation of responder T cells. Blockade of ST2 abrogated the immunosuppression caused by IL-33. Our data demonstrate that stromal IL-33 both expands the Treg population and enhances their functions in the tumor microenvironment. Furthermore, stromal IL-33 has prognostic value for tumor progression. Thus, stromal IL-33 is a potential target for future HNSCC immunotherapy.

Background: Induction chemotherapy (ICT) has become an initial treatment for late-stage hypopharyngeal squamous cell carcinoma (SCC); however, there are no data regarding ICT sensitivity for this population., Objective: This study investigated the predictive value of various inflammation markers for ICT responses in hypopharyngeal SCC., Methods: The data from 72 patients who received initial ICT treatment were obtained and associations between pretreatment inflammation markers and overall responses to ICT were calculated., Results: According to receiver operating characteristic curves, pretreatment lymphocyte count (PLC), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) achieved diagnostic accuracy for overall responses to ICT. These indicators were classified into two groups according to their cut-off values. Overall response rates were significantly higher in the low PLC (p < 0.01), high NLR (p = 0.035), and high PLR (p = 0.012) groups., Conclusion: Our results showed that low PLC, high NLR, and high PLR are predictors of positive responses to ICT in hypopharyngeal SCC patients., (© 2019 S. Karger AG, Basel.)

Background: Regulatory T cells (Tregs) have become promising candidates for immunotherapy in allergic rhinitis (AR). The contributing role of tolerogenic dendritic cells (tDCs) in the augmentation of Tregs in AR remains to be determined., Methods: The properties of tDCs in expanding Tregs and their potential to ameliorate AR were evaluated in vitro and in vivo., Results: Monocyte-derived tDCs stimulated with Dermatophagoides pteronyssinus allergen 1 favored the generation of activated Tregs (aTregs) and suppressed effector T-cell responses in a transforming growth factor-beta/interleukin-10 (TGF-β/IL-10)-dependent manner in vitro. The adoptive transfer of tDCs inhibited allergic airway inflammation in the mouse model, whereas depletion of CD25 + cells or blocking TGF-β/IL-10 signaling eliminated the inhibitory effect, indicating that Tregs were involved in the anti-inflammatory activity of tDCs., Conclusion: Our data show that tDCs are a potential therapeutic target in AR., (© 2018 ARS-AAOA, LLC.)

Background: Group 2 innate lymphoid cells (ILC2s) were closely associated with asthma. However, there were no perspective studies about the effects of glucocorticoid on ILC2s in asthma patients. Our objective was to perform a perspective study and evaluate the ILC2 activity after glucocorticoid therapy in asthma patients., Methods: The asthma and asthma with allergic rhinitis patients were treated with glucocorticoid for 3 months. The circulating ILC2 levels were evaluated. The effects of glucocorticoid on ILC2s and possible signalling pathways were investigated in vitro., Results: The patients were well-controlled, and the high ILC2 levels were significantly decreased at 1 and 3 months after treatment. Peripheral blood monocytes from allergic patients produced dramatic IL-5, IL-13 and IL-9 in response to IL-25, IL-33 plus IL-2, and glucocorticoid significantly decreased their levels. Moreover, ILC2s were identified to be the predominant source of IL-5, IL-13 and IL-9, and glucocorticoid treatment was able to reverse their high levels. STAT3, STAT5, STAT6, JAK3 and MEK signalling pathways were proved to be involved in regulating ILC2 activity under the glucocorticoid treatment., Conclusion: The data suggested that glucocorticoid administration could be effective in treating asthma by regulating ILC2s via MEK/JAK-STAT signalling pathways. This provides a new understanding of glucocorticoid application in regard to allergic diseases., (© 2018 The Authors. Allergy Published by John Wiley & Sons Ltd.)

Objective: To determine the correlation between the expression of IL-33 and significance in cancer biologial and patient's prognosis in head and neck squamous cell carcinoma (HNSCC). Method: Twenty pairs of tumor tissue and adjacent normal tissue were collected. qRT-PCR and immunohistochemistry (IHC) were used to detect the expression of IL-33 mRNA and protein in tissues. Correlation between IL-33 expression with clinicopathologic features of 107 HNSCC patients were analyzed. Result: IL-33 mRNA and protein expression levels in normal tissue were higher than paired tumor tissue. IL-33 level was significantly lower in patients with advanced T stages, lymph node metastases and advanced clinical stages, IL-33 expression was higher in well differentiated tumor than moderate or poor differentiated tumor. Low IL-33 expression predicts poor prognosis. Multivariate analysis indicated that IL-33 expression was an independent predictive factor. Conclusion: IL-33 is related with the clinicopathological features in HNSCC and could be an independent predictor of HNSCC prognosis., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)