[Tislelizumab monotherapy for the treatment of recurrent/metastatic head and neck squamous cell carcinoma].

Objective:The aim of this retrospective study is to evaluate the safety and efficacy of tislelizumab in patients with recurrent/metastatic head and neck squamous cell carcinoma. Methods:Six patients with recurrent/metastatic head and neck squamous cell carcinoma who received tislelizumab monotherapy in our hospital from 2018 to 2020 were retrospectively analyzed. The information of sex, age, TNM stage, efficacy, and adverse reactions were collected. All patients were recruited from the RATIONALE 102 study. The primary end point was the objective response rate, and other end points included progression-free survival and overall survival. We performed tumor immune-related gene sequencing and transcriptome sequencing analysis on the tumor tissues of the patient, and used bioinformatics methods to enrich immune cells and analyze signaling pathways. All analyses were performed using R 4.1. 0 software, SPSS Statistics 24.0 software and GraphPad Prism 8. Results:As of May 31, 2020, the median follow-up time was 26.35 months. The objective response rate with tislelizumab was 50.0%, the median progression-free survival was 6.44 months, and the estimated median survival was 20.07 months. The incidence of grade 3 or higher adverse reactions was 66.7%, including hyponatremia, hypokalemia, hypercalcemia, etc. The expression of macrophage, Treg and neutrophil-related genes are higher in immune-sensitive patients, and the signaling pathways of the intestinal immune network for IgA production, graft versus host disease and autoimmune thyroid disease are significantly activated. Conclusion:Tislelizumab was found to be controllable and tolerable in patients with recurrent/metastatic head and neck squamous cell carcinoma. The response to tislelizumab is related to immune cell infiltration and activation of immune-related signaling pathways.

Prognostic Significance of a Model Based on Acetaldehyde Dehydrogenase 2 Genetic Polymorphisms in Laryngeal Carcinoma.

OBJECTIVE: Because of the high costs associated with early-stage laryngeal carcinoma diagnosis and prognosis prediction, this study attempts to find valuable targets to establish a novel predictive model by focusing on the aldehyde dehydrogenase 2 (ALDH2) genotype and other peripheral blood markers. STUDY DESIGN: Retrospective study. SETTING: Tertiary comprehensive hospital. METHODS: From January 2011 to January 2021, 362 cases of laryngeal carcinoma were included and divided into 2 groups in this retrospective analysis. Information on medical history, alcohol, and tobacco consumption habits, ALDH2 genotypes, and other peripheral blood markers was collected. Endpoints of the current study included disease-free survival and overall survival. A nomogram model for overall survival was established and evaluated using receiver operating characteristic (ROC) curves. RESULTS: A total of 236 patients were included in the training cohort, and the other 126 were included in the validation cohort. The median follow-up of the patients was 9.6 years (interquartile range: 7.5-12.5 years). Peripheral fibrinogen, hemoglobin, and ALDH2 genotypes were significantly associated with an increase in laryngeal carcinoma mortality rate on Kaplan-Meier curves. The ROC curve showed that the effectiveness of overall survival prediction by the nomogram model was better than that of traditional clinical staging. CONCLUSION: A prognostic nomogram of laryngeal carcinoma patients involving ALDH2 and peripheral blood markers and T and N stages was constructed and validated.

Cancer associated fibroblast derived gene signature determines cancer subtypes and prognostic model construction in head and neck squamous cell carcinomas.

BACKGROUND: Head and neck squamous cell carcinomas (HNSCC) are the most common type of head and neck cancer with an unimproved prognosis over the past decades. Although the role of cancer-associated-fibroblast (CAF) has been demonstrated in HNSCC, the correlation between CAF-derived gene expression and patient prognosis remains unknown. METHODS: A total of 528 patients from TCGA database and 270 patients from GSE65858 database were contained in this study. After extracting 66 CAF-related gene expression data from TCGA database, consensus clustering was performed to identify different HNSCC subtypes. Limma package was used to distinguish the differentially expression genes (DEGs) between these subtypes, followed by Lasso regression analysis to construct a prognostic model. The model was validated by performing Kaplan-Meier survival, ROC and risk curve, univariate and multivariate COX regression analysis. GO, KEGG, GSEA, ESTIMATE and ssGSEA analyses was performed to explort the potential mechanism leading to different prognosis. RESULTS: Based on the 66 CAF-related gene expression pattern we stratitied HNSCC patients into two previously unreported subtypes with different clinical outcomes. A prognostic model composed of 15 DEGs was constructed and validated. In addition, bioinformatics analysis showed that the prognostic risk of HNSCC patients was also negatively correlated to immune infiltration, implying the role of tumor immune escape in HNSCC prognosis and treatment option. CONCLUSIONS: The study develops a reliable prognostic prediction tool and provides a theoretical treatment guidance for HNSCC patients.

Upregulated YTHDF1 associates with tumor immune microenvironment in head and neck squamous cell carcinomas.

Background: The nature of the tumor immune microenvironment (TME) is essential for the head and neck squamous cell carcinomas (HNSCC) initiation, prognosis, and response to immunotherapy. However, its gene regulatory network remains to be elucidated. Methods: To identify N6-methyladenosine (m6A) regulators that are involved in regulating the HNSCC TME, a computational screen was applied to The Cancer Genome Atlas (TCGA) HNSCC patient samples. The effects of mutation, copy number variation (CNV), and transcriptional regulation on YTHDF1 expression were analyzed. We analyzed the TME infiltration, cancer-immunity cycle activities, and YTHDF1-related Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Results: Among the 24 m6A regulators, 3 factors (YTHDF1, ELAVL1, and METTL3) were highly correlated with TME infiltration. As the top candidate, YTHDF1 was up-regulated and amplified in HNSCC. YTHDF1 promoter gains active histone marks and high chromatin accessibility, which might be transcriptionally activated by SOX2 and TP63. Moreover, YTHDF1 expression significantly associates with tumor malignant phenotype in HNSCC, which has a positive correlation with CD4+ T cells and a negative correlation with CD8+ T cells infiltration. Specifically, YTHDF1 expression is negatively associated with the cancer-immunity cycle and immune checkpoint inhibitors. In terms of the underlying biological mechanisms, YTHDF1 may interact with YTHDF2/3 to regulate several vital immune-related pathways. Conclusions: We identify YTHDF1 associated with TME and elucidate an underlying mechanism of immune escape in HNSCC, which might be used as a predictive marker in guiding immunotherapy.

A 25-gene panel predicting the benefits of immunotherapy in head and neck squamous cell carcinoma.

Tumor mutation burden high (TMB-H) is widely used in the guidance of immune checkpoint blocking (ICB) therapy for head and neck squamous cell carcinoma (HNSCC) patients. However, a few patients still had a poor response. Therefore, it is necessary to investigate a better model to guide ICB therapy. We constructed a genomic mutation model conducive to ICB therapy using an available HNSCC dataset. Moreover, treatment procedures for patients with HNSCC from our internal cohort confirmed this model. Here, a genomic mutation signature based on a list of 25 candidate genes that are favorable for immunotherapy was established. Patients with combined mutation had a respectable clinical outcome under ICB treatment. Notably, compared with patients who obtained TMB-H (TMB ≥ 10, but did not have combined mutation), those patients with TMB-L (TMB < 10) and combined mutation acquired remarkably beneficial overall survival. Moreover, the combined mutation signature predicting the survival status of patients was superior to TMB, with a Youden index of 0.55. Furthermore, higher immune cell infiltration levels, more active cancer-immunity cycle activities and immune response pathways were observed in patients with combined mutation. Finally, our internal cohort further confirmed that combined mutated patients can benefit from ICB therapy rather than any other patients.

[The research progress of PD-1/L1 inhibitors application in the treatment of head and neck squamous cell carcinoma].

Over the past few years, the FDA has approved PD-1/L1 inhibitor for the treatment of advanced head and neck squamous cell carcinoma, involving PD-1/L1 inhibitor monotherapy, PD-1/L1 inhibitor combined with chemoradiotherapy, combined with targeted therapy, combined with neoadjuvant immunotherapy and duplex-block of immune checkpoints and so on. Herein, we briefly review the latest research results in this field, and summarize the application and efficacy of immunotherapy in the treatment of head and neck squamous cell carcinoma， which will benefits such patients to develop more precise and individualized treatment plans.

Nogo-B promotes invasion and metastasis of nasopharyngeal carcinoma via RhoA-SRF-MRTFA pathway.

Distant metastasis remains the major cause for treatment failure in patients with nasopharyngeal carcinoma (NPC). Thus, it is necessary to investigate the underlying regulation mechanisms and potential biomarkers for NPC metastasis. Nogo-B (neurite outgrowth inhibitor B), encoded by reticulon-4, has been shown to be associated with the progression and advanced stage of several cancer types. However, the relationship between Nogo-B and NPC remains unknown. In this study, we found that higher expression of Nogo-B was detected in NPC cells and tissues. Higher expression of Nogo-B was statistically relevant to N stage, M stage, and poor prognosis in NPC patients. Further functional investigations indicated that Nogo-B overexpression could increase the migration, invasion, and metastasis ability of NPC cells in vitro and in vivo. Mechanistically, Nogo-B promoted epithelial-mesenchymal transition (EMT) and enhanced the invasive potency by interacting directly with its receptor NgR3 in NPC. Additionally, overexpression of Nogo-B could upregulate the protein levels of p-RhoA, SRF, and MRTFA. A positive relationship was found between the expression of Nogo-B and the p-RhoA in NPC patients as well as in mouse lung xenografts. Nogo-Bhigh p-RhoAhigh expression was significantly associated with N stage, M stage, and poor prognosis in NPC patients. Notably, CCG-1423, an inhibitor of the RhoA-SRF-MRTFA pathway, could reverse the invasive potency of Nogo-B and NgR3 in NPC cell lines, and decrease the expression of N-Cadherin, indicating that CCG-1423 may be a potential target drug of NPC. Taken together, our findings reveal that Nogo-B enhances the migration and invasion potency of NPC cells via EMT by binding to its receptor NgR3 to regulate the RhoA-SRF-MRTFA pathway. These findings could provide a novel insight into understanding the metastasis mechanism and targeted therapy of advanced NPC.

Polymorphisms of acetaldehyde dehydrogenase 2 and alcohol dehydrogenase 1B on the malignant transformation of vocal cord leukoplakia: A Chinese cohort.

Severe dysplasia of vocal cord leukoplakia (VCL) is more likely to occur in laryngeal carcinoma. Alcohol dehydrogenase and acetaldehyde dehydrogenase are both important enzymes in alcohol metabolism. This study aimed to investigate the incidence rate of malignant transformation in patients with VCL and the role of drinking habits and ALDH2 and ADH1B genetic polymorphisms in the malignant transformation of VCL. From January 2007 to January 2017, 136 cases of VCL were included in this retrospective analysis. Information on medical history, alcohol and tobacco consumption habits, ALDH2 and ADH1B genotypes, gastroesophageal reflux, and clinical pathological characteristics of VCL was collected. As a result, patients had a median follow-up of 9.6 years (interquartile range: 7.5-12.5 years). Twenty-three of 136 VCL patients finally developed laryngeal carcinoma, resulting in a cumulative malignant transformation rate of 16.9%. Cox regression analysis demonstrated that the independent risk factors for the malignant transformation of VCL included age over 60 years (hazard ratio [HR]: 13.872, p < 0.001), ALDH2 *2 allele status (HR: 9.694, p < 0.001), alcohol (HR: 10.011, p < 0.001) and tobacco (HR: 8.869, p < 0.001) exposure after operation, and drinking frequency (HR: 2.178, p = 0.016). Therefore, among patients over 60 years old, an ALDH2-inactivating mutation and excessive ethanol and tobacco consumption are potential contributors to the malignant transformation of VCL.

Identification of key genes for HNSCC from public databases using bioinformatics analysis.

BACKGROUND: The cause and underlying molecular mechanisms of head and neck squamous cell carcinoma (HNSCC) are unclear. Our study aims to identify the key genes associated with HNSCC and reveal potential biomarkers. METHODS: In this study, the expression profile dataset GSE83519 of the Gene Expression Omnibus database and the RNA sequencing dataset of HNSCC of The Cancer Genome Atlas were included for analysis. Sixteen differentially expressed genes were screened from these two datasets using R software. Gene Expression Profiling Interactive Analysis 2 (GEPIA2) was then adopted for survival analysis, and finally, three key genes related to the overall survival of HNSCC patients were identified. Furthermore, we verified these three genes using the Oncomine database and from real-time PCR and immunohistochemistry results from HNSCC tissues. RESULTS: The expression data of 44 samples from GSE83519 and 545 samples from TCGA-HNSC were collected. Using bioinformatics, the two databases were integrated, and 16 DEGs were screened out. Gene Ontology (GO) enrichment analysis showed that the biological functions of DEGs focused primarily on the apical plasma membrane and regulation of anoikis. Kyoto Encyclopedia of Genes and Genomes (KEGG) signalling pathway analysis showed that these DEGs were mainly involved in drug metabolism-cytochrome P450 and serotonergic synapses. Survival analysis identified three key genes, CEACAM5, CEACAM6 and CLCA4, that were closely related to HNSCC prognosis. The Oncomine database, qRT-PCR and IHC verified that all 3 key genes were downregulated in most HNSCC tissues compared to adjacent normal tissues. CONCLUSIONS: This study indicates that integrated bioinformatics analyses play an important role in screening for differentially expressed genes and pathways in HNSCC, helping us better understand the biomarkers and molecular mechanism of HNSCC.

Endoscope-Assisted Surgery of the Elongated Styloid Process Using the Retroauricular Approach: An Anatomic Study for Clinical Application.

PURPOSE: Surgical shortening of the styloid process (SP) mainly involves intraoral and transcervical approaches. A retroauricular incision was performed by our surgical team in endoscope-assisted shortening of the SP. This study aimed to clarify the important anatomic landmarks and adjacent structures around the SP through a retroauricular approach. METHODS: Fifteen fresh corpses (30 sides) were dissected via a retroauricular approach, and indexes were measured. RESULTS: The great auricular nerve (GAN) was divided into the anterior ear branch, lobe branch, and posterior ear branch. The distance from the branch of the GAN to the root of the ear lobe was 21.96 ± 2.55 mm. In the space around the SP, the vertical distance from the junction of the diabetic posterior belly and the mastoid tip to the SP was found to be 12.29 ± 2.46 mm, with a total distance between the skin in front of the mastoid and the facial nerve of 21.63 ± 3.27 mm. The distance between the facial nerve across the SP and the root of the SP was 11.93 ± 2.32 mm. CONCLUSIONS: The retroauricular incision starts from the level of the notch between the tragus and extends backward in an arc to avoid injury to the retroauricular branch of the GAN. The posterior fascia of the parotid gland and the leading edge of the sternocleidomastoid muscle, posterior belly of the digastric muscle, and styloid hyoid muscle are regarded as landmarks for the SP.