Fibroblast activation protein (FAP) as a prognostic biomarker in multiple tumors and its therapeutic potential in head and neck squamous cell carcinoma

Background:Fibroblast activation protein(FAP),a cell surface serine protease,plays roles in tumor invasion and immune regulation.However,there is currently no pan-cancer analysis of FAP.Objective:We aimed to assess the pan-cancer expression profile of FAP,its molecular function,and its potential role in head and neck squamous cell carcinoma(HNSC).Methods:We analyzed gene expression,survival status,immune infiltration,and molecular functional pathways of FAP in The Cancer Genome Atlas(TCGA)and Genotype Tissue Expression(GTEx)tumors.Furthermore,to elucidate the role of FAP in HNSC,we performed proliferation,migration,and invasion assays post-FAP overexpression or knock-down.Results:FAP expression was elevated in nine tumor types and was associated with poor survival in eight of them.In the context of immune infiltration,FAP expression negatively correlated with CD8+T-cell infiltration infive tumor types and positively with regulatory T-cell infiltration in four tumor types.Our enrichment analysis highlighted FAP’s involvement in the PI3K-Akt signaling pathway.In HNSC cells,FAP overexpression activated the PI3K-Akt pathway,promoting tumor proliferation,migration,and invasion.Conversely,FAP knockdown showed inhibitory effects.Conclusion:Our study unveils the association of FAP with poor tumor prognosis across multiple cancers and highlights its potential as a therapeutic target in HNSC.

PPP1R14A is Associated with Immunotherapy Resistance in Head and Neck Squamous Cell Carcinoma Identified by Single-Cell and Bulk RNA-Sequencing

Objective To identify nivolumab resistance-related genes in patients with head and neck squamous cell carcinoma(HNSCC)using single-cell and bulk RNA-sequencing data.Methods The single-cell and bulk RNA-sequencing data downloaded from the Gene Expression Omnibus database were analyzed to screen out differentially expressed genes(DEGs)between nivolumab resistant and nivolumab sensitive patients using R software.The Least Absolute Shrinkage Selection Operator(LASSO)regression and Recursive Feature Elimination(RFE)algorithm were performed to identify key genes associated with nivolumab resistance.Functional enrichment of DEGs was analyzed with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses.The relationships of key genes with immune cell infiltration,differentation trajectory,dynamic gene expression profiles,and ligand-receptor interaction were explored.Results We found 83 DEGs.They were mainly enriched in T-cell differentiation,PD-1 and PD-L1 checkpoint,and T-cell receptor pathways.Among six key genes identified using machine learning algorithms,only PPP1R14A gene was differentially expressed between the nivolumab resistant and nivolumab sensitive groups both before and after immunotherapy(P<0.05).The high PPP1R14A gene expression group had lower immune score(P<0.01),higher expression of immunosuppressive factors(such as PDCD1,CTLA4,and PDCD1LG2)(r>0,P<0.05),lower differentiation of infiltrated immune cells(P<0.05),and a higher degree of interaction between HLA and CD4(P<0.05).Conclusions PPP1R14A gene is closely associated with resistance to nivolumab in HNSCC patients.Therefore,PPP1R14A may be a target to ameliorate nivolumab resistance of HNSCC patients.

Nanomaterials for refining tumor microenvironment and enhancing therapy in head and neck squamous cell carcinoma: a review

Head and neck squamous cell carcinoma (HNSCC) is a prevalent and lethal solid tumor with a high mortality rate. Conventional cancertreatments, including surgery, radiotherapy, and chemotherapy, primarily target cancer cell eradication. However, uncontrolled proliferation and metabolic activities of these cells result in abnormalities in nutrient levels, hypoxia, and immunosuppression within the tumor microenvironment (TME). These factors constrain the efficacy of traditional treatments by promoting drug resistance, recurrence, and metastasis. Nanomaterials (NMs), such as nanozymes, can exhibit enzymatic activity similar to that of natural enzymes and offer a promising avenuefor the direct modification of the TME through catalytic oxidation-reduction processes. Moreover, they can serve as sensitizers or drug deliverycarriers, enhancing the efficacy of traditional treatment methods. Recently, NMs have garnered significant attention from oncologists. Thisreview begins with an overview of the composition and unique characteristics of the TME. Subsequently, we comprehensively exploredthe application of NMs in the treatment of HNSCC. Finally, we discuss the potential prospects and challenges associated with usingNMs in biomedical research.

ATM is a Prognostic Biomarker of Survival in Head and Neck Squamous Cell Carcinoma Patients

This review examines the role of ATM expression in head and neck squamous cell carcinoma(HNSCC).Analysis revealed significant overexpression of ATM in HNSCC cells compared to normal control samples,suggesting its involvement in cancer proliferation.ATM expression was notably upregulated across various clinical parameters,including different stages of cancer,racial groups,genders,and age groups,highlighting its role in cancer progression.Validation using the GEPIA2 tool confirmed strong ATM expression throughout all four stages of HNSCC,with the highest levels in stage II and the lowest in stage I.Promoter methylation analysis of ATM showed distinct patterns across different demographics and cancer stages,reinforcing its significance.The study also explored the relationship between ATM expression and patient outcomes using the KM plotter tool,finding that high ATM expression was associated with better overall survival(OS),while low ATM expression correlated with better disease-free survival(DFS).Genetic mutation analysis via cBioPortal identified minimal ATM mutations in HNSCC,including in-frame,splice,truncating,and missense mutations,suggesting their role in ATM dysregulation.The STRING tool was used to construct a protein-protein interaction(PPI)network,revealing that the ATM gene interacts with ten key genes(NBN,ATR,CHEK2,MDC1,MSH2,MSH6,MRE11,TP53,TP53BP1,BRCA1),indicating its involvement in various biological functions.Functional annotation of differentially expressed genes(DEGs)through the DAVID web server revealed their participation in critical biological processes,including double-strand break repair,cellular response to DNA damage,and DNA damage checkpoints.KEGG pathway analysis further linked DEGs to cellular senescence,platinum drug resistance,homologous recombination,p53 signaling,and the cell cycle,underscoring ATM’s multifaceted role in HNSCC.

PTEN as a Novel Diagnostic and Prognostic Biomarker of Head and Neck Squamous Cell Carcinoma

This review article explores phosphatase and tensin homolog(PTEN)’s role in head and neck squamous cell carcinoma(HNSCC)through comprehensive expression and methylation examinations,genetic mutation investigation,and prognostic evaluation.Using the UALCAN informational collection,PTEN expression examination uncovered a critical over-expression in HNSCC cells isolated from normal control samples,proposing its role in HNSCC multiplication.Further,analysis of PTEN expression across various clinical limits has shown critical up-regulation in different cancer development stages,racial groups,gender,and age classes within the context of HNSCC patients,suggesting its major role in cancer duplication.PTEN expression was validated by utilizing the GEPIA2.0 online tool,which showed PTEN expression was particularly significantly expressed in HNSCC cancer improvement when it appeared differently from normal control samples.Accordingly,examining PTEN validation across different phases of cancer advancement showed dysregulation in each of the four phases with the most raised expression in stage I and the least expression in stage IV.Thus,this study investigated the promoter methylation level of PTEN,figuring out a basic relationship between HNSCC samples and normal control samples.Analyzing promoter methylation across various clinical limits uncovered massive variations,with specific methylation patterns seen across malignant growth stages,race groups,gender,and age groups.Overall survival and disease-free survival(OS and DFS)utilizing the KM plotter tool showed a critical relationship between PTEN expression levels in HNSCC patients,showing high PTEN expression exhibited good overall survival when showed up distinctively comparable to low PTEN expression levels.In addition,in disease-free survival(DFS)evaluation HNSCC patients showing low PTEN expression experienced great DFS relative to HNSCC patients with high PTEN expression.Moreover,to validate PTEN expression against survival,the study examined the HNSCC patients into low and high-expression groups of PTEN.In HNSCC,low PTEN expression was connected with great overall survival(OS)when it appeared contrastingly relative to the high PTEN expression.In like manner,the study found that low PTEN expression level was connected with great DFS in HNSCC when it appeared contrastingly related to the high PTEN expression group.Genetic mutation analysis via cBioPortal identifies a minimal proportion of PTEN mutations in HNSCC,predominantly in-frame mutation,missense mutation,splice mutation,truncating mutation,and structural variant,indicating their basal significance in PTEN dysregulation within HNSCC.Further investigation of PTEN molecular components and their exchange inside the HNSCC microenvironment might disclose novel roads for designated treatment and accurate medication approaches in battling this harmful disease.

Application of single-cell RNA sequencing in head and neck squamous cell carcinoma

Single-cell RNA sequencing has been broadly applied to head and neck squamous cell carcinoma(HNSCC) for characterizing the heterogeneity and genomic mutations of HNSCC benefiting from the advantage of single-cell resolution. We summarized most of the current studies and aimed to explore their research methods and ideas, as well as how to transform them into clinical applications. Through single-cell RNA sequencing, we found the differences in tumor cells’ expression programs and differentiation tracks. The studies of immune microenvironment allowed us to distinguish immune cell subpopulations, the extensive expression of immune checkpoints, and the complex crosstalk network between immune cells and non-immune cells. For cancerassociated fibroblasts(CAFs), single-cell RNA sequencing had made an irreplaceable contribution to the exploration of their differentiation status, specific CAFs markers, and the interaction with tumor cells and immune cells. In addition, we demonstrated in detail how single-cell RNA sequencing explored the HNSCC epithelial-tomesenchymal transition(EMT) model and the mechanism of drug resistance, as well as its clinical value.

Glucocorticoid reduces the efficacy of afatinib on the head and neck squamous cell carcinoma

Glucocorticoids(GC)are widely used to counter the adverse events during cancer therapy;nonetheless,previous studies pointed out that GC may reduce the efficacy of chemotherapy on cancer cells,especially in epidermal growth factor receptor(EGFR)-targeted therapy of head and neck squamous cell carcinoma(HNSCC)remaining to be elucidated.The primary aim of the present study was to probe into the GC-induced resistance of EGFR-targeted drug afatinib and the underlying mechanism.HNSCC cell lines(HSC-3,SCC-25,SCC-9,and H-400)and the human oral keratinocyte(HOK)cell lines were assessed for GC receptor(GR)expression.The promoting tumor growth effect of GC was evaluated by the CCK-8 assay and flow cytometry.Levels of signaling pathways participants GR,mTOR,and EGFR were determined by quantitative polymerase chain reaction and western blotting.GC increased the proliferation of HNSCC cells in a GR-dependent manner and promoted AKT/mTOR signaling.But GC failed in counteracting the inhibition of rapamycin in the mTOR signaling pathway.Besides,GC also induced resistance to EGFR-targeted drug afatinib through AKT/mTOR instead of the EGFR/ERK signaling pathway.Thus,GCs reduce the efficacy of afatinib on HNSCC,implicating a cautious use of glucocorticoids in clinical practice.

Neoadjuvant Immunotherapy for Head and Neck Squamous Cell Carcinoma:Expecting Its Application in Temporal Bone Squamous Cell Carcinoma

Temporal bone malignant tumors are characterized by atypical clinical symptoms,and easy recurrence and metastasis.They account for 0.2%of head and neck tumors,and the most common pathological type is squamous cell carcinoma.Patients with squamous cell carcinoma of the temporal bone are often at advanced stages when diagnosed,and lose the chance for surgery.Neoadjuvant immunotherapy has recently been approved as the first-line treatment for refractory recurrent/metastatic squamous cell carcinoma of the head and neck.However,it remains to be determined whether neoadjuvant immunotherapy can be used as the first-line treatment for temporal bone squamous cell carcinoma to reduce the tumor stage before surgery,or as a palliative treatment for patients with unresectable advanced stage carcinoma.The present study reviews the development of immunotherapy and its clinical application in head and neck squamous cell carcinoma,summarizes the treatment of temporal bone squamous cell carcinoma,and prospects the neoadjuvant immunotherapy as the first-line treatment for temporal bone squamous cell carcinoma.

Comprehensive bioinformatics analysis and experimental validation:An anoikis-related gene prognostic model for targeted drug development in head and neck squamous cell carcinoma

We analyzed RNA-sequencing(RNA-seq)and clinical data from head and neck squamous cell carcinoma(HNSCC)patients in The Cancer Genome Atlas(TCGA)Genomic Data Commons(GDC)portal to investigate the prognostic value of anoikis-related genes(ARGs)in HNSCC and develop new targeted drugs.Differentially expressed ARGs were screened using bioinformatics methods;subsequently,a prognostic model including three ARGs(CDKN2A,BIRC5,and PLAU)was constructed.Our results showed that the model-based risk score was a good prognostic indicator,and the potential of the three ARGs in HNSCC prognosis was validated by the TISCH database,the model’s accuracy was validated in two independent cohorts of the Gene Expression Omnibus database.Immune correlation analysis and half-maximal inhibitory concentration were also performed to reveal the different landscapes of TIME between risk groups and to predict immuno-and chemo-therapeutic responses.Potential small-molecule drugs for HNSCC were subsequently predicted using the L1000FWD database.Finally,in vitro experiments were used to verify the database findings.The relative ARG mRNA expression levels in HNSCC and surrounding normal tissues remained consistent with the model results.BIRC5 knockdown inhibited anoikis resistance in WSU-HN6 and CAL-27 cells.Molecular docking,real-time PCR,cell counting kit-8(CCK-8),plate clone,and flow cytometry analyses showed that small-molecule drugs predicted by the database may target the ARGs in the prognostic model,inhibit HNSCC cells survival rate,and promote anoikis in vitro.Therefore,we constructed a new ARG model for HNSCC patients that can predict prognosis and immune activity and identify a potential small-molecule drug for HNSCC,paving the way for clinically targeting anoikis in HNSCC.

Regulation of RNA methylation and immune infiltration patterns by m5C regulators in head and neck squamous cell carcinoma

5-Methylcytosine(m5C)methylation contributes to the development and progression of various malignant tumors.This study aimed to explore the potential role of m5C methylation regulators(m5CMRs)in head and neck squamous cell carcinoma(HNSCC).Methods:The transcription data of HNSCC samples were obtained from The Cancer Genome Atlas(TCGA)and the Gene Expression Omnibus(GEO)databases.Subsequently,the m5C patterns in HNSCC were evaluated based on 14 m5CMRs.Then,the m5Cscore was developed to quantify m5C patterns by using principal component analysis(PCA)algorithms.Two single-cell RNA sequencing datasets and various methods were employed to assess the prognostic value and sensitivity to immunotherapy.Finally,key prognostic m5CMRs were identified using univariate COX regression analysis,and their clinical significance was validated based on the Human Protein Atlas(HPA)database and by using immunohistochemistry.Results:Two distinct m5C clusters were identified.m5C cluster A is characterized by an immune-activated microenvironment and is associated with a favorable prognosis.Notable differences were observed in prognosis,immune infiltration,and immunotherapy response between the high-and low-m5Cscore groups.Patients in the high-m5Cscore group exhibited high TMB,which is correlated with poor prognosis.The m5Cscore of epithelial cells in HNSCC was higher than that in other cells.Key prognostic m5CMRs,including NSUN2,DNMT3B,ALKBH1,and Y-Box Binding Protein 1(YBX1),were associated with poor prognosis.Conclusion:Our research indicates that in head and neck squamous cell carcinoma,the m5C modification profoundly affects the TME’s diversity and complexity,influencing prognosis and the success of immunotherapy.Targeting m5C regulatory elements may be a new method for enhancing the efficacy of immunotherapy in HNSCC.

Towards system genetics analysis of head and neck squamous cell carcinoma using the mouse model,cellular platform,and clinical human data

Head and neck squamous cell cancer(HNSCC)is a leading global malignancy.Every year,More than 830000 people are diagnosed with HNSCC globally,with more than 430000 fatalities.HNSCC is a deadly diverse malignancy with many tumor locations and biological characteristics.It originates from the squamous epithelium of the oral cavity,oropharynx,nasopharynx,larynx,and hypopharynx.The most frequently impacted regions are the tongue and larynx.Previous investigations have demonstrated the critical role of host genetic susceptibility in the progression of HNSCC.Despite the advances in our knowledge,the improved survival rate of HNSCC patients over the last 40 years has been limited.Failure to identify the molecular origins of development of HNSCC and the genetic basis of the disease and its biological heterogeneity impedes the development of new therapeutic methods.These results indicate a need to identify more genetic factors underlying this complex disease,which can be better used in early detection and prevention strategies.The lack of reliable animal models to investigate the underlying molecular processes is one of the most significant barriers to understanding HNSCC tumors.In this report,we explore and discuss potential research prospects utilizing the Collaborative Cross mouse model and crossing it to mice carrying single or double knockout genes(e.g.Smad 4 and P53 genes)to identify genetic factors affecting the development of this complex disease using genome-wide association studies,epigenetics,micro RNA,long noncoding RNA,lnc RNA,histone modifications,methylation,phosphorylation,and proteomics.

Optimization of Culture Medium and Transfection Method for Head and Neck Squamous Cell Carcinoma Organoids

[Objectives] To optimize the culture medium for head and neck squamous cell carcinoma patient-derived organoid and screen suitable cytokines;compare the transfection efficiency of direct transfection and short-term suspension transfection for organoid in matrigel. [Methods] Advanced DMEM/F12 medium, GlutaMax and HEPES buffer, nicotinamide, N-acetylcysteine, B27, A83-01, EGF, Y-27632 and Primocin primary cell antibiotics were prepared. On this basis, fibroblast growth factor 10(FGF10), Neuregulin 1, Noggin and R-spondin-1 were added in turn to prepare the selection medium, and the organoid diameter was used as the evaluation index to evaluate the effect of organoid medium. Using lentivirus, mCherry red fluorescent protein was transfected into HNSCC—PDO in different ways, and the transfection effect was evaluated by the fluorescence intensity of organoid sphere. [Results] Nrg1 Noggin and R-Spondin-1 promoted the growth of head and neck squamous cell carcinoma sphere(P<0.05) while FGF10 did not significantly promote the growth of head and neck squamous cell carcinoma sphere(P>0.05). Compared with direct transfection, short-term suspension transfection had higher transfection efficiency for HNSCC—PDO in matrigel. [Conclusions] R-Spondin-1 Nrg1 and Noggin may be the key cytokines in culture of HNSCC—PDO whereas FGF10 played an insignificant role in this study. Short-term suspension transfection could improve the transfection efficiency of lentivirus to HNSCC—PDO.

New perspectives on biology,disease progression,and therapy response of head and neck cancer gained from single cell RNA sequencing and spatial transcriptomics

Head and neck squamous cell carcinoma(HNSCC)is one of the most frequent cancers worldwide.The main risk factors are consumption of tobacco products and alcohol,as well as infection with human papilloma virus.Approved therapeutic options comprise surgery,radiation,chemotherapy,targeted therapy through epidermal growth factor receptor inhibition,and immunotherapy,but outcome has remained unsatisfactory due to recurrence rates of~50%and the frequent occurrence of second primaries.The availability of the human genome sequence at the beginning of the millennium heralded the omics era,in which rapid technological progress has advanced our knowledge of the molecular biology of malignant diseases,including HNSCC,at an unprecedented pace.Initially,microarray-based methods,followed by approaches based on next-generation sequencing,were applied to study the genetics,epigenetics,and gene expression patterns of bulk tumors.More recently,the advent of single-cell RNA sequencing(scRNAseq)and spatial transcriptomics methods has facilitated the investigation of the heterogeneity between and within different cell populations in the tumor microenvironment(e.g.,cancer cells,fibroblasts,immune cells,endothelial cells),led to the discovery of novel cell types,and advanced the discovery of cell-cell communication within tumors.This review provides an overview of scRNAseq,spatial transcriptomics,and the associated bioinformatics methods,and summarizes how their application has promoted our understanding of the emergence,composition,progression,and therapy responsiveness of,and intercellular signaling within,HNSCC.

Classificatory updates in verrucous and cuniculatum carcinomas:Insights from the 5^(th) edition of WHO-IARC head and neck tumor classification

The International Agency for Research on Cancer(IARC)and World Health Organization(WHO)collaboratively produce the'WHO Blue Books'essential tools standardizing the diagnostic process for human cancers.Regular updates in this classification accommodate emerging molecular discoveries,advances in immunohistochemical techniques,and evolving clinical insights.The 5th edition of the WHO/IARC classification of head and neck tumors refines the'Oral Cavity and Mobile Tongue'chapter,including sections for non-neoplastic lesions,epithelial tumors,and tumors of uncertain histogenesis.Notably,the epithelial tumors section is rearranged by tumor behavior,starting with benign squamous papillomas and progressing through potentially malignant oral disorders to oral squamous cell carcinoma(OSCC).The section on OSCC reflects recent information on epidemiology,pathogenesis,and histological prognostic factors.Noteworthy is the specific categorization of verrucous carcinoma(VC)and carcinoma cuniculatum(CC),both associated with the oral cavity and distinct in clinical and histologic characteristics.This classification adjustment emphasizes the oral cavity as their predominant site in the head and neck.Designating specific sections for VC and CC aims to provide comprehensive insights into these unique subtypes,elucidating their clinical features,distinct histological characteristics,prevalence,significance,and clinical relevance.By categorizing these subtypes into specific sections,the 5th edition of the WHO classification aims to provide a more nuanced and detailed account,enhancing our understanding of these specific variants within the broader spectrum of head and neck tumors.

Long-term survivor of metastatic squamous-cell head and neck carcinoma with occult primary after cetuximab-based chemotherapy:A case report

BACKGROUND Cancer of unknown primary(CUP)is a histological proven malignant tumor whose origin cannot be detected despite careful examination.Most cervical lymph node metastases in CUP(80%)will originate from head and neck sites,and 15%show infiltration of squamous carcinoma cells.The survival rates of CUP are poor:The 5-year-survival rate ranges from 10%to 15%.First-line treatment recommendation for advanced,inoperable squamous cell carcinoma of head/neck(HNSCC)was cetuximab plus platinum-fluorouracil chemotherapy until recently,when checkpoint inhibitors proved clinically beneficial therapies.CASE SUMMARY Here,we report a case of a 42-year-old female patient with cervical and abdominal lymph node and distant bone metastases of an occult primary of the head and neck(squamous cell carcinoma,human papillomavirus positive).The cancer was diagnosed during pregnancy 10 years ago,and after giving birth,the patient was treated with cetuximab plus platinum-fluorouracil chemotherapy achieving complete remission(CR).CR lasted 26 mo when new metastases(abdominal lymph node,lumbar vertebral body)emerged.Both manifestations were irradiated.From then on,the patient has not received any further treatment,and her disease has remained controlled.Ten years after the initial cancer diagnosis,the patient is still alive and in good health,representing an exceptional case of HNSCC.CONCLUSION This case illustrates the exceptional clinical course and benefits of combined therapy approaches in advanced metastatic HNSCC with occult primary.

Immune checkpoint inhibitors in head and neck squamous cell carcinoma:A systematic review of phase-3 clinical trials

BACKGROUND The outcomes of patients diagnosed with head and neck squamous cell carcinoma(HNSCC)who are not candidates for local salvage therapy and of those diagnosed with recurrent or metastatic disease are dismal.A relatively new systemic therapy option that emerged in recent years in the treatment of advanced HNSCC is immunotherapy using immune checkpoint inhibitors(ICIs).The safety profile and anti-tumor activity of these agents demonstrated in early phase clinical trials paved the way to the initiation of several promising phase-3 trials in the field.AIM To evaluate the evidence on the effectiveness of ICIs in HNSCC,based on published phase-3 clinical trials.METHODS We searched PubMed,Cochrane Library,Embase,and Scopus to identify published literature evaluating immunotherapy using ICIs in recurrent or metastatic HNSCC(R/M HNSCC)and locally advanced head and neck squamous cell carcinoma(LAHNSCC).We used a combination of standardized search terms and keywords including head and neck squamous cell carcinoma,recurrent,metastatic,locally advanced,immunotherapy,immune checkpoint inhibitors,monoclonal antibodies,programmed cell death protein-1(PD-1),programmed death-ligand 1(PD-L1),cytotoxic T-lymphocyte associated protein-4(CTLA-4),and phase-3 clinical trial.A sensitive search filter was used to limit our results to randomized controlled trials.RESULTS Five phase-3 clinical trials have reported the data on the effectiveness of immunotherapy in HNSCC so far:Four in R/M HNSCC and one in LAHNSCC.In patients with R/M HNSCC,anti-PD-1 agents nivolumab and pembrolizumab demonstrated improved survival benefits in the second-line treatment setting compared to the standard of care(standard singleagent systemic therapy).While the net gain in overall survival(OS)with nivolumab was 2.4 mo[hazard ratio(HR)=0.69,P=0.01],that with pembrolizumab was 1.5 mo(HR=0.80 nominal P=0.0161).The anti-PD-L1 agent durvalumab with or without the anti-cytotoxic T-lymphocyte associated protein-4 agent tremelimumab did not result in any beneficial outcomes.In the first-line setting,in R/M HNSCC,pembrolizumab plus platinum-based chemotherapy resulted in significant improvement in survival with a net gain in OS of 2.3 mo(HR=0.77,P=0.0034)in the overall population and a net gain in OS of 4.2 mo in the PD-L1 positive(combined positive score>20)population compared to standard of care(EXTREME regime).In patients with PD-L1 positive R/M HNSCC,monotherapy with pembrolizumab also demonstrated statistically significant improvement in survival compared to EXTREME.In LAHNSCC,immunotherapy using avelumab(an anti-PD-L1 agent)along with standard chemoradiation therapy did not result in improved outcomes compared to placebo plus chemoradiation therapy.CONCLUSION Anti-PD-1 agents provide survival benefits in R/M HNSCC in the first and second-line settings,with acceptable toxicity profiles compared to standard therapy.There is no proven efficacy in the curative setting to date.

Novel insights on oral squamous cell carcinoma management using long non-coding RNAs

Oral squamous cell carcinoma(OSCC)is one of the most prevalent forms of head and neck squamous cell carcinomas(HNSCC)with a poor overall survival rate(about 50%),particularly in cases of metastasis.RNA-based cancer biomarkers are a relatively advanced concept,and non-coding RNAs currently have shown promising roles in the detection and treatment of various malignancies.This review underlines the function of long non-coding RNAs(lncRNAs)in the OSCC and its subsequent clinical implications.LncRNAs,a class of non-coding RNAs,are larger than 200 nucleotides and resemble mRNA in numerous ways.However,unlike mRNA,lncRNA regulates multiple druggable and non-druggable signaling molecules through simultaneous interaction with DNA,RNA,proteins,or microRNAs depending on concentration and localization in cells.Upregulation of oncogenic lncRNAs and downregulation of tumor suppressor lncRNAs are evident in OSCC tissues and body fluids such as blood and saliva indicating their potential as valuable biomarkers.Targeted inhibition of candidate oncogenic lncRNAs or overexpression of tumor suppressor lncRNAs showed potential therapeutic roles in in-vivo animal models.The types of lncRNAs that are expressed differentially in OSCC tissue and bodily fluids have been systematically documented with specificity and sensitivity.This review thoroughly discusses the biological functions of such lncRNAs in OSCC cell survival,proliferation,invasion,migration,metastasis,angiogenesis,metabolism,epigenetic modification,tumor immune microenvironment,and drug resistance.Subsequently,we addressed the diagnostic and therapeutic importance of lncRNAs in OSCC pre-clinical and clinical systems,providing details on ongoing research and outlining potential future directions for advancements in this field.In essence,this review could be a valuable resource by offering comprehensive and current insights into lncRNAs in OSCC for researchers in fundamental and clinical domains.

Clinical impact of surveillance for head and neck cancer in patients with esophageal squamous cell carcinoma

To evaluate the clinical impact of surveillance for head and neck (HN) region with narrow band imaging (NBI) in patients with esophageal squamous cell carcinoma (ESCC).METHODSSince 2006, we introduced the surveillance for HN region using NBI for all patients with ESCC before treatment, and each follow-up. The patients with newly diagnosed stage I to III ESCC were enrolled and classified into two groups as follows: Group A (no surveillance for HN region); between 1992 and 2000), and Group B (surveillance for HN region with NBI; between 2006 and 2008). We comparatively evaluated the detection rate of superficial head and neck squamous cell carcinoma (HNSCC), and the serious events due to metachronous advanced HNSCC during the follow-up.RESULTSA total 561 patients (group A: 254, group B: 307) were enrolled. Synchronous superficial HNSCC was detected in 1 patient (0.3%) in group A, and in 12 (3.9%) in group B (P = 0.008). During the follow up period, metachronous HNSCC were detected in 10 patients (3.9%) in group A and in 30 patients (9.8%) in group B (P = 0.008). All metachronous lesions in group B were early stage, and 26 patients underwent local resection, however, 6 of 10 patients (60%) in group A lost their laryngeal function and died with metachronous HNSCC.CONCLUSIONSurveillance for the HN region by using NBI endoscopy increase the detection rate of early HNSCC in patients with ESCC, and led to decrease serious events related to advanced metachronous HNSCC.

Downregulation of iASPP Expression Suppresses Proliferation, Invasion and Increases Chemosensitivity to Paclitaxel of Head and Neck Squamous Cell Carcinoma In Vitro

Objective Our previous study has revealed that iASPP is elevated in human head and neck squamous cell carcinoma(HNSCC)and iASPP overexpression signifcantly correlates with tumor malignant progression and poor survival of HNSCC.This study investigated the function of iASPP playing in proliferation and invasion of HNSCC in vitro.Methods HNSCC cell line Tu686 transfected with Lentiviral vector-mediated iASPP-specific shRNA and control shRNA were named the shRNA-iASPP group and shRNA-NC group,respectively.The non-infected Tu686 cells were named the CON group.CCK-8 assay,flow cytometry,transwell invasion assay were performed to detect the effects of iASPP inhibition in vitro.Results Our results demonstrated that the proliferation of shRNA-iASPP cells at the time of 72 h(F=32.459,P=0.000),96 h(F=51.407,P=0.000),120 h(F=35.125,P=0.000)post-transfection,was significantly lower than that of shRNANC cells and CON cells.The apoptosis ratio of shRNA-iASPP cells was 9.42%±0.39%(F=299.490,P=0.000),which was significantly higher than that of CON cells(2.80%±0.42%)and shRNA-NC cells(3.18%±0.28%).The percentage of shRNA-iASPP cells in G0/G1 phase was 74.65%±1.09%(F=388.901,P=0.000),which was strikingly increased,compared with that of CON cells(55.19%±1.02%)and shRNA-NC cells(54.62%±0.88%).The number of invading cells was 56±4 in the shRNA-iASPP group(F=84.965,P=0.000),which decreased significantly,compared with the CON group(111±3)and the shRNA-NC group(105±8).The survival rate of shRNA-iASPP cells administrated with paclitaxel was highly decreased,compared with CON cells and shRNA-NC cells(F=634.841,P=0.000).Conclusion These results suggest iASPP may play an important role in progression and aggressive behavior of HNSCC and may be an efficient chemotherapeutic target for the treatment of HNSCC.

The prognostic value of Tiaml proteinexpression in head and neck squamous cellcarcinoma： a retrospective study

Introduction Head and neck squamous cell carcinoma （HNSCC） is a common cancer worldwide and has a poorprognosis. A biomarker predicting the clinical outcome of HNSCC patients could be useful in guiding treatment planning.Overexpression of theT lymphoma invasion and metastasis 1 （Tiaml） protein has been implicated in the migrationand invasion of neoplasms. However, its role in HNSCC progression needs to be further validated. We detectedthe expression of Tiaml in normal and tumor tissues and determined its association with clinical outcomes in patientswith HNSCCMethods： We measured the expression of Tiaml in normal and cancerous tissue samples from the patients withHNSCC treated at Sun Yat-sen University Cancer Center between 2001 and 2008. The Tiaml expression was scoredfrom 0 to 12 based on the percentage of positively stained cells and the staining intensity. We then determined thediagnostic performance of this score in predicting overall survival （OS） and disease-free survival （DFS）.Results： Of the 194 evaluable patients, those with advanced disease, lymph node metastasis at diagnosis, and recurrenceor metastasis during follow-up had a highertendency of having high Tiaml expression as compared with theircounterparts （P 〈 0.05）. The proportion of samples with high Tiaml expression was also higher in cancerous tissuesthan in non-cancerous tissues （57.7% vs. 13.9%, P 〈 0.001）. Cox proportional hazards regression analysis revealed thatTiaml expression scores of 5 and greater independently predicted short OS and DFS.Conclusion： TheTiaml expression is shown as a promising biomarker of clinical outcomes in patients with HNSCCand should be evaluated in prospective trials.