Identification of ferroptosis-associated tumor antigens as the potential targets to prevent head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma(HNSC)represents nearly 90%of all head and neck tumors.The current treatment modality for HNSC patients primarily involves surgical intervention and radiotherapy,but its therapeutic efficacy remains limited.The mRNA vaccine based on tumor antigens seems promising for cancer treatment.Ferroptosis,a novel form of cell death,is linked to tumor progression and cancer immunotherapy.Nevertheless,the effectiveness of ferroptosis-associated tumor antigens in treating HNSC remains uncertain.In this study,we identified three ferroptosis-associated tumor antigens,namely caveolin1(CAV1),ferritin heavy chain(FTH1),and solute carrier 3A2(SLC3A2),as being overexpressed and mutated based on data obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases.These antigens were strongly associated with poor prognosis and infiltration of antigen-presenting cells in HNSC.We further identified two ferroptosis subtypes(FS1 and FS2)with distinct molecular,cellular,and clinical properties to identify antigen-sensitive individuals.Our findings indicate that FS1 exhibits an immune“hot”phenotype,whereas FS2 displays an immune“cold”phenotype.Additionally,differential expression of immunogenic cell death modulators and immune checkpoints was observed between these two immune subtypes.Further exploration of the HNSC's immune landscape revealed significant heterogeneity among individual patients.Our findings suggest that CAV1,FTH1,and SLC3A2 are potential targets to prevent HNSC in FS2 patients.Overall,our research reveals the potential of ferroptosis-associated mRNA vaccines for HNSC and identifies an effective patient population for vaccine treatment.

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.

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.

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.

Boron neutron capture therapy: moving towards targeted therapy for locally recurrent head and neck squamous cell carcinoma

Locally recurrent head and neck squamous cell carcinoma(HNSCC)is often unresectable,and a repeat course of radiotherapy is associated with incremental toxicities.Boron neutron capture therapy(BNCT)is a novel targeted radiotherapy modality that can achieve a high dose gradient between cancerous and adjacent normal tissues.However,the relationships among the dose resulting from BNCT,tumor response to BNCT,and survival are not completely understood.Recently,a study published in Radiotherapy and Oncology investigated the efficacy of BNCT in the treatment of patients with locally recurrent HNSCC and the factors associated with favorable treatment response and survival.In this article,the findings,strengths and limitations of this study are discussed in depth,and the significance of the study and motivations for future research are highlighted.

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.

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.

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.

Association of microRNA polymorphisms with the risk of head and neck squamous cell carcinoma in a Chinese population:a case-control study

Background:MicroRNA(miRNA) polymorphisms may alter miRNA-related processes,and they likely contribute to cancer susceptibility.Various studies have investigated the associations between genetic variants in several key miRNAs and the risk of human cancers;however,few studies have focused on head and neck squamous cell carcinoma(HNSCC) risk.This study aimed to evaluate the associations between several key miRNA polymorphisms and HNSCC risk in a Chinese population.Methods:In this study,we genotyped five common single-nucleotide polymorphisms(SNPs) in several key miRNAs(miR-149 rs2292832,miR-146 a rs2910164,miR-605 rs2043556,miR-608 rs4919510,and miR-196a2 rs11614913) and evaluated the associations between these SNPs and HNSCC risk according to cancer site with a case-control study including 576 cases and 1552 controls,which were matched by age and sex in a Chinese population.Results:The results revealed that miR-605 rs2043556[dominant model:adjusted odds ratio(OR) 0.71,95%confidence interval(CI) 0.58-0.88;additive model:adjusted OR 0.74,95%CI 0.62-0.89]and miR-196a2 rs11614913(dominant model:adjusted OR 1.36,95%C11.08-1.72;additive model:adjusted OR 1.28,95%C11.10-1.48) were significantly associated with the risk of oral squamous cell carcinoma(OSCC).Furthermore,when these two loci were evaluated together based on the number of putative risk alleles(rs2043556 A and rs11614913 G),a significant locus-dosage effect was noted on the risk of OSCC(P_(trend) < 0.001).However,no significant association was detected between the other three SNPs(miR-149 rs2292832,miR- 146 a rs2910164,and miR-608 rs4919510) and HNSCC risk.Conclusion:Our study provided the evidence that miR-605 rs2043556 and miR-196a2 rs11614913 may have an impact on genetic susceptibility to OSCC in Chinese population.

Sustained complete response to erlotinib in squamous cell carcinoma of the head and neck:A case report

BACKGROUND Squamous cell carcinoma of head and neck(SCCHN) is the fifth most common cancer worldwide. Inhibition of epidermal growth factor receptor signaling has been shown to be a critical component of therapeutic option. Herein, we report a case of durable complete response to erlotinib.CASE SUMMARY An 81-year-old Caucasian male who presented with metastatic poorly differentiated squamous cell carcinoma of right cervical lymph nodes(levels 2 and 3). Imaging studies including(18)F-fluorodeoxyglucose positron emission tomography/computed tomography(CT) and contrast-enhanced CT scan of neck and chest did not reveal any other disease elsewhere. Panendoscopic examination with random biopsy did not reveal malignant lesion in nasopharynx,oropharynx, and larynx. He underwent modified neck dissection and postoperative radiation. Within 2 mo after completion of radiation, he developed local recurrence at right neck, which was surgically removed. Two mo after the salvage surgery, he developed a second recurrence at right neck. Due to suboptimal performance status and his preference, he started erlotinib treatment.He achieved partial response after first 2 mo of erlotinib treatment, then complete response after total 6 mo of erlotinib treatment. He developed sever skin rash and diarrhea including Clostridium difficile infection during the course of erlotinib treatment requiring dose reduction and eventual discontinuation. He remained in complete remission for more than two years after discontinuation of erlotinib.CONCLUSION We report a case of metastatic SCCHN achieving durable complete response from erlotinib. Patient experienced skin rash and diarrhea toxicities which were likely predictors of his treatment response.

Multimodality functional imaging using DW-MRI and 18F-FDG-PET/CT during radiation therapy for human papillomavirus negative head and neck squamous cell carcinoma: Meixoeiro Hospital of Vigo Experience

AIMTo noninvasively investigate tumor cellularity measured using diffusion-weighted magnetic resonance imaging (DW-MRI) and glucose metabolism measured by 18F-labeled fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) during radiation therapy (RT) for human papillomavirus negative (HPV-) head and neck squamous cell carcinoma (HNSCC).METHODSIn this prospective study, 6 HPV- HNSCC patients underwent a total of 34 multimodality imaging examinations DW-MRI at 1.5 T Philips MRI scanner [(n = 24) pre-, during- (2-3 wk), and post-treatment (Tx), and 18F-FDG PET/CT pre- and post-Tx (n = 10)]. All patients received RT. Monoexponential modeling of the DW-MRI data yielded the imaging metric apparent diffusion coefficient (ADC) and the mean of standardized uptake value (SUV) was measured from 18F-FDG PET uptake. All patients had a clinical follow-up as the standard of care and survival status was documented at 1 year.RESULTSThere was a strong negative correlation between the mean of pretreatment ADC (ρ = -0.67, P = 0.01) and the pretreatment 18F-FDG PET SUV. The percentage (%) change in delta (∆) ADC for primary tumors and neck nodal metastases between pre- and Wk2-3 Tx were as follows: 75.4% and 61.6%, respectively, for the patient with no evidence of disease, 27.5% and 32.7%, respectively, for those patients who were alive with disease, and 26.9% and 7.31%, respectively, for those who were dead with disease.CONCLUSIONThese results are preliminary in nature and are indicative, and not definitive, trends rendered by the imaging metrics due to the small sample size of HPV- HNSCC patients in a Meixoeiro Hospital of Vigo Experience.

Nimotuzumab with Concurrent Chemoradiation in Inoperable Locally Advanced Squamous Cell Carcinoma of Head and Neck: An Indian Experience

Background: The prognosis of patients with Epidermal Growth Factor Receptor (EGFR) overexpression in inoperable Locally Advanced Squamous Cell Carcinoma of Head and Neck (LASCCHN) remains poor. Nimotuzumab is an Anti EGFR humanized monoclonal antibody approved for treatment of LASCCHN, with concurrent chemoradiation. Objective: To assess the efficacy and safety of nimotuzumab with concurrent chemoradiation in inoperable LASCCHN patients. Methodology: This is a single-centre, single arm, retrospective study evaluating 35 patients with histologically confirmed inoperable LASCCHN (stages III-IV). The patients were administered IV cisplatin 50 mg/m2 and IV nimotuzumab 200 mg for 6 - 7 weeks, along with radiotherapy of 6600 - 7000 cGy over 35 fractions. Patients were evaluated over response evaluation criteria in solid tumors (RECIST) criteria 12 weeks after the last cycle of chemotherapy. They were also followed up for overall survival and relapse free survival. Results: The median duration of follow-up was 20 months. The most common site of cancer was oropharynx (68.6%). One patient was lost to follow up. Objective Response Rate (ORR) was observed in 97% of the patients with 17 patients (48.6%) achieving complete response (CR) and 17 patients (48.6%) achieving partial response (PR). The median overall survival was 22.7 months (95% CI: 21.30, 34.27). The median relapse free survival was 16.7 months (95% CI: 9.80, 24.50). Nimotuzumab was safe and well tolerated with few mild, self-limiting adverse events. Conclusion: Nimotuzumab with chemoradiation is a safe and efficacious option in patients with LASCCHN. Larger studies are needed to verify the same.

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.

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.

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.

Extraordinary Potential of High Technologies Applications: A Literature Review and a Model of Assessment of Head and Neck Squamous Cell Carcinoma (HNSCC) Prognosis

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cause of cancer mortality in the world and the 5th most commonly occurring cancer (Siegel, R. 2014). In the last few decades a growing interest for the emerging data from both tumor biology and multimodality treatment in HNSCC has been developed. A huge number of new markers need to be managed with bio-informatics systems to elaborate and correlate clinical and molecular data. Data mining algorithms are a promising medical application. We used this technology to correlate blood samples with clinical outcome in 120 patients treated with chemoradiation for locally advanced HNSCC. Our results did not find a significant correlation because of the sample exiguity but they show the potential of this tool.

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.