xCT as a Predictor for Survival in a Population-Based Cohort of Head and Neck Squamous Cell Carcinoma.

BACKGROUND: xCT, also known as SLC7A11 (solute carrier Family 7 Member 11), is a cystine/glutamate antiporter protein that mediates regulated cell death and antioxidant defense. The aim of this study was to investigate the effect of xCT on the outcome of patients diagnosed with new head and neck squamous cell carcinoma (HNSCC). METHODS: This retrospective cohort study utilized a population-based dataset, comprising all patients (n = 1033) diagnosed with new HNSCC during 2005-2015 in a population of 697,000 people. All patients (n = 585) with a tumor tissue sample available for immunohistochemical (IHC) staining were included. The follow-up rates were 97% and 81% at 3 and 5 years, respectively. Also, the specificity of the anti-xCT antibody was validated. RESULTS: The expression level and prognostic significance of xCT were strongly dependent on tumor location. In oropharyngeal squamous cell carcinoma (OPSCC) patients, xCT expression was a significant prognostic factor for 5-year overall survival (OAS) (HR: 2.71; 95% CI 1.67-4.39; p < 0.001), disease-specific survival (DSS) (HR: 2.58; 95% CI 1.47-4.54; p = 0.001), and disease-free survival (DFS) (HR: 2.69; 95% CI 1.55-4.64; p < 0.001). Five-year survival rates for OPSCC patients with high and low levels of xCT were OAS 34% versus 62%; DSS 51% versus 73%; DFS 43% versus 73%, respectively. According to a multivariate model adjusted for age, T-class, nodal positivity, and tobacco consumption, xCT was an independent prognostic factor for 3-year survival, in which it outperformed p16 IHC. Similar associations were not observed in squamous cell carcinomas of oral cavity or larynx. Regarding treatment modalities, xCT was most predictive in HNSCC patients who received radiotherapy. CONCLUSIONS: High xCT expression was associated with poor prognosis in OPSCC. Our findings suggest that joint analysis of xCT and p16 may add significant value in OPSCC treatment stratification.

Tertiary lymphoid structure-related score as a predictor for survival prognosis and immunotherapy response in head and neck squamous cell carcinoma.

Background: Substantial studies reveal that tertiary lymphoid structure (TLS) correlate with prognosis and immunotherapy response in various types of cancers. However, the predictive value of TLS, the specific immune cell subtype within TLS and their anti-tumor mechanisms remain unclear. Methods: Based on 23 TLS-related genes (TLSRGs), we utilized bioinformatics methods to construct a scoring system, named TLSscore. By integrating RNA and single-cell sequencing data, we assessed the utility of TLSscore in head and neck squamous cell carcinoma (HNSCC). Flow cytometric sorting was used to isolate specific T cells subtypes, in vivo and in vitro experiments were conducted to demonstrate its anti-tumor effects. Results: The TLSscore model was constructed and specific TLSscore-genes were found to consistently align with the spatial location of TLS. TLSscore has proven to be a robust predictive model for predicting survival prognosis, immune cell infiltration, somatic mutation and immunotherapy response. Notably, a specific PD1+CXCL13+CD8+T cell subtype was identified within TLS. Both in vivo and in vitro experiments demonstrated that PD1+CXCL13+CD8+T cell might represent a functional cell subtype exerting anti-tumor effects during the process of immune surveillance. Conclusions: Our study presents a predictive model for TLS, which can evaluate its presence and predicts survival prognosis and immunotherapy response in HNSSC patients. Additionally, we identify a specific subtype of T cells that might elucidate the mechanism of TLS function in anti-tumor activities. This T cell subtype holds the potential to be a prognostic marker and a target for adoptive cell therapy (ACT) in the future.

Construction of a novel tumor mutation burden-related mRNA signature for prognosis prediction in laryngeal squamous cell carcinoma.

Laryngeal squamous cell carcinoma (LSCC) is a common cancer with high mortality and tumor mutation burden (TMB), and high TMB is associated with favorable survival. The expression, mutation, and survival data were obtained from The Cancer Genome Atlas database. The mutation and differentially expressed genes were analyzed using limma R package. The function enrichment was analyzed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. TMB-related genes were identified by Weighted correlation network analysis. Univariate, multivariate and Lasso cox analyses were used to determine hub genes. The risk model and mRNA expression was validated by Receiver Operating Characteristic curve and qRTPCR. The immune infiltration was analyzed by xCELL. The drug sensitivity was determined through gene set cancer analysis database. We identified 1129 differentially expressed genes related to TMB. Enrichment analysis showed they were associated with immune response. ANKLE1 and PPP1R14A were screened out as hub genes. Receiver Operating Characteristic curve identified that the risk model had an effective prognosis value in progression-free interval of LSCC. Immune infiltration levels of 16 immune cells were significantly changed in high risk score group compared with low risk score group. ANKLE1 and PPP1R14A expressions were significantly upregulated in tumor group, which was consistent with qRTPCR results, and associated with better prognosis. ANKLE1 was negatively related to many drug sensitivities, while PPP1R14A was positively related to some drug sensitivities. We constructed an effective risk model constructed by ANKLE1 and PPP1R14A which was related to TMB in LSCC.

BANF1 is a novel prognostic biomarker linked to immune infiltration in head and neck squamous cell carcinoma.

Background: Barrier-to-autointegration factor 1 (BANF1) is an abundant and ubiquitously expressed postnatal mammalian protein that is overexpressed in numerous human cancers and can promote cancer cell proliferation. However, the role of BANF1 in prognosis remains unclear in head and neck squamous cell carcinoma (HNSCC). Methods: BANF1 expression data were obtained from the GEO and TCGA databases. We used Cox regression and Kaplan-Meier curves to assess the prognostic potential of BANF1. The role of BANF1-related genes was investigated using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses. In addition, we explored the link between BANF1, drug sensitivity, and the tumor immune microenvironment. Finally, functional in vitro and in vivo assays were used to explore the effects of BANF1 on tumor growth and metastasis of HNSCC. Results: BANF1 was markedly overexpressed in HNSCC and was correlated with clinicopathological characteristics. According to survival analysis, BANF1 can be inversely correlated with patient survival and can act as a prognostic risk indicator. IC50 values for chemotherapeutic treatments indicated that the group with high BANF1 expression was more responsive to most antitumor treatments. Furthermore, higher TIDE scores were observed in the low BANF1 expression group, indicating a decline in the efficacy of immune checkpoint inhibitor therapy. Functionally, the malignant biological behavior of HNSCC cell lines was inhibited when BANF1 expression was knocked down. Conclusion: BANF1 can promote tumor progression in patients with HNSCC. BANF1 shows great promise as a potential biomarker to assess the prognosis.

Cancer cell-specific PD-L1 expression is a predictor of poor outcome in patients with locally advanced oral cavity squamous cell carcinoma.

BACKGROUND: Locally advanced oral cavity squamous cell carcinoma (OCSCC) presents a significant clinical challenge despite being partially responsive to standard treatment modalities. This study investigates the prognostic implications of programmed death-ligand 1 (PD-L1) expression in these tumors, focusing on its association with treatment outcomes and the immune microenvironment. METHODS: We assessed tumor-infiltrating lymphocytes (TILs) in 132 patients with OCSCC to evaluate their impact on survival. Multiplex immunohistochemistry staining for CD3, CD68, CD11c, PD-L1, and P40 was used to explore correlations with clinical outcomes in patients with early-stage (n=22) and locally advanced (n=36) OCSCC. These initial findings were validated through differential gene expression analysis, gene set enrichment, and immune cell deconvolution in a The Cancer Genome Atlas cohort of 163 locally advanced OCSCC tumors. Additionally, single-cell RNA sequencing (scRNA-seq) on a smaller cohort (n=10) further characterized the PD-L1hi or PD-L1lo cancer cells in these tumors. RESULTS: Elevated PD-L1 expression was associated with poor outcomes in patients with locally advanced OCSCC undergoing standard adjuvant therapy, irrespective of "hot" or "cold" classification based on TILs assessment. PD-L1hi tumors exhibited an active immune response phenotype, enriched with M1 macrophages, CD8+ T cells and T regulatory cells in the tumor microenvironment. Notably, the negative impact of PD-L1 expression on outcomes was primarily attributed to its expression by cancer cells, rather than immune cells. Furthermore, scRNA-seq revealed that immune interactions were not essential for PD-L1 upregulation in cancer cells, instead, complex regulatory networks were involved. Additionally, PD-L1lo locally advanced tumors exhibited more complex pathway enrichment and diverse T-cell populations compared with those in the early-stage. CONCLUSION: Our findings underscore the prognostic significance of PD-L1 expression in locally advanced OCSCC, and unveil the complex interplay between PD-L1 expression, immune responses, and molecular pathways in the tumor microenvironment. This study provides insights that may inform future therapeutic strategies, including the possibility of tailored immunotherapeutic approaches for patients with PD-L1hi locally advanced OCSCC.

Retinol-binding protein type 1 expression predicts poor prognosis in head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent malignancy worldwide, with high incidence and poor survival rates. RBP1 is highly expressed in several kinds of cancer and plays a potential prognostic factor. However, the relationship between RBP1 and HNSCC were analyzed based on The Cancer Genome Atlas (TCGA) database. MATERIALS AND METHODS: RBP1 expression and clinical information were obtained from the Cancer Genome Atlas (TCGA) database. Tumor tissue and adjacent normal tissue of 6 HNSCC patients were collected to analyze the RBP1 mRNA expression level by quantitative PCR. Cox regression analysis was used to evaluate the prognostic values of RBP1 and clinical data in HNSCC. A nomogram was also established to predict the impact of RBP1 on prognosis based on Cox multivariate results. The methylation level of RBP1 in HNSC and its prognosis were analyzed in UALACN and MethSurv. Finally, the potential biological functions of RBP1 were investigated using gene set enrichment analysis (GSEA) and single sample GSEA (ssGSEA). RESULTS: The mRNA expression levels of RBP1 were highly expressed in HNSCC tissue. The Cox analyses demonstrate that highly-expressed RBP1 is an independent prognosis marker(P < 0.05). ROC curve analysis showed that performances of RBP1 (area under the ROC curve: 0.887, sensitivity: 84.1%, specificity: 79.9%). The methylation was increased in HNSCC patients compared with normal subjects(P < 0.05) and was associated with better prognosis at sites cg06208339, cg12298268, cg12497564, cg15288618, cg20532370, cg23448348. Additionally, RBP1 expression is mildly associated with immune cell infiltration and immunological checkpoints. CONCLUSION: RBP1 is overexpressed and associated with poor patient prognosis in head and neck squamous cell carcinoma.

Prognostic factors and risk-stratification model of recurrent or metastatic head and neck squamous cell carcinoma treated with cetuximab containing regimen.

BACKGROUND: In recent years, the addition of cetuximab to chemotherapy has improved treatment outcomes for patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). In this study, we present the real-world survival data of R/M HNSCC patients who received cetuximab-containing regimens from thirteen medical centers in Taiwan, as well as a three-level risk stratification model for this patient population. METHODS: This study enrolled R/M HNSCC patients from thirteen medical centers in Taiwan who received cetuximab-containing regimens from January 1, 2017 to June 6, 2022. The cases were divided into a training cohort and a validation cohort based on the start of treatment. Overall survival (OS) was evaluated in both cohorts and exploratory analysis was performed to identify associated adverse clinical and laboratory factors. The results of the exploratory analysis were used to construct a three-level risk stratification prediction model for OS. RESULTS: A total of 1434 patients with R/M HNSCC were enrolled in this study and received cetuximab-containing regimens. The overall population had a median OS of 8.57 months (95% CI: 8.07 - 9.08). Multivariate analysis of the training cohort identified poor ECOG performance status, heavy alcohol consumption, and prior adjuvant CCRT or lack of prior RT as adverse prognostic factors. Comparison of laboratory data between patients with OS≦6 and OS > 6 also revealed unfavorable factors, including increased white blood cell count, decreased hemoglobin level, increased platelet count, increased absolute neutrophil count, decreased absolute lymphocyte count, and increased neutrophil-to-lymphocyte ratio. Using forward prediction, a three-level risk stratification prediction model was constructed using the variables of ECOG performance status, alcohol consumption, skin metastasis, modality of radiation therapy, hemoglobin level, and neutrophil-to-lymphocyte ratio. The median OS in the low-risk, intermediate-risk, and high-risk groups were 12.02 months (95% CI 10.44-13.61), 7.5 months (95% CI 7.33-8.17), and 4.01 months (95% CI 3.94-4.08), respectively, with a log-rank test p-value < 0.001. CONCLUSION: This study presents a three-level risk stratification model with strong prediction ability for OS in R/M HNSCC patients who received cetuximab-containing regimens. The results are based on real-world data and may provide valuable information for clinicians in treatment planning and future drug development.

Overexpression of TPD52L2 in HNSCC: prognostic significance and correlation with immune infiltrates.

BACKGROUND: Evidence has been presented that the tumor protein D52 (TPD52) family plays a critical role in tumor development and progression. As a member of the TPD52 family, the changes in TPD52L2 gene status are instrumental in kinds of cancer development. However, its effects on patient prognosis and immune infiltration in Head and Neck Squamous Carcinoma (HNSCC) are still poorly understood. METHODS: The Tumor Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and c-BioPortal database was used to explore the expression pattern, prognostic value, and variation of gene status in HNSCC. The LinkedOmics database was used to obtain the co-expression genes of TPD52L2 and identify the diagnostic value of TPD52L2 in HNSCC. The correlations between TPD52L2 expression and six main types of immune cell infiltrations and immune signatures were explored using Tumor Immune Estimation Resource (TIMER). The correlation between TPD52L2 expression and immune checkpoint genes (ICGs) was analyzed by TCGA database. Immunohistochemistry (IHC) was performed to validate the expression of three ICGs (PDL1, PDL2, EGFR) and TPD52L2 using 5 paired HNSCC and normal head and neck tissues. Polymerase Chain Reaction (PCR) and Western Blot (WB) of HNSCC and normal head and neck cell lines were performed to verify the high level of TPD52L2 mRNA and protein expression. protein expression of TPD52L2 in pan-cancer was also validated using UALCAN. RESULTS: TPD52L2 was overexpressed in tumor tissues, and it predicted worse survival status in HNSCC. ROC analysis suggested that TPD52L2 had a diagnostic value. Multivariate Cox analysis identified TPD52L2 as an independent negative prognostic marker of overall survival. Functional network analysis suggested that TPD52L2 was associated with immune-related signaling pathways, cell migration pathways, and cancer-related pathways. High expression of TPD52L2 was associated with a more mutant frequency of TP53. Notably, we found that the expression of TPD52L2 was closely negatively correlated with the infiltration levels of 15 types of immune cells and positively correlated with several immune markers. PCR, WB experiments, and UALCAN database verified the high level of TPD52L2 mRNA and protein expression. CONCLUSION: TPD52L2 is upregulated in HNSCC, which is an independent factor for adverse prognosis prediction. It probably plays a role in the negative regulation of immune cell infiltration. TPD52L2 might be a promising prognostic biomarker and therapeutic target in HNSCC.

ITGA5 is associated with prognosis marker and immunosuppression in head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a major tumor that seriously threatens the health of the head and neck or mucosal system. It is manifested as a malignant phenotype of high metastasis and invasion caused by squamous cell transformation in the tissue area. Therefore, it is necessary to search for a biomarker that can systematically correlate and reflect the prognosis of HNSCC based on the characteristics of head and neck tumors. METHODS: Based on TCGA-HNSCC data, R software was used to analyze gene expression, correlation, Venn diagram, immune invasive and immunosuppressive phenotypes respectively. The intrinsic effect of ITGA5 on the malignant phenotype of HNSCC cells was verified by cell experiments. Immunohistochemical images from The Human Protein Atlas (THPA) database display the differences in the expression of related proteins in HNSCC tissues. Based on functional enrichment and correlation analysis, the prognostic value of ITGA5 for HNSCC was explored, and the expression level of ITGA5 may affect the chemotherapy of targeting the PI3K-AKT. RESULTS: In this study, the target gene ITGA5 may be identified as a valuable prognostic marker for HNSCC. The results of enrichment analysis showed that ITGA5 was mainly involved in the dynamic process of extracellular matrix, which may affect the migration or metastasis of tumor cells. Meanwhile, ITGA5 may be closely related to the infiltration of M2 macrophages, and its secretory phenotypes TGFB1, PDGFA and PDGFB may affect the immunosuppressive phenotypes of tumor cells, which reflects the systemic influence of ITGA5 in HNSCC. In addition, the expression levels of ITGA5 were negatively correlated with the efficacy of targeting PI3K-AKT chemotherapy. CONCLUSION: ITGA5 can be used as a potential marker to systematically associate with prognosis of HNSCC, which may be associated with HNSCC malignant phenotype, immunosuppression and chemotherapy resistance.

Identification and validation of M2 macrophage-related gene signature as a novel prognostic model for head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous tumor. Commonly used tumor staging don't sufficiently and accurately assess the prognosis of HNSCC patients, resulting in a lack of guidance for clinical treatment decisions. M2 macrophage infiltration has been shown to be strongly associated with the tumor prognosis. In this study, we used the Cancer Genome Atlas (TCGA) data to screen for genes co-expressed with M2 macrophages in HNSCC. We used univariate Cox regression to screen out the genes associated with HNSCC prognosis, and constructed a HNSCC prognosis model by Lasso regression analysis. The results confirmed that the model had good predictive value and accuracy for the prognosis of HNSCC patients by survival analysis, ROC curve and nomogram. We divided the HNSCC samples into high-risk and low-risk groups according to the risk score, and the results showed that patients in the high-risk group were more prone to genetic mutations and had a higher tumor mutational burden. In addition, there were significant differences between risk groups in terms of immune cell infiltration and drug sensitivity. The HNSCC prognostic model established in this study may provide guidance for clinical therapeutic decision-making and provide a theoretical foundation for the development of new immunotherapy methods.

Upfront Surgery Versus Upfront Concurrent Chemoradiotherapy as Primary Modality in Hypopharyngeal Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis.

IMPORTANCE: The management of hypopharyngeal squamous cell carcinoma (HPSCC) continues to be one of the most formidable challenges in the realm of head and neck oncology. OBJECTIVES: The aim of this meta-analysis was to evaluate the disparity in survival outcomes between upfront surgery and upfront concurrent chemoradiotherapy as the primary treatment modality in patients with HPSCC. DESIGN: Systemic review with meta-analysis. SETTING: The meta-analysis was conducted in strict accordance with the PRISMA guideline. A literature search through PubMed, EMBASE, and the Cochrane Library were conducted until January 2023. The adjusted hazard ratio (aHR) with 95% confidence intervals (CIs) of different survival outcomes were extracted and pooled. PARTICIPANTS: Studies that incorporated HPSCC patients without receiving induction chemotherapy. INTERVENTIONS: Upfront surgery versus upfront concurrent chemoradiotherapy. MAIN OUTCOME MEASURES: Overall survival (OS) and disease-free survival (DFS). RESULTS: Eight studies published between 2015 and 2023, with a pooled patient population of 1619, were included in this meta-analysis. The outcomes reveal that upfront surgery was notably linked with improved OS (aHR 0.66, 95% CI 0.57-0.78) and DFS (aHR 0.75, 95% CI 0.63-0.90). Subgroup analyses were conducted to investigate the impact of the overall stage of the tumor and the extent of surgery on OS. In patients with advanced HPSCC (stages III and IV), upfront surgery remained associated with better OS (aHR 0.65, 95% CI 0.56-0.77). Concerning the extent of surgery, both subgroups exhibited a superior OS outcome associated with upfront surgery (exclusive total laryngopharyngectomy group: aHR 0.54, 95% CI 0.39-0.75; total/partial laryngopharyngectomy group: aHR 0.71, 95% CI 0.59-0.84). CONCLUSIONS AND RELEVANCE: The results demonstrated that upfront surgery showed better OS and DFS than concurrent chemoradiation and remind the clinicians of the potential reduction in survival outcomes when choosing concurrent chemoradiotherapy as primary treatment.

Prognostic significance of adjuvant therapy and specific radiation dosages in Taiwanese patients with oral cavity cancer and extra-nodal extension: a nationwide cohort study.

BACKGROUND: The evidence for adjuvant chemoradiotherapy (CRT) of oral cavity squamous cell carcinoma (OCSCC) with extra-nodal extension (ENE) in National Comprehensive Cancer Network (NCCN) guidelines is derived from patients with head and neck cancer. The guidelines further suggest a radiation dose ranging from 6000 to 6600 cGy. In this nationwide study, we sought to evaluate the prognostic significance of adjuvant therapy and the specific radiation dosage in Taiwanese patients with pure OCSCC and ENE. METHODS: A retrospective analysis of 1577 OCSCC patients with ENE who underwent resection and received adjuvant CRT or radiotherapy (RT) between January 2011 and December 2020 was conducted. RESULTS: Multivariable analysis revealed that adjuvant RT, more than four pathologically positive nodes, and radiation dosage below 6000 cGy were independent risk factors for unfavorable 5-year disease-specific survival (DSS) and overall survival (OS). Comparing patients who received CRT (n = 1453) to those treated with RT (n = 124) before and after propensity score (PS) matching, the 5-year outcomes were as follows: before PS matching, DSS (54% versus 30%, p < 0.0001), OS (42% versus 18%, p < 0.0001); after PS matching (n = 111 in each group), DSS (52% versus 30%, p = 0.0016), OS (38% versus 21%, p = 0.0019). For patients who underwent CRT, the 5-year outcomes for different radiation dose groups (6600 - 7000 cGy, n = 1155 versus 6000 - 6500 cGy, n = 199) were as follows: before PS matching, DSS (52% versus 54%, p = 0.1904), OS (43% versus 46%, p = 0.1610); after PS matching (n = 199 in each group), DSS (55% versus 54%, p = 0.8374), OS (46.5% versus 46.3%, p = 0.7578). CONCLUSIONS: For OCSCC patients with ENE, our study shows CRT improved survivals than RT alone, underscoring the clinical significance of chemotherapy. Patients undergoing CRT with irradiation doses ranging from 6000 to 6500 cGy exhibited comparable survival outcomes to those receiving doses of 6600-7000 cGy. This observation suggests that irradiation doses exceeding the 6600 cGy may not confer the survival advantage in these patients. Further research is needed to confirm our results and explore the optimal irradiation dose for managing these patients.

Impact of immune-related adverse events on survival among patients with head-and-neck squamous cell carcinoma.

Aim: Immune-checkpoint inhibitors (ICIs) have revolutionized treatment of metastatic head and neck squamous cell carcinomas (HNSCCs). Our goal was to assess for an association between immune-related adverse events (irAEs) and clinical outcomes for patients on ICIs.Methods: We analyzed a cohort of 110 HNSCC patients who received ICI therapy at the University of Virginia.Results: On review, 48% of our patients experienced an irAE with the most common events being hypothyroidism (30%), dermatitis (14%) and hepatitis (11%). Women were more likely to experience irAEs. Treatment interruption/discontinuation occurred in 43% patients with irAEs. Development of irAEs was associated with superior objective response rate (68 vs. 39%, p = 0.009), with a greater rate of CR (17 vs. 5%) and PR (32 vs. 16%). Twelve patients underwent ICI re-treatment following irAE, with 17% attaining a complete disease response, 25% attaining a partial response, 33% achieving stable disease and 25% experiencing disease progression with ICI resumption.Conclusion: Development of irAE was associated with superior objective response rate, with a greater rate of CR and PR. ICI re-treatment following irAE was feasible in a significant proportion of patients and can be attempted in carefully selected patients, given the dearth of second-line therapies for these patients.

While outcomes for patients who receive immunotherapy for advanced head and neck cancer are greatly improved compared with traditional chemotherapy, a feared complication of this treatment is immune-related side effects. The exact incidence of these side effects is not known in head and neck cancer but are well described in other cancers. In this study, about half of head and neck cancer patients who received immunotherapy developed side effects due to immune over-activation. Women and patients who did not receive radiation were more likely to develop these side effects. Patient who developed immune side effects were more likely to see shrinkage in their tumors, and may have a higher likelihood of longer survival, although the findings were not statistically significant.

Histologic spectrum and outcome of Human papillomavirus (HPV)-associated oral cavity squamous cell carcinoma: a single center experience and a survey of The Cancer Genome Atlas (TGCA) cohort.

While high-risk human papillomavirus (HPV) serves as an essential pathogen and an important prognostic and predictive biomarker for oropharyngeal squamous cell carcinoma, it occurs at low frequency (2.2-6%) in oral cavity squamous cell carcinoma (OCSCC). To date, the pathologic features of HPV-associated OCSCC (HPV( +)-OCSCC) have been sparsely reported and its prognosis is not well-defined. We herein described detailed clinicopathologic features and outcomes of a retrospective series of 27 HPV( +)-OCSCC, including 13 from Memorial Sloan Kettering Cancer Center (MSKCC) and 14 from The Cancer Genomic Atlas program (TCGA). The frequency of HPV positivity in OCSCC was 0.7% in MSKCC cohort and 4.9% in TCGA cohort. Although HPV( +)-OCSCC was predominantly non-keratinizing (in 81%) with various degree of maturation, its histologic spectrum was expanded to include keratinizing subtype (19%), adenosquamous carcinoma (7%), and papillary architecture (subtype, 7%). HPV( +)-OCSCC predominantly affected male patients (male:female ratio = 12.5:1) and (ex) smokers (77%). It might occur in mandibular mucosa, floor of mouth, tongue, retromolar trigone, buccal mucosa, maxillary mucosa, or hard palate. In oral cavity, positivity of HPV by RNA in situ hybridization was required, and p16 immunohistochemistry alone was insufficient to confirm the HPV + status. The positive predictive value of p16 immunopositivity in detecting HPV infection was 68%. HPV-positivity did not appear to affect outcomes, including disease specific survival and progression free survival in OCSCC.

TNM 8 staging system beyond p16: Double HPV/p16 status is superior to p16 alone in predicting outcome in oropharyngeal squamous cell carcinoma.

PURPOSE: The assessment of p16INK4a (p16) in oropharyngeal squamous cell carcinoma (OPSCC) has been incorporated into tumor classification, as p16 has been shown to impact survival probability. However, a recent study demonstrated that human papillomavirus (HPV) status in addition to p16 may have a better discriminatory effect on survival probability. This study aims to determine the impact of combined evaluation of p16 and HPV on prognosis. METHODS: This was a multicenter, multinational analysis including retrospective and prospective cohorts of patients treated for primary OPSCC with curative intent, based on the data of the HNCIG-EPIC study. The primary outcome was to determine how the combined assessment of HPV and p16 status predicts prognosis of patients with OPSCC compared to p16 assessment alone. We employed multivariable analyses models to compute hazard ratios regarding survival. Analyses were stratified by stage, smoking status, and sub-anatomical region. RESULTS: The study included 7654 patients, with approximately half of the tumors being p16-negative (50.3 %, n = 3849). A total of 9.2 % of patients had discordant p16 and HPV status (n = 704). HPV status significantly impacted overall survival and disease-free survival regardless of p16 status and across both UICC 8th stage I-II and III-IVb cancers. p16-positive/HPV-positive OPSCC patients exhibited the best survival probability. CONCLUSION: The detection of HPV had a significant impact on survival probability for OPSCC patients with both p16-positive and p16-negative tumors. HPV testing should be integrated in cancer staging, especially in regions of low attributable fraction, alongside p16 evaluation to ensure a comprehensive assessment of prognosis.

Risk Factors of Oral Squamous Cell Carcinoma with Special Emphasis on Areca Nut Usage and Its Association with Clinicopathological Parameters and Recurrence.

Introduction: Oral squamous cell carcinoma (OSCC) is the most prevalent type of head and neck cancer and is associated with high mortality, particularly in Southeast Asian countries. Areca nut usage, smoking, and alcohol consumption are the most common risk factors for OSCC. Areca nut chewing is highly prevalent in Pakistan and has been attributed to an increase in OSCC cases. This study aimed to determine the association between areca nut usage and various clinicopathological features of OSCC and further evaluate the association of clinicopathological parameters of OSCC with tumor recurrence. Materials and Methods: The study was conducted using the data of 228 patients with OSCC resected at Liaquat National Hospital, Karachi, Pakistan, over 5 years between 2018 and 2022. Clinicopathological data were collected from hospital archives, and associations between various risk factors and clinicopathological parameters were determined. Results: Males were more commonly affected (77.2%), and the most common age group was <50 years (54.4%). Areca nut usage was reported in 59.6% of cases, and the buccal mucosa was the most common site (62.7%). Areca nut usage was significantly associated with male gender, greater tumor size, greater depth of invasion (DOI), higher tumor stage, nodal stage, presence of perineural invasion (PNI), and recurrence. In addition, multivariate analysis revealed that OSCC recurrence was significantly associated with older age, larger tumor size and DOI, nodal metastasis, and areca nut usage. Conclusion: Areca nut-related OSCCs were associated with poor prognosis and recurrence in our study population. Furthermore, OSCC recurrence was associated with various clinicopathological parameters, such as larger tumor size, a higher DOI, and nodal metastasis.

Tailoring nonsurgical therapy for elderly patients with head and neck squamous cell carcinoma: A deep learning-based approach.

To assess deep learning models for personalized chemotherapy selection and quantify the impact of baseline characteristics on treatment efficacy for elderly head and neck squamous cell carcinoma (HNSCC) patients who are not surgery candidates. A comparison was made between patients whose treatments aligned with model recommendations and those whose did not, using overall survival as the primary metric. Bias was addressed through inverse probability treatment weighting (IPTW), and the impact of patient characteristics on treatment choice was analyzed via mixed-effects regression. Four thousand two hundred seventy-six elderly HNSCC patients in total met the inclusion criteria. Self-Normalizing Balanced individual treatment effect for survival data model performed best in treatment recommendation (IPTW-adjusted hazard ratio: 0.74, 95% confidence interval [CI], 0.63-0.87; IPTW-adjusted risk difference: 9.92%, 95% CI, 4.96-14.90; IPTW-adjusted the difference in restricted mean survival time: 16.42 months, 95% CI, 10.83-21.22), which surpassed other models and National Comprehensive Cancer Network guidelines. No survival benefit for chemoradiotherapy was seen for patients not recommended to receive this treatment. Self-Normalizing Balanced individual treatment effect for survival data model effectively identifies elderly HNSCC patients who could benefit from chemoradiotherapy, offering personalized survival predictions and treatment recommendations. The practical application will become a reality with further validation in clinical settings.

Comprehensive Analysis Identifies Hyaluronan Mediated Motility Receptor and Cell Division Cycle 25C as Potential Prognostic Biomarkers in Head and Neck Squamous Cell Carcinoma.

INTRODUCTION: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, but its pathogenic mechanisms remain unclear. This study aimed to identify the potential biomarkers underlying the diagnosis and treatment of HNSCC. METHODS: Weighted gene co-expression network analysis (WGCNA) followed by pathway enrichment analysis, analysis of infiltrating immune cells, survival analysis, and methylation analysis were applied to identify the potential hub genes underlying the prognosis of HNSCC. The expression of hub genes was validated by immunofluorescence staining. RESULTS: A total of 10,274 differentially expressed genes (DEGs) were identified. Through WGCNA, the yellow module (R2 = 0.33, P = 2e-14) was confirmed to be the most significantly associated with the histological grade of HNSCC, and the "Cell Cycle" proved to be the most enriched signaling pathway. Based on the results of survival analysis and immune cell infiltration, 10 hub genes (HMMR, CENPK, AURKA, CDC25C, FEN1, CKS1B, MAJIN, PCLAF, SPC25, and STAG3) were identified. Eight of these (excluding MAJIN and STAG3) were confirmed by performing survival analysis using another dataset (GSE41613). Further, we identified 4 methylation loci in 3 hub genes (cg15122828 and cg20554926 in HMMR, cg12519992 in CDC25C, and cg2655739 in KIAA0101/PCLAF) as being significantly related to survival. Finally, we demonstrated the high mRNA and protein expression of HMMR and CDC25C in HNSCC patients. CONCLUSION: Two real hub genes (HMMR and CDC25C) and 3 methylation loci were identified that could potentially serve as prognostic and therapeutic targets for HNSCC, which is significant for studying the pathological mechanisms underlying HNSCC and for developing novel therapies for this disease.

Squamous cell carcinoma metastatic to the lymph nodes of the parapharyngeal space: case series and systematic review.

Objective: Parapharyngeal space (PPS) is a rare and unusual site of head and neck squamous cell carcinoma (SCC) metastases. Treatment strategy for PPS metastases is still not well defined. This research aims to investigate the clinical implications and oncological outcomes of SCC metastases in PPS. Material and methods: A systematic review was conducted according to PRISMA criteria. The authors considered only articles reporting the history and treatment of patients with PPS SCC metastases. A retrospective chart review was conducted in two tertiary referral academic centers collecting data of patients with diagnosis of PPS SCC metastases between 2010 and 2023 to study their outcome based on clinical presentation and treatment strategy. Results: The retrospective chart review showed that the oropharynx was the most frequent primary tumour site. The advanced stage at the time of diagnosis was related to poorer survival and higher recurrence rates. A significant difference in 2-year overall survival in the subgroup of patients who experienced PPS metastases within the primary treatment and those who experienced PPS metastases as regional recurrence (66.7 vs 30.8%) was observed. Similar low survival rates were reported in the literature review with a mean overall and disease-free survival of 19.8 and 8.6 months, respectively. Conclusions: PPS metastases are associated with a dismal prognosis, especially when diagnosed as regional recurrence after primary treatment, due to patients' poor general conditions and difficulty of treatment.

Exosomal transcript cargo and functional correlation with HNSCC patients' survival.

BACKGROUND: HPV status in a subset of HNSCC is linked with distinct treatment outcomes. Present investigation aims to elucidate the distinct clinicopathological features of HPV-positive and HPV-negative HNSCC and investigate their association with the HNSCC patient survival. MATERIALS AND METHODS: The total RNA of exosomes from HPV-positive (93VU147T) and HPV-negative (OCT-1) HNSCC cells was isolated, and the transcripts were estimated using Illumina HiSeq X. The expression of altered transcripts and their clinical relevance were further analyzed using publicly available cancer transcriptome data from The Cancer Genome Atlas (TCGA). RESULTS: Transcriptomic analyses identified 3785 differentially exported transcripts (DETs) in HPV-positive exosomes compared to HPV-negative exosomes. DETs that regulate the protein machinery, cellular redox potential, and various neurological disorder-related pathways were over-represented in HPV-positive exosomes. TCGA database revealed the clinical relevance of altered transcripts. Among commonly exported abundant transcripts, SGK1 and MAD1L1 showed high expression, which has been correlated with poor survival in HNSCC patients. In the top 20 DETs of HPV-negative exosomes, high expression of FADS3, SGK3, and TESK2 correlated with poor survival of the HNSCC patients in the TCGA database. CONCLUSION: Overall, our study demonstrates that HPV-positive and HPV-negative cells' exosomes carried differential transcripts cargo that may be related to pathways associated with neurological disorders. Additionally, the altered transcripts identified have clinical relevance, correlating with patient survival in HNSCC, thereby highlighting their potential as biomarkers and as therapeutic targets.